Advanced Physiology and Pathophysiology Essentials... - (Chapter 11 Lungs)

11
LUNGS
Nancy C. Tkacs, Charrell S. Porter, and Nicholas A. Barker
carbon dioxide (CO2)—a gas that causes acidosis and

THE CLINICAL CONTEXT that must be continuously eliminated by the lungs.
Average oxygen (O2) requirements and CO2 production
T he lungs have the central and critical function

of oxygen intake and carbon dioxide removal
that sustains life. Data from the National Health
of an adult human depend on size and activity level. At
rest, an adult man may consume 3.5 mL O2/kg/min, or
about 250 mL/min for a 70-kg person. Typically, CO2
Interview Survey indicate that lung diseases are production is about 80% of O2 consumption. During
common: Asthma affects 8.2% of the adult pop- exercise, O2 consumption can increase to ten to 15
ulation, whereas reported rates of emphysema, times the resting level, and the respiratory system must
chronic bronchitis, sinusitis, and hay fever are increase O2 intake and CO2 elimination accordingly.4
1.8%, 4.1%, 13.6%, and 8.6%, respectively.1 If one Additional lung functions include acid–base bal-
combines chronic lower respiratory disease ance, immune surveillance and protection from inhaled
with influenza and pneumonia, then lung dis- pathogens, metabolism of certain endogenous and
eases are the third leading cause of death in the exogenous molecules, and contributing to communica-
United States.2 Worldwide, the burden of lung tion in the form of spoken language. Average respira-
disease in terms of years lived with disability is tory rate in adults is 10 to 16 breaths/min, with average
almost equal to that of cardiovascular disease, tidal volume of 500 mL at rest. Thus, minute ventilation,
and the prevalence of all chronic respiratory dis- stated as respiratory rate multiplied by tidal volume, is
eases combined is actually higher than that for about 5 to 8 L/min. Air movement into the lungs (inspi-
cardiovascular disease at more than 570 million ration) and out of the lungs (expiration) is generated by
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.
patients. The greatest contributors to lung dis- a sequence of contraction and relaxation of the major
ease burden are chronic obstructive pulmonary muscles of inspiration, creating movements of the
disease and asthma.3 Chronic lung disease can chest wall and diaphragm surrounding the lungs. The
impair quality of life and reduce functional status lungs closely follow the movements of these structures
for many years before causing death, which often due to surrounding negative intrapleural pressure. In
is due to an acute event such as pneumonia after this chapter, these processes are described first, fol-
many years of reduced lung function. lowed by descriptions of lung mechanics and disorders
of lung mechanics. Processes of alveolar gas exchange
are detailed, along with disorders of gas exchange.
Finally, unique aspects of the pulmonary vasculature
OVERVIEW OF LUNG STRUCTURE
are described, along with disorders of lung circulation.
AND FUNCTION
To maintain homeostasis and accomplish movement STRUCTURES OF THE RESPIRATORY SYSTEM

and cellular work requires energy. Energy in the form of The structures of the respiratory system are shown in
adenosine triphosphate (ATP) is derived from dietary Figure 11.1. Air enters and exits via the nose and mouth.
nutrients such as sugars and fats, and is released in pro- On inspiration, air is drawn in, primarily via the nose,
cesses of anaerobic and aerobic metabolism, with the moving successively through the upper respiratory tract,
majority of energy derived from oxygen-requiring oxi- including the pharynx and larynx, followed by the pro-
dative metabolism. Metabolic processes also generate gressively branching structures of the lower respiratory
389
Tkacs, N., Herrmann, L., & Johnson, R. (Eds.). (2020). Advanced physiology and pathophysiology : Essentials for clinical practice. Springer Publishing Company, Incorporated.
Created from apus on 2024-01-28 19:08:47.
390 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice
Generation
Trachea 0
Nasal cavity
Conducting zone
Bronchi 1
Pharynx 2
Larynx
3
Trachea Bronchioles
Primary 4
bronchi Parietal
Secondary pleura 5
Terminal
bronchi Visceral
bronchioles
pleura 16
Tertiary
Pleural Respiratory 17
bronchi
space bronchioles 18
respiratory zone
Transitional and
19
20
Acinus
Alveolar 21
Bronchiole
ducts 22
Terminal
bronchi Alveolar 23
sacs
Branch of Branch of
pulmonary pulmonary artery
vein Alveolar
duct FIGURE 11.2 Branching airways. As the airways branch,
total cross-sectional area and surface area increase markedly.
Alveolus
Alveolar The total surface area for gas exchange in the adult lung is
sac estimated to be >70 m2, about the size of a tennis court.
CO2 O2
output—the output of the right ventricle—via the right

and left pulmonary arteries.
Capillary Red blood
cell
MECHANISMS OF RESPIRATION
The major muscles of inspiration are the diaphragm
FIGURE 11.1 Structures of the respiratory system. The and the external intercostal muscles. (Figures 11.3
respiratory system consists of upper airway structures of the
and 11.4) Contraction of the diaphragm requires acti-
nose, mouth, throat, and larynx, and lower respiratory system
vation of phrenic motor neurons found at cervical spi-
structures of the trachea, bronchi, and successive airway
generations within the lung tissue, ending in the delicate nal levels C3–C5. Axons of these neurons travel in the
alveoli—sites of gas exchange. right and left phrenic nerves to innervate the diaphragm.
Diaphragmatic contraction results in downward move-

ment and flattening of this arched muscle, enlarging
tract—trachea, bronchi, bronchioles, alveolar ducts, and the chest cavity and compressing the abdominal cavity.
alveoli. The successive levels of airway branching are Simultaneously, the external intercostal muscles (inner-
referred to as airway generations (Figure 11.2). From vated by motor neurons in the thoracic spinal cord)
the trachea, airways branch repeatedly into smaller contract, causing the ribs to elevate and move outward,
tubes. Each level of branching (generation) is smaller in increasing the circumference of the chest.
diameter than the previous level, but total cross-sectional The increase in thoracic volume pulls the lungs to a
area increases dramatically. Within the conducting zone, more open position, dropping pressure in the airways
no gas exchange is possible; thus, this volume is known and alveoli. This causes air to flow in, drawn by a pres-
as the anatomical dead space. sure gradient from atmospheric pressure to negative
Beginning with generation 17, alveoli are present, pressure inside the lungs. When strenuous exertion
budding off from the walls of the respiratory bronchi- increases body O2 consumption and CO2 production,
oles and permitting gas exchange. Branching continues respiratory rate and depth increase. Although the alter-
until terminating at alveolar sacs, which are clusters of ations depend on physical training, for an untrained
alveoli. Each alveolus is surrounded by a capillary net- athlete, maximal exercise can be associated with a five-
work. This proximity allows rapid exchange of O2 and to six-fold increase in both respiratory rate and tidal
CO2 between the blood flowing in the alveolar capillar- volume, with minute ventilation increasing about 20
ies and alveolar air that is refreshed with O2 and has times the resting level.5 Augmented tidal volume can be
CO2 removed with each breath. Each lung has 200 to achieved by the additional effort of accessory muscles of
300 million alveoli and receives about half the cardiac respiration, including the scalene, sternocleidomastoid,
Chapter 11 • Lungs 391
FIGURE 11.3 Major muscles of inspiration. The

Lung boundaries of the thoracic cavity are made up of
Pleural sac
the bones of the spine (posteriorly) and sternum
Intercostal
(anteriorly), the ribs and their associated intercostal
muscles Intercostal muscles, and the diaphragm inferiorly. These
muscles structures are lined with a membrane termed the
Lung parietal pleura. A thin virtual space, the pleural
Parietal
pleura
cavity, separates the parietal pleura from the visceral
Visceral
pleura, making up the outer covering of the lungs. A
pleura small volume of pleural fluid is spread thinly through
the pleural space, and the pleural membranes
Pleural
move almost as one structure as the thoracic cavity
cavity
Diaphragm expands during inspiration and contracts during
expiration. This elegant system allows the muscles
of inspiration to create lung expansion and filling.
During quiet breathing, expiration is passive as the
Chest wall inspiratory muscles relax, returning the thoracic
cavity to its preinspiratory size.
(Figure 11.6). The internal intercostal muscles pull

the ribs down and narrow the ribcage and thoracic
cavity, compressing the lungs from the circumference.
The abdominal muscles compress the abdominal con-
tents, forcing them upward against the diaphragm and
causing the diaphragm to move further upward, com-
pressing the lungs within the chest cavity. These com-
bined movements create positive intrapleural pressure
that translates to positive pressure inside the airways,
d d increasing expiratory airflow. This maneuver is lim-
ited, however, by simultaneous airway compression,
Increase in anteroposterior as described later in this section.
diameter of the rib cage Similar to the cardiovascular system, breathing is
characterized by automaticity: Conscious control is
FIGURE 11.4 Rib movements. Contraction of external not required for regular breathing to occur, although
intercostal muscles lifts the ribs up and out—a movement breathing rate and depth can be controlled volun-
that has been described as similar to lifting a bucket handle. tarily. Neural control of respiration is initiated within
d, diameter. the brainstem, primarily from a pattern generator that

influences clusters of medullary neurons controlling
inspiratory muscles (Box 11.1 and Figure 11.7).
and trapezius muscles, which expand the chest cavity These inspiratory neurons project to the spinal cord,
in the upward and outward direction. Increased respi- where they synapse on phrenic motor neurons, exter-
ratory efforts in many conditions of lung pathology are nal intercostal motor neurons, and accessory muscle
also associated with recruitment of accessory muscles. motor neurons. Inspiration ends when the medullary
During inspiration, the contraction of the inspi- inspiratory neurons cease firing, decreasing the drive
ratory muscles stores potential energy in the elastic to motor neurons and allowing the inspiratory muscles
tissues of the lung. During quiet breathing, expira- to relax, with expiration occurring passively. In the
tion occurs when the diaphragm and external inter- case of forced expiration, separate medullary expira-
costal muscles relax, decreasing the volume of the tory neurons stimulate expiratory motor neurons. The
thoracic cavity, and creating positive pressure within respiratory control system is pathologically disrupted
the recently expanded lungs (Figure 11.5). Lung by neurological conditions such as stroke, brainstem or
elastic recoil converts potential energy to kinetic high spinal cord injury, lower motor neuron lesions of
energy, contributing to this positive pressure that the phrenic nerve due to Guillain–Barré syndrome or
drives expiration of the tidal volume. When exercise polio, or prescribed or street drugs that suppress the
increases respiratory demands, or during pulmonary respiratory centers, such as opioids, alcohol, benzodi-
function testing, forced (active) expiration occurs. azepines, and barbiturates. Hypoventilation or apnea
The muscles of forced expiration are the internal (an absence of inspiratory effort) occurring from any of
intercostal muscles and the abdominal muscles these causes can be fatal.
Trachea
Chest wall
Parietal
pleura
Pleural
space
Visceral
pleura
Lungs
Diaphragm
(a) (b)
FIGURE 11.5 (a) At rest, the diaphragm and external intercostal muscles are relaxed and
lung volume is at functional residual capacity. (b) Contraction of the diaphragm and external
intercostal muscles increases the total volume of the thoracic cavity, reducing the pressure in the
airways and causing inspiration. Relaxation of these muscles at the end of inspiration decreases
the volume of the thoracic cavity and passively generates positive pressure within the lungs that
causes expiration. This is assisted by elastic recoil of the lungs also exerting pressure on the air
held within the air spaces (alveoli and airways).
air and tissue; at this level, the inspired air is

warmed and humidified. Mucus lining the nasal pas-
sages begins to trap particulate matter before it can
enter the lungs, and cilia move the mucus toward the
oropharynx. The pharynx consists of the nasophar-
Internal ynx, oropharynx, and laryngopharynx, encountered
intercostal in succession as the inspired air moves to the lower
muscles respiratory tract. The pharyngeal structures include
tonsils and adenoids—lymphoid tissues able to con-

duct immune surveillance of the air entering the
airways.
Rectus abdominis muscle
Beginning with the trachea, the airways are generally
External oblique muscle
divided between the conducting zone that begins with
Internal oblique muscle
the strong, cartilage-reinforced trachea and progres-
Transversus sively divides into smaller bronchi and bronchioles, and
abdominis the respiratory zone, consisting of small bronchioles
muscle
with alveoli budding off, and ending in alveolar sacs
appearing like clusters of grapes. The walls of the air-
FIGURES 11.6 Muscles of forced expiration. Forced expira ways are lined with epithelial cells that get progressively
tion is used during heavy exertion when tidal volume goes
thinner in the respiratory zone (Figure 11.8). In the
up to provide increased oxygen intake and carbon dioxide
removal. Measurement of airflow during forced expiration is
conducting zone, the walls have abundant goblet cells
also part of pulmonary function testing. that produce and secrete mucus. The ciliated epithelial
cells have numerous cilia that beat in one direction—
toward the mouth, continually moving the mucus layer
ANATOMY AND HISTOLOGY OF AIRWAYS to the mouth from which it can be swallowed or expec-
AND ALVEOLI torated. As the airways get smaller, they have less or no
Air is inhaled first into the upper respiratory struc- supporting cartilage, with two significant consequences:
tures, beginning with the nose. The nasal epithelium first, the airways are prone to collapse if the pressure
has a folded surface that increases contact between surrounding the airway is greater than pressure inside
BOX 11.1
Overview of Neural Control of Respiration
• The medulla contains several clusters of neurons • Alterations in arterial blood gases (O 2 and
that are the source of rhythmic outputs causing CO2) provide chemoreceptor feedback to the
regular contractions of inspiratory muscles and brainstem respiratory nuclei.
initiating the respiratory cycle. (Figure 11.7)
• Other peripheral receptors detect irritant
• These brainstem respiratory pattern generator substances (initiating coughing) or vascular
neurons signal spinal cord (and in some cases, congestion.
cranial) motor neurons that stimulate the
• Inputs from higher centers can modify the
primary muscles of inspiration. Motor neurons
respiratory pattern for voluntary activities such
to accessory muscles of inspiration are recruited
as speaking and singing. In addition, involuntary
upon physiological need.
actions like belching, swallowing, and vomiting
• Respiratory muscles contract, providing relay through brainstem pathways to alter the
mechanoreceptor feedback to brainstem and pattern of breathing.
spinal cord.
Peripheral Central
chemoreceptors chemoreceptors
Other Respiratory Phrenic nerve (C3-C5)

peripheral neurons of External intercostal nerves
receptors the medulla (thoracic)
Cerebral Contraction of diaphragm,

cortex external intercostal muscles
FIGURE 11.7 Overview of neural control of respiration.

the airway; second, bronchial smooth muscle contrac- alveoli, the final small particles that arrive are phago-
tion is able to narrow the collapsible airway. cytosed by resident alveolar macrophages, in addition
to being neutralized by IgG. Once activated, alveolar
MECHANISMS OF LUNG PROTECTION macrophages secrete cytokines that recruit additional
monocytes, neutrophils, and lymphocytes to assist in
Inspiration of 5 to 8 L of air each minute of the day
host defense. Natural killer cells are present in the alve-
represents a large risk of exposure of the delicate air-
oli and can contribute to a rapid response to invading
ways to environmental toxins, particulate matter, and
pathogens. Finally, protective antimicrobial proteins
pathogens such as bacteria and viruses. The lungs are
are also components of the surfactant that lines the
well protected from larger particles by the mucocili-
alveoli.
ary escalator mechanism described earlier. Epithelial
cells of the mucosa are tightly joined and prevent
movement of pathogens across that surface lining. Cystic Fibrosis: A Genetic Disorder
Nonspecific defenses such as lysozyme, defensins, That Compromises Lung Protection
and antimicrobial peptides attack many pathogens. Cystic fibrosis (CF ) is a common autosomal recessive
Mucosal dendritic cells phagocytose and present anti- genetic disorder among certain populations. The prev-
gen to T lymphocytes, activating the adaptive immune alence of CF is highest in people of northern European
system to produce secretory immunoglobulin isotype ancestral descent. CF is screened for at birth in the
A (IgA). IgA provides protection against specific invad- United States, and neonatal screening results indicate a
ers by intercepting incoming pathogens and marking prevalence of 1:3,500 infants who are Caucasian, 1:7,000
them for phagocytosis and destruction. At the level of infants who are Latinx, and 1:17,000 in those of African
poor digestion and nutrition, abnormalities of bile

Respiratory Conducting
secretion, and infertility. With respect to lung func-
tion, without normal CFTR function, the mucociliary
clearance mechanism is severely impaired. Lack of
Cl− transport across the epithelial cell membranes
reduces the associated water movement, so the
mucus layer is abnormally thin and very viscous,
and the cilia are unable to properly move the mucus
toward the mouth. Loss of HCO3− secretion makes
the mucus acidic, reducing effectiveness of white
blood cells in attacking pathogens. The function of an
Height of the associated Na+ transporter (epithelial sodium chan-
epithelium nel, or ENaC) is increased, promoting intracellular
Goblet cells Na+ accumulation and water retention, contributing
Ciliated cells to the thick mucus (Figure 11.9). Patients with CF
Glands have chronic lung infections that result in localized
Hyaline cartilage inflammation, and plug formation that leads to airway
Smooth muscle dilation, termed bronchiectasis.7,8
Elastic fibers
LUNG VOLUMES AND CAPACITIES
FIGURE 11.8 Characteristics of respiratory tract segments. Pulmonary function testing is the primary laboratory
As airways repeatedly branch from trachea to alveoli, assessment of lung function in health and disease.
the smaller segments begin to have alveoli capable of In spirometry, an individual is instructed to breath
gas exchange. The transition from conducting airways to in and out through a tube—normally for several
respiratory airways begins at about generation 16 to 17 (as breaths—followed by taking the deepest possible
discussed in text). The upper airways have mucus-producing
breath (maximal inspiration) and then expiring until
goblet cells and submucosal glands. The lining epithelial
cells are ciliated. Protection from inhaled particulate matter
all of the air possible has been expelled. The result-
is achieved by mucociliary clearance. Smooth muscle ing graph of volume of air moved during the time of
cells are responsive to autonomic nervous influences the test allows calculation of certain lung volumes
producing dilation (sympathetic control) or constriction and capacities (see Box 11.2 and Figure 11.10). In
(parasympathetic control). Elastic fibers contribute to elastic conjunction with this test, either plethysmography
recoil that drives passive expiration. or helium dilution are used to measure the residual
Source: Artwork by Holly Fischer. volume (RV)—the amount of air that remained in
the lungs after the maximal expiration, which can-
not be measured by the spirometer. Once the RV is
ancestral origin.6 There are close to 2,000 mutations in
known, additional measures can be calculated based

the gene coding for the cystic fibrosis transmembrane on the spirometry measurements and the RV. An addi-
conductance regulator (CFTR) channel, a large trans- tional maximal inspiration and expiratory maneuver
membrane protein found in cell membranes that permits measures the airflow rate during forced expiration
movement of Cl− and HCO3− across an epithelial mem- (by contracting abdominal and internal intercostal
brane. Normally, movement of these ions attracts water, muscles). Forced expiratory maneuvers are used in
resulting in production of fluid secretions, such as that assessment of obstructive lung diseases.
of mucus lining the airways. Most of the known CFTR Pulmonary function values vary with body size, age,
mutations are extremely rare; the most common muta- sex, and obesity. Reports will typically include the raw
tion is present in about 90% of disease alleles globally. values as well as the percent of predicted values for a
This F508del mutation results from a deletion of three person’s height, weight, age, and sex.
nucleotides that code for a phenylalanine at amino acid
position 508 within this very large and complex protein.
The result is a misfolded protein that accumulates in the LUNG–CHEST WALL INTERACTIONS
endoplasmic reticulum and is targeted for degradation The pleural space is a virtual space lying between the
without ever reaching the plasma membrane of the cell. parietal pleura lining the chest cavity and the visceral
The pathophysiological consequences of CFTR pleura, the membrane covering the lungs. Pleural pres-
mutations are manifested in tissues that depend on sure (Ppl) within the space is subatmospheric, at about
a lining layer of mucus that can support movement minus 5 centimeters of water pressure (−5 cm H2O) at
of secretions along tubular structures. Thus, these functional residual capacity (FRC). The source of the
mutations are associated with chronic lung disease, negative pressure is the competing tendencies of the
diminished pancreatic enzyme secretion leading to lung to collapse down versus the chest wall to expand
CFTR degradation Acidification and/or Airway obstruction Damage of Respiratory failure

Inflammation
depletion of water epithelial cells
content in the airway
Defective CFTR surface liquid Decreased Impairment of
protein ciliary beating lung function
Imbalance of ionic
permeability Infection
Mutated CFTR gene Accumulation of thick
ENaC Aqp Fibrosis
in both chromosomes and sticky mucus
H+
Na+ H2O
CFTR
FIGURE 11.9 Cystic fibrosis pathology. Transcription and translation of the CFTR gene with the
F508 deletion produces a protein that cannot pass through the Golgi apparatus to be inserted in
the membrane. Rather, the abnormal protein is moved to the proteasome for degradation. Because
Cl−, HCO3−, and water cannot diffuse across the epithelial barrier, the mucus layer becomes very
acidic, viscous, and difficult to move. Abnormally high Na+ absorption further depletes water from
the mucus layer. Ciliary function is lost, and pathogens begin to accumulate in the mucus lining
of the airways. Ultimately, chronic infection and inflammation lead to scarring and obstruction of
airways with loss of lung capacity.
Aqp, aquaporin; ENaC, epithelial sodium channel.
BOX 11.2
Key Lung Volume and Capacity Measurements and Their Significance
• Tidal volume (VT )—the volume of air inspired the greatest volume of air the respiratory system
and expired during quiet breathing at rest; when can move in response to a maximal expiratory
multiplied by respiratory rate (breaths/min), effort. VC is sensitive to disease processes
resting minute ventilation is calculated. affecting the lung, the chest wall, and the neural
control of muscles of respiration.
• Functional residual capacity (FRC)—the volume
of air in the lungs at the end of each expiration at • Residual volume (RV)—the amount of air left
rest. This represents the resting position of the in the lungs after a maximal expiratory effort.
respiratory system (lungs plus chest wall). At this The RV depends on elastic recoil of the lung and
point, there is an equilibrium between the intrinsic is altered by diseases that affect either lung or
tendency of the lungs to collapse down, and the chest wall compliance. It is measured by helium
intrinsic tendency of the chest wall to expand dilution or plethysmography.
outward. FRC is sensitive to disease processes
• Total lung capacity (TLC)—the total amount
that alter lung or chest wall mechanical properties.
of air in the lungs after a maximal inhalation;
• Vital capacity (VC)—the maximum volume of air also equal to VC + RV. TLC is similarly affected
that can be exhaled after a maximal inhalation. by lung and chest wall disorders, as well as
Depending on the context, this value can also be neuromuscular disorders affecting the muscles
called forced vital capacity (FVC). This represents of respiration.
(continued)
BOX 11.2 (continued)

Key Lung Volume and Capacity Measurements and Their Significance
Inspiratory Inspiratory Vital Total

80 reserve capacity capacity lung
volume (IC) (VC) capacity
(IRV) (TLC)
Volume (mL/kg)
Tidal
volume
37 (TV or VT)
Expiratory
30 reserve
volume Functional
(ERV) residual
capacity
15 Residual (FRC) Residual
volume volume
(RV) (RV)
0
FIGURE 11.10 Lung volumes and capacities.
outward. At FRC, these two forces are balanced, tug-

Normal Pneumothorax
ging with equal strength in opposite directions. The
negative pressure acts like a vacuum, pulling together Chest wall
the surfaces of the parietal and visceral pleural mem- Parietal pleura
Ppl = –5
branes, with the stiffer structures of the chest wall pull- cm H2O Pleural space
ing the delicate lungs open (Figure 11.11). Another
Air
way to think of this relationship is that the lungs are Visceral pleura
inflated because the pressure inside the lungs (atmo-
PA = 0
spheric pressure at rest) is higher than the surrounding
PA = 0
pleural pressure, which is negative. This transpulmo- Ppl = 0
nary pressure gradient (pressure difference across
the lungs—between inside and outside the airways) Mediastinal
membrane
consists of about 5 cm H2O, keeping the lungs open.
This relationship is disrupted when a spontaneous Diaphragm
pneumothorax occurs and air accumulates in the pleu-
ral space, allowing the lung to collapse. In a similar fash- FIGURE 11.11 Lung/chest wall relationships. The volume of
ion, a traumatic or surgical wound through the entire air inside the lungs at end-expiration (i.e., the FRC) is deter
thickness of the chest wall (such as a stab wound, bullet mined by two factors: the elastic recoil tendency of the lung to
wound, or incision to perform lung surgery) allows the collapse down, and the tendency of the chest wall structures
(ribs and intercostal muscles) to expand outward. The
pleural space to equilibrate with atmospheric pressure
balance between these tendencies creates a negative pressure
(defined as 0 cm H2O with respect to the respiratory sys-
in the pleural space that holds the visceral and parietal pleura
tem). As soon as this happens, the chest wall expands in together. If a pneumothorax occurs, air enters the pleural space
the outward direction and the lung collapses down. and Ppl equilibrates with atmospheric pressure. Immediately,
The pleural space contains a small amount of pleural the lung collapses down and the chest wall expands.
fluid that keeps the tissues lubricated and reduces the FRC, functional residual capacity; Pa, alveolar pressure;
friction between chest wall and lungs. As inspiration Ppl, pleural pressure.
Symptoms include shortness of breath, cough, and pain

(a) (b)
that increases with breathing. With larger volumes of
pleural fluid accumulation, there may be dullness to
percussion and decreased tactile fremitus. A friction
PA = 0 rub may be auscultated over the affected area.
PA = 0
Treatment is directed to correcting the original cause
PPI = –5 cm H2O and draining the excess fluid by thoracentesis.
PPI = –8 cm H2O
PT = 0 – (–5)
PT = +5 cm H2O PT = 0 – (–8) Thought Questions
PT = +8 cm H2O
1. How is the lung protected against the

FIGURE 11.12 Lung pressures and relative volumes at the particulates and pathogens that can enter the
beginning and end of quiet inspiration. (a) At the end of a airways?
normal expiration, the lung volume is FRC, the diaphragm
and external intercostals are relaxed, and Ppl is −5 cm H2O. 2. How do the structures of the lung and chest wall
Thus, the distending (transpulmonary) pressure holding the create lung inflation based on musculoskeletal
lungs open (Pt) is the pressure inside the lungs (Pa) minus movements of the chest wall and diaphragm?
the pressure outside the lungs (Ppl), or +5 cm H2O. (b) At
the end of a normal inspiration, the external muscles are 3. Which of the lung volumes and capacities cannot
contracted, pulling the chest wall upward and outward, and be measured by using simple spirometry?
the diaphragm is contracted, descending and lengthening
the thoracic cavity between neck and abdomen. Volume is
increased to FRC + Vt, and the distending pressure on the
lung has increased to +8 cm H2O.
FRC, functional residual capacity; Pa, alveolar pressure; Ppl, COMPLIANCE OF THE LUNGS AND
pleural pressure; Pt, transpulmonary pressure; Vt, tidal volume. CHEST WALL IN HEALTH AND DISEASE
begins with diaphragm descent and external intercostal The lungs are very compliant, readily stretching to
muscle contraction, the lungs follow the movements of accommodate the addition of the Vt and greater
these surrounding structures, held to them by surface inspired volume as needed. By convention, pressure
tension—the lungs are pulled to a more open position, changes during the respiratory cycle are measured in
and the pleural membranes slide smoothly along one units of centimeters of water pressure (cm H2O), rather
another. At the end of inspiration, Ppl is more negative than millimeters of mercury (mm Hg). Because 1 mm Hg
and the lung has reached its end-inspiratory volume pressure equals 1.36 cm H2O (notice the change in units:
(Figure 11.12). To achieve greater lung volumes if 1 cm = 10 mm), increasing the distending lung pressure
by 3 cm H2O to inspire a Vt of 500 mL represents about
needed, during inspiration, greater action potential fir-

ing rates of neurons to inspiratory muscles will result in 2 mm Hg pressure, a relatively small amount.
a more forceful muscle contraction, increasing the tidal Pathophysiological changes in lung compliance
volume (Vt). can occur in both acute and chronic lung disorders
(Figure 11.13). In pulmonary fibrosis, compliance is
Pleural Effusion chronically decreased, and many acute disorders cause
Pleural fluid is produced by capillary filtration, under temporary decreases in compliance that are reversible
the influence of Starling forces of capillaries of the as the condition resolves. Emphysema, discussed in
visceral and parietal pleura. Pleural fluid is reab- this section, is the most common disease of increased
sorbed across the visceral pleura and drained by compliance, although degenerative tissue changes with
lymph vessels of the lungs. Inflammation of the pleu- lungs during aging are also associated with increased
ral membranes, or loss of lubricating pleural fluid, can compliance.
cause pain with each breath. States of systemic fluid
imbalance such as pulmonary edema, nephrotic syn-
drome, or cirrhosis can increase pleural fluid, causing SURFACTANT AND LUNG COMPLIANCE
pleural effusion by a transudative process. On the Surfactant, the fluid that lines the alveoli, is a major
other hand, disease processes directly affecting the factor in lung compliance. The air–alveolar tissue inter-
lungs, such as pneumonia, malignancy, or inflamma- face is not completely dry; rather, there is a thin layer of
tory disorders, can increase pleural fluid by an exuda- liquid at that interface. This aqueous fluid has high sur-
tive process. Fluid accumulation in the pleural space face tension (as described in Chapter 2, Chemical and
impinges on the lung, limiting ventilatory capacity. Biochemical Foundations). Intermolecular attractions
TLC
↑ Compliance Normal
(emphysema, compliance
older adults)
Lung volume (normal) ↓ Compliance

(fibrosis,
pneumonia,
pulmonary
edema)
FRC
+VT
FRC
0 –10 –20 –30
Pleural pressure (cm H2O)
FIGURE 11.13 Compliance of the lung in health and disease. The relationship between the volume
change of the lung with the distending pressure is termed the compliance of the lung. From FRC,
it takes about 3 cm H2O pressure to inflate the lungs with the usual Vt. In response to physiological
needs (e.g., during exercise), the inspiratory muscles are able to create a more negative intrapleural
pressure and drive intake of a greater inspired volume. Diseases of decreased lung compliance
create a stiffer structure—greater pressure changes are needed to maintain even normal Vt. As a
compensation, in certain of these conditions there is an increase in respiratory rate and decreased Vt,
creating more work (particularly dead space ventilation), but reducing stress on inspiratory muscles.
Diseases of increased lung compliance, primarily emphysema, make it easier to inflate the lungs on
inspiration, but also result in a much higher FRC that can limit the maximum inspired volume.
FRC, functional residual capacity; TLC, total lung capacity; Vt, tidal volume.
that pull water molecules toward each other contribute which causes neonatal respiratory distress syndrome.
to this surface tension that would tend to collapse alve- This condition may require pressure-assisted ventila-
oli and make them quite difficult to inflate. tion to inflate the lungs (see Pediatric Considerations,
This problem is solved by a layer of surfactant lin- later in this chapter). Artificial surfactant can be used
ing all alveoli under healthy conditions. Type 2 alveolar to replace the endogenous fluid until production
cells produce this phospholipid/protein solution rich in begins. Similarly, in adults, critical injuries such as
amphipathic molecules that spread out over the alveo- sepsis can damage type 2 alveolar cells and reduce sur-
lar surface. Surfactant greatly reduces surface tension, factant production, resulting in acute respiratory dis-
making inspiration easier. Think of blowing a soap bub- tress syndrome (ARDS); see later discussion. In either
ble using a bubble wand: A small amount of air pres- neonates or adults lacking surfactant, lung compliance
sure causes slight bowing outward of the bubble fluid, is greatly reduced, and lung inflation will often require
but if you stop blowing, the fluid comes right back to a pressure-assisted ventilation.
flat surface, because of the surface tension between the The inverse of compliance is elastance—the abil-
liquid molecules. After blowing with a bit more force, ity to recoil and return to the original size after being
the bubble gets larger, and it takes less force to enlarge stretched. As noted earlier, expiration occurs as the
it further. Eventually the developing bubble forms a inspiratory muscles relax at the end of inspiration; the
sphere and detaches. lung’s elastic recoil and conversion of stored energy
In a similar fashion, from the moment of birth when generates pressure that drives expiration. For this
a full-term newborn takes its first breath, the alveoli reason, diseases that alter lung compliance also alter
require a fair amount of pressure to inflate as the previ- elastic recoil. Diseases of decreased compliance are
ously liquid-filled lungs fill with air for the first time. The associated with increased elastic recoil. Although it
pressure needed is reduced by the fact that fetal surfac- takes more pressure and effort to inflate the lung during
tant secretion begins during labor and increases with inspiration, expiration occurs quickly and forcefully.
alveolar expansion during the first few breaths. When Diseases of increased lung compliance reduce elastic
babies are born prematurely, before surfactant pro- recoil; the lungs become floppy and difficult to empty
duction is adequate, their lungs have low compliance, during expiration (Figure 11.14). This is manifested
Type I Surfactant layer

AEC
Air Surface
liquid
(a) (b)
Type 2
AEC
Alveolar FIGURE 11.15 Elastic recoil of normal alveoli is lost in
macrophage emphysema. (a) Normal alveoli: Elastin fibers in alveolar
walls create elastic recoil upon expansion (due to inspiration).
FIGURE 11.14 Surfactant reduces alveolar surface tension. Relaxing diaphragm and external intercostal muscles
Type 1 AECs are the thin cells making up the majority of the promotes passive expiration proportional to the degree of
alveolar wall. The interface between alveolar air and tissue fluid lung elastic recoil. (b) Emphysema: Elastic recoil decreases
lining the alveolar wall is the source of potential surface tension when elastin fibers are destroyed by the disease emphysema.
that would oppose alveolar expansion during inspiration There is little elastic recoil, and air remains trapped in ever-
(decreasing compliance). Type 2 AECs synthesize and secrete larger spaces within the lung.
surfactant, a fluid rich in amphipathic phospholipid molecules
that spread out on top of the fluid facing the alveolar air, greatly
reducing surface tension and making alveolar expansion easier.
AEC, alveolar epithelial cell. (a) (b)
by increased RV and FRC, which is particularly evident

in emphysema.
Emphysema
Emphysema is, above all, a disease of increased
compliance and decreased lung elastic recoil due to
an imbalance of forces that damage the structural
fibers of the lung and the forces that protect against FIGURE 11.16 (a) Autopsy specimen of a patient who
such damage. Exposure of the lung to repeated insults died of combined pulmonary fibrosis and emphysema, who
also had lung cancer. Dilated air spaces with thin walls are
of cigarette smoke, environmental particulate mat-
characteristic of emphysema. (b) Enlargement from panel
ter, inflammation, and oxidative stress stimulates (a) inset shows a region of fibrotic cyst formation and smooth
the resident alveolar macrophages, recruits addi-
muscle hyperplasia consistent with pulmonary fibrosis.

tional neutrophils and lymphocytes, and results in Source: From Inomata M, et al. An autopsy study of combined
the release of proteases and reactive oxygen species. pulmonary fibrosis and emphysema: correlations among
Proteases break down extracellular matrix, and local clinical, radiological, and pathological features. BMC Pulm
inflammation perpetuates neutrophil recruitment Med. 2014;14:104.
and induces alveolar epithelial cell apoptosis. This
leads to loss of alveolar structure and dilation of air
spaces, disrupting lung mechanics and gas exchange (COPD) described later. Further complexity arises
surface area. Normally, lung protective mechanisms when patients have a combination of emphysema-
include antioxidant defenses and antiproteases, par- tous changes (enlargement of air spaces, thinning
ticularly circulating a1–antiprotease (also known as of extracellular matrix) with fibrotic changes due to
a1–antitrypsin [AAT]); however, these protections are chronic inflammation. This combination is common
blunted by smoking. As air spaces enlarge, air trap- in heavy smokers, leading to mixed findings on pul-
ping occurs in a vicious cycle wherein the enlarged monary function tests, imaging, and tissue pathology
spaces have reduced ability to empty on expiration. (Figures 11.15 and 11.16). A major genetic disor-
Emphysematous effects on pulmonary function der that increases emphysema risk is α1-antitrypsin
are described later in this chapter, in the context of deficiency ( AATD ), which is also discussed in
obstructive lung disease pathophysiology. Chapter 14, Liver, under Pediatric Considerations.
Emphysema is characterized as an obstruc- AAT is synthesized by the liver and circulates system-
tive disorder and overlaps with chronic bronchi- ically, counteracting the activity of protease enzymes
tis, another chronic obstructive pulmonary disease in many tissues. The lung is particularly dependent
on this antiprotease for protection. Individuals with reduces fibroblast proliferation) and pirfenidone (an
AATD are counseled to avoid cigarette smoking, as antiinflammatory and antioxidant treatment that slows
the combination greatly accelerates development of fibrosis progression). Evidence indicates that these
emphysema. medications may reduce progression of the disorder
and delay death. Lung transplantation is another treat-
DISEASES OF DECREASED LUNG COMPLIANCE ment, depending on patient characteristics and donor
availability.9,10
Lung stiffness increases acutely in cases of pneumo-
nia or ARDS, and chronically in many diseases of lung
injury, inflammation, and connective tissue accu- CHEST WALL COMPLIANCE
mulation that may affect the lung interstitial tissues. Although not as common, changes to chest wall prop-
Collectively, these are termed restrictive lung disorders, erties can also alter compliance of the lung–chest
due to the restriction on lung expansion. Interstitial wall unit, resulting in compromised ventilation.
lung disease is another term that encompasses many Musculoskeletal conditions such as kyphosis and
of these conditions. They include idiopathic pulmonary scoliosis can impinge on volume of the thoracic cav-
fibrosis (discussed here in detail), sarcoidosis, sys- ity, surgery and trauma to the chest wall can reduce
temic lupus erythematosus, rheumatoid arthritis, and mobility, and obesity can decrease thoracic volume—
scleroderma. Pneumoconiosis is a similar restrictive in part due to increased abdominal fat deposition. In
disease normally related to occupational exposures to each of these cases, the presentation is as a restrictive
inhaled fine particulates and dusts, including the specific defect, and treatment is based on management of the
syndromes of silicosis, asbestosis, and coal workers’ underlying cause of the disorder.
pneumoconiosis.
Idiopathic Pulmonary Fibrosis

Thought Question
The pathogenesis of progressive lung fibrosis appears to
depend on both environmental exposures (particularly
cigarette smoke) and genetic predisposition, although
4. How does smoking-induced damage to lung
tissue lead to emphysema?
it is not a monogenic disorder. Mutations in telomerase
genes and mucin genes have been shown to contribute
to pulmonary fibrosis susceptibility. Idiopathic pulmo-
nary fibrosis (IPF) is diagnosed more often in adults
over the age of 50, but it is likely that pathological
changes of mild IPF occur before symptoms develop, AIRWAY RESISTANCE
resulting in delayed detection of the disorder.
In IPF, the tissues around the alveoli accumulate OVERVIEW OF AIRWAY RESISTANCE
fibroblasts, and formation of extracellular matrix with Movement of air or fluid through a cylindrical tube is
collagen deposition increases (see Figure 11.16). governed by the pressure difference between the inflow
These changes cause generalized stiffening of the nor- and outflow, and the relative resistance of the tube. The
mally compliant lung tissue. In addition to the loss of resistance is inversely proportional to the fourth power
lung compliance, IPF also reduces gas exchange by of the tube’s radius; therefore, the smaller the tube,
limiting diffusion across the alveolar membrane. As the the greater the resistance. The movement of air during
fibrosis progresses, it limits lung expansion, and RV, respiration is facilitated by the large number and large
FRC, vital capacity (VC), and total lung capacity (TLC) cross-sectional area of airways. Although the repeated
all decrease, along with the anterior–posterior size of branching pattern means that individual terminal air-
the chest. Greater pressure changes are required during ways have a very small radius, air can flow through so
inspiration, leading to a sensation of dyspnea and the many paths that the total resistance to airflow is very low
appearance of labored breathing. Vt decreases and under normal conditions. The greatest degree of resis-
respiratory rate increases; these adaptations reduce tance is encountered in the upper airways—generations
the work of breathing as it is optimal to take more fre- 1 to 8. Beyond generation 8, total cross-sectional area
quent and shallower breaths. Because gas exchange increases and resistance decreases rapidly. A major
is impaired as well as lung mechanics, an early and determinant of airway resistance is lung volume; from
prominent finding is dyspnea and hypoxemia on FRC up to TLC, distensible airways progressively fill
exertion—the system is unable to adequately increase and their radius increases, reducing airway resistance.
ventilation to keep up with increased oxygen demands. Therefore, at TLC, resistance is lowest, while expiration
Recent changes in IPF treatment approaches include is associated with progressive increases in airway resis-
the use of nintedanib (a tyrosine kinase inhibitor that tance that reaches a maximum at RV.
FORCED EXPIRATORY MANEUVERS explain this decrement: First, as volume in the airways
ARE USED TO ASSESS AIRWAY RESISTANCE decreases, the radius of each airway also decreases,
During pulmonary function testing, the subject’s abil- increasing resistance; second, forced expiration gen-
ity to deeply inspire and then forcefully expire a max- erates positive Ppl that tends to collapse airways. As
imal breath is measured. The volume of air (in liters) shown in Figure 11.19, the Ppl, which is normally neg-
inspired and then expired is measured, and the rate of ative and contributes to airway expansion, becomes
airflow (in liters per minute) is determined. These data positive during forced expiration, tending to collapse
are then graphically displayed in two ways. One dis- airways. In this way, forced expiratory testing is able
play shows the volume expired during the time of the to detect disease processes in which airways are patho-
forced expiration (volume/time analysis) and the other logically narrowed. In primary care and home settings,
plots the rate of airflow during expiration relative to a handheld peak flowmeter can be used to get a quick
the volume of air remaining in the lungs (flow/volume measurement of forced expiratory flow.
analysis). Volume/time analysis in a person without
airway disease is shown in Figure 11.17. Beginning CONCEPTS IN OBSTRUCTIVE LUNG DISEASE
at TLC, close to 80% of the forced vital capacity (FVC) The major obstructive lung diseases are asthma and
is expired within the first second. This value is termed COPD, which has two major presentations: chronic bron-
the forced expiratory volume in 1 second, or FEV1. chitis and emphysema. There is some overlap among
Expiration of the remaining volume, down to RV, occu- these three, and some patients have manifestations of
pies the remaining time.
Flow/volume analysis is shown in Figure 11.18. By
convention, the airflow is plotted against the volume in
the lungs from RV (on the right) to the TLC (on the left).
Forced expiratory flow is associated with a character- *
istic triangle-shaped flow/volume curve. Maximum
Forced expiration
expiratory flow (peak flow) is achieved at the begin- Outward
ning of the maneuver, reflecting the fact that airway
resistance is lowest at TLC. From that point, airflow
steadily decreases until RV is reached. Two factors can
Flow (L/sec)
5 TLC RV
FRC
Maximal inspiration
4 FEV1
Inward
Volume expired (L)
2
Total lung Residual
capacity volume
1 Lung volume
FIGURE 11.18 Spirometry flow/volume analysis. Airflow (with

0 directional arrows) is depicted during a maximal inspiration
0 1 2 3 4 5 6
Time (sec)
(lower box) and a forced expiration from TLC to RV (upper
box). Note volumes on x-axis are plotted from lowest (RV, on
Normal FVC the right) to highest (TLC, on the left). The small circle shows
the usual flow/volume relationship during a normal quiet
breath—from a volume of FRC to FRC + Vt. Inspiration is
FIGURE 11.17 Plot of the volume of air expired over time associated with increasing flow rate to a maximum, a plateau
during spirometry. The FEV1 represents the volume of air region at that maximum, and then decreasing flow rate until
expired in the first second of a forced expiratory maneuver. TLC is reached. Forced expiration, however, is associated
This corresponds to the time of minimal airway resistance as with an early increase to peak expiratory flow (asterisk) and
the maneuver begins at total lung capacity. FEV1 is generally progressively diminishing flow until RV remains in the lungs.
75% to 85% of the FVC. The mechanism is termed dynamic airway compression.
FEV1, forced expiratory volume in 1 second; FVC, forced vital FRC, functional residual capacity; RV, residual volume; TLC, total
capacity. lung capacity.
4 FEV1
Volume expired (L)

3
PA = 15
cm H2O
2
PPI = +30 cm H2O FEV1
0
0 1 2 3 4 5 6
PT = 15 – 30
PT = –15 cm H2O Time (sec)
Normal FVC Airway obstruction FVC

FIGURE 11.19 Lung pressures during forced expiration. During
a forced expiration, the abdominal muscles contract, pushing
the diaphragm up and compressing the chest cavity from the FIGURE 11.20 Obstructive diseases alter the volume/time
bottom. Internal intercostal muscles contract, drawing the chest relationship during forced expiration. Obstructive airway
wall down and in. Ppl becomes positive (represented as +30 cm pathology in asthma or COPD limits the rate of expiratory flow
H2O). Thus, the airways are subjected to greater pressure on and promotes air trapping, increasing residual volume and
the outside (Ppl) than the inside (Pa), giving a negative pres decreasing FVC. The FEV1/FVC ratio is about 52%, indicating a
sure gradient that tends to collapse the airways. moderate to severe degree of obstruction.
Pa, alveolar pressure; Ppl, pleural pressure; Pt, transpulmon COPD, chronic obstructive pulmonary disease; FEV1, forced
ary pressure. expiratory volume in 1 second; FVC, forced vital capacity.
all forms. In all three disorders, when airway resistance

increases due to chronic changes or acute exacerbation,
pulmonary function is markedly compromised. Airway
obstruction and premature airway closure during expi-
ration are manifested by decreased peak flow, and FEV1
Expiration
and FVC are both reduced. FEV1 shows the greatest

changes, and the FEV1/FVC ratio is abnormally low. Normal
Following inspiration, air is trapped behind closed air-

ways, often increasing RV, FRC, and TLC. These changes
Flow (L/sec)
are readily apparent on graphical representations of spi-

rometry data (Figures 11.20 and 11.21). TLC COPD RV
Airway resistance is partly determined by the
contractile state of bronchial smooth muscle. The
Inspiration
parasympathetic branch of the autonomic nervous

system innervates most of the conducting airways of
the lung, whereas sympathetic innervation is more
limited. The airways also have receptors for systemic
and locally generated mediators. It is useful here to
briefly review the mechanisms of smooth muscle con-
traction and relaxation (Figure 11.22). As described Volume (L)
in Chapter 4, Cell Physiology and Pathophysiology,
smooth muscle cells have irregular alignment of FIGURE 11.21 Obstructive diseases alter the flow/volume
relationship during forced expiration. COPD produces
actin and myosin, and crossbridge formation lead-
marked changes in the flow/volume loop, with reduced peak
ing to cell contraction and shortening is mediated by
flow, increased RV and TLC due to air trapping, and a concave
increases in intracellular calcium. The sequence of “scooped out” appearance of the expiratory flow decline from
events leading to bronchial smooth muscle contrac- peak. The concave flow pattern indicates premature airway
tion consists of intracellular calcium accumulation, closure during forced expiration.
calcium–calmodulin binding, phosphorylation of COPD, chronic obstructive pulmonary disease; RV, residual
myosin light chain kinase (MLCK), and actin–myosin volume; TLC, total lung capacity.
ACh LT
PLC Gq
Gq LTR
M
PIP2
IP3 DAG
Ca2-Calmodulin
SR
Ca2
MLCK
Myosin Myosin-P
PKA MLCP
cAMP
ATP Smooth
muscle cell
2R
AC Gs
EPi
FIGURE 11.22 Neural and humoral control of bronchial smooth muscle. Bronchial smooth
muscle contraction is under three major influences. Under normal conditions, there is modest
bronchoconstriction due to ACh released from vagal innervation of the airways, acting on
bronchial smooth muscle cell muscarinic receptors (M). During exercise or stress, circulating
Epi binds to β2-adrenergic receptors (β2 Rs), causing bronchodilation. In an acute asthma
attack, mast cell–generated LTs bind to LTRs and cause bronchoconstriction. The actions of
ACh and LT are mediated by the Gq–phospholipase C system, increasing intracellular DAG,
IP3, and calcium (Ca2+). The Ca2+–calmodulin system phosphorylates MLCK, producing smooth
muscle contraction. The action of epinephrine is mediated by the Gs–adenylyl cyclase system,
converting ATP to cAMP, and activating PKA. PKA activates MP and inhibits MLCK, producing
bronchodilation. These receptor-mediated actions are the targets of many drugs used to manage
both asthma and chronic obstructive pulmonary disease.
AC, adenylyl cyclase; ACh, acetylcholine; ATP, adenosine triphosphate; cAMP, cyclic adenosine
monophosphate; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol triphosphate; LT, leukotriene;
LTRs, leukotriene receptors; MLCK, myosin light chain kinase; MLCP, myosin light chain
phosphatase; MP, myosin phosphatase; PIP2, phosphatidylinositol-4,5-bisphosphate; PKA, protein
kinase A; PLC, phospholipase C; SR, sarcoplasmic reticulum.
crossbridge formation, shortening the cells. Because In asthma, local release of histamine and leukotrienes
the airway smooth muscle cells are arranged radially contributes to bronchoconstriction.
around the airway walls, smooth muscle contraction
leads to airway narrowing. Conversely, activation of Asthma
the enzyme myosin light chain phosphatase, or inhi- Asthma is an obstructive airway disease character-
bition of MLCK, produces smooth muscle relaxation ized by acute exacerbations with dyspnea, coughing,
and increased airway diameter, or bronchodilation. wheezing, and airflow obstruction measured by spi-
Under normal conditions, parasympathetic tone pre- rometry that usually reverts to almost-normal airway
vails, with modest bronchoconstriction. Exercise or function on prompt treatment. Asthma prevalence in
the fi ght-or-fl ight response increases sympathetic adults averages 4.3% worldwide.11 Asthma attacks often
tone to the airways, promoting bronchodilation. begin in childhood, during which the most common
pathogenesis is type 1 hypersensitivity (allergy). The in the absence of an exacerbation, an individual with
hallmarks of allergic disorders include the following: chronic asthma often has persistent airway narrowing
evidenced by concavity of the expiratory flow/volume
• Elevated production of T-helper 2 (Th2)-generated curve that becomes more pronounced during an acute
cytokines, including interleukin (IL)-4, IL-5, and asthma attack (Figure 11.23).
IL-13 In addition to allergic causes, other asthma triggers
• Class-switching by B cells that produce IgE rather include respiratory infections, exercise (particularly
than IgG outdoors in cold, low-humidity conditions), aspirin in
• Binding of IgE to mast cells, thus priming them sensitive patients, and occupational exposures. Initial
to respond to allergen exposure by degranu- management generally involves a stepwise approach
lation, releasing histamine and inflammatory that includes inhaled corticosteroids to reduce airway
prostaglandins inflammation, a long-acting β-agonist drug to promote
• Recruitment of eosinophils to the affected tissue, bronchodilation, while providing a separate rescue
perpetuating inflammatory mediator production and inhaler with a short-acting β-agonist drug. If these strat-
releasing eosinophil major basic protein, which fur- egies are not sufficient, leukotriene antagonists and
ther inflames tissues muscarinic receptor blockers are additional options.
Omalizumab, a monoclonal antibody to IgE, is an
In adults, other asthma subtypes have been identified, additional treatment option for patients with allergic
with airway accumulation of both neutrophils and asthma.
eosinophils, or neutrophil accumulation alone.11 Some To summarize, the pathophysiology of asthma is
forms of asthma have minimal airway granulocyte colo- characterized by acute but reversible airflow obstruc-
nization. Regardless of the histological profile, all forms tion. In response to allergic and other triggers, mucus
of asthma have chronic changes to the airways, includ- secretion increases, the mucosa becomes swollen
ing bronchial smooth muscle hypertrophy and hyperre- with inflammatory cells and mediators that cause
sponsiveness, altered goblet cell function with mucus vasodilation and increased capillary permeability, and
hypersecretion, and airway narrowing due to fibroblast bronchial smooth muscle contracts. All three factors
accumulation. Although not often done, airway provo- contribute to severely constricted airways and limited
cation testing with a muscarinic agonist such as metha- airflow. Over time, airway changes persist with modest
choline shows an exaggerated bronchoconstrictor degrees of airway narrowing between acute attacks.
response, whereas inhalation of a β-adrenergic agonist These airway changes include continued white blood
usually improves spirometry measures.11,12 Thus, even cell infiltration, particularly with eosinophils and
Normal airway During asthma symptoms

Inflamed/
thickened
Airway
airway wall
wall
Mucus
Narrowed airway
Muscle (limited airflow)
Tightened muscles
constrict airway
Muscle Thickened
airway wall
Airway
wall
Mucus
Airway cross section Muscle

(a) (b)
FIGURE 11.23 Airway changes with asthma. (a) Cross section of a normal airway. (b) Cross
section of an airway during asthma symptoms.
Source: United States National Institutes of Health: National Heart, Lung, and Blood Institute.
lymphocytes; bronchial smooth muscle hypertrophy; narrowing, dyspnea, and cough. Fibrotic changes can also
hyperplasia; and hyperreactivity. With advancing age, thicken bronchiolar walls and reduce the airway lumen.
asthma can overlap with the development of COPD. Airway obstruction in COPD is associated with air
trapping and can chronically increase RV, FRC, and
Chronic Obstructive Pulmonary Disease TLC. Chest anterior–posterior dimension may be vis-
Chronic obstructive pulmonary disease (COPD) is ibly increased (visible as a barrel-shaped chest) and
the third leading cause of death in the United States, identifiable on chest x-ray. CT of the chest is able to
with prevalence estimated at 12% of the population, or distinguish features such as bronchiectasis in some
30 million people. Globally, COPD is the fourth lead- cases of COPD. Progression of the disease is associ-
ing cause of death, and the mortality rate due to COPD ated with development of hypoxia and hypercapnia.
is increasing over time.13 COPD is defined by reduced Respiratory infections are the most common causes
expiratory airflow (particularly FEV1 and FEV1/FVC) of exacerbations, and vaccinations for pneumococcal
that is not reversible (unlike asthma), along with exer- pneumonia and influenza are strongly recommended.
tional dyspnea, cough, and sputum production. COPD Management approaches are similar to those used for
is a complex disorder with overlapping disease pro- asthma, including inhaled corticosteroids and long-
cesses that include air space enlargement due to tissue acting β-adrenergic agonists, but better understanding
destruction (as in emphysema), and chronic inflam- of subtypes within the broad COPD diagnosis is needed
mation with cough and sputum production (chronic to refine and target treatment options.15,16
bronchitis). Most cases are caused by current or
former smoking, although environmental exposures
(smoking in the environment, cooking indoors with
biomass fuel) can also produce these manifestations.
Having a history of asthma is a risk factor for later
COPD development. Most studies of COPD pathophys-
iology involve individuals who currently or formerly
were smokers, making this the best-understood group
regarding pathological mechanisms. Smoking-induced
injury of airway epithelial cells recruits white blood
cells and initiates local inflammation. Generation of
reactive oxygen species and neutrophil proteases dam-
ages lung tissues, and chronic inflammation can persist
even if the individual stops smoking.14
Expiratory airflow limitation in patients with emphy-
sema is due to decreased elastic recoil and occurs
simultaneously with the increase in lung compliance
(elastance, or elastic recoil, is the inverse of compli- PA = 35

ance). In addition, airways are prone to collapse because
of the loss of adjacent tissue that would normally exert
a tethering function, helping to keep airways open.
Pursed-lip breathing may help to reduce airway collapse
and support expiratory flow (Figure 11.24). Exhaling
PPI = +30 cm H2O
through pursed lips creates positive pressure in the
mouth and along the airways, maintaining a pressure PT = 35 – 30
gradient that holds the airways open and counteracts the PT = +5 cm H2O
tendency of floppy airways to collapse. Using pursed-lip
breathing during pulmonary function testing can result FIGURE 11.24 Forced expiration with pursed-lip breathing.
in improved measurement of VC, sometimes called slow Individuals with obstructive airway disease can reduce airway
vital capacity, in comparison with the usual forced expi- collapse during expiration by slowing down expiratory flow
ratory measurement. and by pursing the lips to create a block to airflow. This
maneuver allows airway pressure to increase and reduces
The diagnosis of chronic bronchitis is based on the
the tendency of positive Ppl to collapse the airways. In older
clinical history of persistence of productive cough for
adults and those with obstructive disease, airway collapse
at least 3 months that is documented in at least 2 con- can even occur in the absence of forced expiration, so the
secutive years. Chronic inflammation with neutrophil pursed-lip breathing maneuver is helpful for maintaining vital
and macrophage infiltration is similar to emphysema. In capacity at normal levels and reducing residual volume.
addition to increased mucus production, airway muco- Pa, alveolar pressure; Ppl, pleural pressure; Pt, transpulmon-
sal tissue becomes edematous, contributing to airway ary pressure.
Obstructive Sleep Apnea airway provide the initial risk factor for apnea during
Obstructive sleep apnea (OSA) is the most com- sleep. In particular, obesity is associated with fat accu-
mon example of sleep-disordered breathing, a condi- mulation in the tissues surrounding the airway, pro-
tion of abnormal breathing patterns occurring during viding the initial narrowing and predisposing to OSA.
sleep. In OSA, the upper airway becomes partly or Obesity is also associated with decreased lung volume
completely obstructed for 20- to 40-second episodes (due to increased abdominal contents pushing upward
during sleep, causing apnea (complete airflow cessa- on the diaphragm). As lung volume decreases, airway
tion despite inspiratory muscle contraction) or hypo- resistance increases due to loss of tethering pulling
pnea (decreased depth or duration of a breath). These airways open. Other factors narrowing upper airways
episodes cause blood oxygen levels to decline and during sleep include dilator muscle dysfunction, abnor-
carbon dioxide levels to rise, terminating in (often mal cycling between arousals and sleep that disrupts
unconscious and unsuccessful) respiratory efforts, a the usual respiratory cycle, and altered chemoreceptor
brief arousal and surge of sympathetic nervous system sensitivity.19
activity before sleep resumes. During an episode of airway obstruction, blood O2
The diagnosis of OSA depends on sleep laboratory levels fall and CO2 levels rise, stimulating increased
documentation of the apnea/hypopnea index (AHI) inspiratory efforts through chemoreceptor drive. This
of greater than five episodes per hour, in conjunction leads to greater depth of negative pleural pressures
with signs and symptoms of sleep loss, or AHI greater as the diaphragm and the external intercostal mus-
than 15. Using the AHI cutoff of greater than 5 AHI, cles contract in an attempt to bring air in through the
prevalence varies from 9% to 38%; while using the AHI obstructed airway. The more negative Ppl leads to a
cutoff of greater than 15, prevalence varies from 6% to more negative airway pressure, sucking the soft tis-
17%. Prevalence is higher in men and increases with sues in and collapsing additional airways. Brief arousal
age.17 Some patients with OSA have 100 or more epi- may occur at the time of this activation of inspiratory
sodes per hour. Findings that confirm an OSA diagnosis activity. Pathophysiological consequences of repeated
in someone with an AHI greater than five include the arousals, nocturnal spikes of sympathetic activity,
following18: intermittent hypoxia, and oxidative stress include car-
diovascular pathology—heart disease, hypertension,
• Patient complains of sleepiness, fatigue, or insomnia and atrial fibrillation. Excessive daytime sleepiness
symptoms. can disrupt work and psychosocial functioning. Driving
• Patient wakes experiencing breath holding, gasping, while drowsy can lead to automobile accident–related
or choking. morbidity and mortality.20
• Bed partner reports snoring, grunting, or snorting OSA management with continuous positive airway
(signs of partial airway obstruction) or breathing pressure (CPAP) has been shown to mitigate some of
interruptions during sleep. the cardiovascular consequences of OSA. Nevertheless,
• Patient has a diagnosis of hypertension, mood disor- adherence has been challenging, and other approaches
der, cognitive dysfunction, coronary heart disease, should be incorporated in the management strategy,
stroke, heart failure, atrial fibrillation, or type 2 dia- including weight loss, regular exercise, avoidance of
betes mellitus. smoking and alcohol, and avoidance of sleeping in the
supine position.
The soft tissues surrounding the back of the mouth Finally, a subset of patients has central sleep
and extending to the larynx (soft palate, oropharynx, apnea, in which there is a failure of brainstem respira-
and laryngopharynx) are collapsible and are capable of tory drive to the inspiratory muscles. Although the con-
occluding the open space of the airway. In addition, in sequences of central sleep apnea are similar to those
the supine position, the tongue tends to relax toward of OSA, the risk factors differ. In particular, patients
the back of the pharynx, also occluding the airway. with heart failure, stroke, and atrial fibrillation have an
The neural circuits controlling inspiratory muscles also increased risk of developing central sleep apnea—and
control upper airway dilator muscles, thus favoring air- sleep apnea can also worsen heart failure and atrial
way opening during inspiration. The genioglossus mus- fibrillation.
cle that extends the tongue is the best studied of these To summarize, biophysical properties of the respira-
muscles. Although coordinated activation of upper tory system, compliance and resistance, shape pulmo-
airway dilation is very effective while awake, activity nary function in health and disease. Understanding these
drops with sleep onset and is particularly low during general principles provides the foundation for ordering
rapid eye movement (REM) sleep. and interpreting diagnostic tests, as well as devising
Airway obstruction during sleep is not the only fac- management strategies. Table 11.1 lists pulmonary
tor leading to OSA; rather, conditions that narrow the function test findings in several pathological states.
Simultaneously, CO2 diffuses in the opposite direction,

TABLE 11.1 Findings in Common Lung Disorders from capillary blood to alveolar air. Each breath refreshes
the alveolar air with fresh O2 and removes CO2. Oxygen
RV, TLC,
Disorder FEV1/FVC FVC FRC DLCO
delivery within the body is accomplished by binding to
the oxygen-carrying protein hemoglobin (Hb) in red
COPD/emphysema ↓ ↓ ↑ ↓ blood cells. Carbon dioxide is carried bound to Hb and
also dissolved in blood plasma. The majority of CO2 trav-
Pulmonary fibrosis –, ↑ ↓ ↓ –, ↓
els in the blood in the form of bicarbonate ions (HCO3−).
COPD/chronic ↓ ↓ RV, FRC ↑ –
bronchitis TLC – OXYGEN–HEMOGLOBIN DISSOCIATION CURVE
Asthma (acute ↓ ↓ ↑ – Oxygen is poorly soluble in blood plasma, and dissolved
phase)* O2 in the blood is not adequate to supply the body’s O2
needs. To solve this problem, Hb produced in red blood
*
In asthma, most changes are reversible upon recovery from exacer-
bation or are relieved by acute bronchodilator treatment.
cells works as the major oxygen-carrying protein of the
−, no change; ↑, increase; ↓, decrease; COPD, chronic obstructive body. From the alveolar air, O2 molecules diffuse into
pulmonary disease; DLco, diffusing capacity of the lung for carbon pulmonary capillary blood and then diffuse across red
monoxide, a measure of gas exchange area and thickness; FEV1, blood cell membranes, after which they are able to bind
forced expiratory volume in 1 second; FRC, functional residual to Hb. Hb must bind O2 efficiently at the partial pressure
capacity; FVC, forced vital capacity; RV, residual volume; TLC, total
lung capacity.
of the oxygen (Po2) of the alveolus (referred to as load-
Source: From Levitzky MG. Pulmonary Physiology. 9th ed. New York, ing the Hb with O2), retain O2 while in the arteries and
NY: McGraw-Hill; 2018. arterioles, and release it to tissues at the Po2 of tissue
capillary beds (referred to as unloading O2 from Hb).
Each protein chain of the Hb tetramer contains a heme
molecule with an attached iron ion (Fe2+). The heme
Thought Questions irons are the sites to which O2 can bind reversibly, at rel-
atively high O2 partial pressures in the alveoli, and from
5. What is the rationale for the use of β-agonist which O2 can be released to the tissues, where local Po2
drugs in diseases of increased airway resistance? is lower due to tissue O2 utilization (Figure 11.25).
6. What are the mechanisms linking allergic airway The relationship between the local Po2 and percent
disease and increased airway resistance? saturation of hemoglobin (Hb % sat) is a nonlinear rela-
tionship graphically depicted in the oxygen–Hb (oxyhe-
7. How is CPAP treatment for obstructive sleep moglobin) dissociation curve (Figure 11.26). Oxygen
apnea similar to pursed-lip breathing in COPD? partial pressure (Po2, in units of mm Hg) is on the x-axis as
the independent variable, whereas Hb percent saturation
with O2 (HbO2/total Hb) is on the y-axis as the dependent
variable. When the surrounding Po2 is low, Hb is partially

deoxygenated. As Po2 rises, the first O2 molecule binds
GAS EXCHANGE IN THE LUNG to Hb. After this process is initiated, the shape of the Hb
molecule changes, its oxygen-binding affinity increases,
OVERVIEW OF GAS EXCHANGE and the slope of the oxyhemoglobin dissociation curve
As previously noted, the main function of the lungs increases. Once each Hb molecule has achieved 75% sat-
is to provide an interface between alveolar airflow uration (three binding sites are filled with O2), the curve
(referred to as ventilation) and pulmonary capillary flattens out. Oxygen binding to Hb reaches close to 100%
blood flow (referred to as perfusion). At this interface, Hb saturation when the Po2 reaches about 100 mm Hg,
inspired O2 can diffuse into the blood for transport which is the average Po2 of alveolar air.
to tissues, and tissue-generated CO2 can be removed A person’s oxygen-carrying capacity is directly depen-
from the body via the alveolar–capillary membrane. dent on the amount of Hb in the blood: The greater
Alveolar surface area is estimated to be at least 75 m2 the Hb concentration, the greater will be the oxygen-
in a young adult, although it declines with aging.21 Each carrying capacity. If a person has anemia—decreased Hb
alveolus is surrounded by a dense capillary network. concentration—he or she will have lower oxygen-carrying
Most of the surface area between the alveolar epithe- capacity. Oxygenation by the lungs can only increase
lium and capillary endothelium is a fused basal lamina blood O2 content—the actual amount of oxygen carried—
with a few fibers of elastin, the protein responsible for to the extent that Hb is available for loading. A person with
lung elastic recoil. anemia may have normal Po2 and Hb saturation as shown
Oxygen diffuses across the thin alveolar–capillary on the oxyhemoglobin dissociation curve; however, if his
interface relatively easily, down its partial pressure or her Hb concentration is decreased, O2 content will be
gradient from alveolar air to capillary blood plasma. decreased and the tissues may develop anemic hypoxia.
100 ↑ pH
Hb ↓ Pco2
90
saturation ↓ 2,3-DPG
0 25% 50% 75% 100% 80 ↓ Temperature
Hb% saturation with O2

70
Alveolar air
Mixed venous PO2 ~ 100 mm Hg Arterial PO2 ~ 60
PO2 ~ 40 mm Hg 100 mm Hg ↓ pH
50 ↑ Pco2
40 ↑ 2,3-DPG
↑ Temperaturet
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
Po2 (mm Hg)
Systemic capillary
FIGURE 11.26 Oxyhemoglobin dissociation curve. Average
mixed venous Po2 is 40 mm Hg, which corresponds to 75%
saturation of Hb (Hb % sat) with oxygen. This is the usual
composition of blood entering alveolar capillaries. Average
alveolar gas Po2 is 100 mm Hg, so loading of oxygen onto
Hb occurs, up to the usual arterial level of 97.5% Hb sat,
with Po2 averaging 100 mm Hg. Systemic and local factors
Tissue PO2 ~ 40 mm Hg alter Hb’s affinity for oxygen, shifting the curve to the left
(greater affinity) or to the right (lesser affinity), as shown.
2,3-DPG, 2,3-diphosphoglycerate; Hb, hemoglobin; Pco2,
FIGURE 11.25 Qualitative display of Hb loading with oxygen
partial pressure of carbon dioxide; Po2, partial pressure of
in the alveolar capillaries and unloading in the tissues. In the top
oxygen.
panel, blood entering the alveolar capillary has an average Po2 of
40 mm Hg, corresponding to 75% saturation of Hb with oxygen.
Immediately on encountering the alveolar Po2 of 100 mm Hg, consists of two a chains and two β chains. This facil-
oxygen moves down its partial pressure gradient to equilibrate itates O2 transfer from maternal blood to fetal blood
with capillary blood. Oxygen molecules then enter red blood at the placenta, providing O2 for fetal development. In
cells and contribute the final oxygen addition to achieve 100%
addition, HbF concentration is higher than maternal
saturation: On each Hb molecule, all four oxygen-binding sites
Hb concentration, so fetal O2 content is predicted to be
are occupied. In the bottom panel, oxygen delivery to the tissues
is shown. Average tissue Po2 is 40 mm Hg, so plasma Po2 rapidly higher, delivering additional O2 to the fetus.
Other physiological factors can alter the shape and
equilibrates to that level, as does the red blood cell cytoplasm.

This favors unloading of oxygen from Hb, until the saturation position of the oxyhemoglobin dissociation curve.
level has reached 75%, the value associated with Po2 of 40, as These can affect loading of O2 onto Hb in the lungs and
seen in the oxyhemoglobin dissociation curve. In tissues with are particularly significant in unloading O2 from Hb at
greater rates of oxidative metabolism and CO2 production, the the tissues. They are described next.
curve shifts to the right, and greater amounts of oxygen are
delivered at the same tissue Po2 level. Effects of Partial Pressure of Carbon Dioxide and pH
Hb, hemoglobin; Po2, partial pressure of oxygen. The influence of pH and partial pressure of CO2 (Pco2)
on the oxyhemoglobin dissociation curve is referred to
Cardiorespiratory adaptations to anemic hypoxia include as the Bohr effect. As pH decreases, the oxyhemoglo-
increased cardiac output and respiratory rate. These bin dissociation curve shifts to the right, and oxygen is
changes allow faster circulation of the blood through released from Hb more easily, at a higher Po2 level. The
the lungs and back to the body to increase O2 delivery to Bohr effect is a result of a stabilizing effect of protons
tissues. Levels of red blood cell 2,3-diphosphoglycerate on deoxyhemoglobin, decreasing its tendency to bind O2.
(2,3-DPG) increase in anemia, improving O2 delivery to Note that the pH of blood falls as its CO2 content and par-
tissues, as discussed in the next sections. tial pressure increase, which normally occurs in the tran-
sit of blood through the tissues. Physiologically this is
Influences on the Oxyhemoglobin Dissociation Curve ideal as Hb will deliver more O2 in the presence of higher
The affinity of Hb for O2 is altered by a number of fac- concentrations of CO2 (and lower pH) in the tissues with
tors. Developmentally, fetal hemoglobin (HbF) con- the highest oxidative metabolism and CO2 generation.22
sists of two a chains and two γ chains. HbF has greater Conversely, low tissue CO2 levels in tissues that have
O2 affinity than HbA, the most common adult Hb, which lower aerobic activity maintain stable pH, normal Hb
affinity for O2, and O2 delivery at a lower level consistent

with tissue requirements. TABLE 11.2 Mechanisms of Hypoxemia
Cause of Hypoxemia Such as That Observed in:

Effect of 2,3-Diphosphoglycerate
2,3-DPG (also called 2,3-bisphosphoglycerate, or 2,3- Generalized hypoventilation OSA/OHS
BPG) is produced by red blood cells during the reac- Opioid/drug overdose
tions of glycolysis. 2,3-DPG binds to Hb and decreases Central nervous system
the affinity of Hb for O2, such that increased 2,3-DPG disease
levels shift the oxyhemoglobin dissociation curve to the Neuromuscular weakness
right, favoring O2 delivery from Hb at higher levels of Po2. Ventilation/perfusion COPD/asthma
Synthesis of 2,3-DPG is favored in chronic conditions of mismatch and regional Pneumonia
hypoxia such as high altitude or chronic lung disease. hypoventilation Pulmonary embolism
Pulmonary fibrosis
Effects of Temperature Pulmonary edema
Body temperature influences the affinity of Hb for O2,
Shunt Anatomical: Cyanotic
with increased temperature decreasing the affinity and
congenital heart defects
shifting the curve to the right. This effect can be mani- Physiological: ARDS
fested at the organ level. For example, in the heart, the
rhythmic muscle contractions and high aerobic meta- Diffusion abnormality Interstitial lung disease (many
bolic rate combine to increase the temperature. Thus, types)
in the myocardial capillaries, the red blood cell Hb is May also occur in
exposed to conditions of increased temperature, in pneumonia—with
alveolar fluid accumulation
addition to lower pH and greater Pco2, with all of these
factors assisting with greater O2 delivery than in other ARDS, acute respiratory distress syndrome; COPD, chronic obstruc-
tissues. On the other hand, at low blood temperatures, tive pulmonary disease; OHS, obesity hypoventilation syndrome;
the curve shifts to the left and Hb has higher O2 affinity, OSA, obstructive sleep apnea.
Source: Reproduced with permission from Naureckas ET, Solway
requiring lower Po2 levels to release its O2.
J. Disturbances of respiratory function. In: Jameson JL, et al., eds.
Harrison’s Principles of Internal Medicine. 20th ed. New York, NY:
HYPOXIA AND HYPOXEMIA McGraw-Hill; 2018.
Hypoxia refers to any deficiency of O2, whereas hypox-

emia refers to below normal levels of O2 in arterial blood. Generalized Hypoventilation
Hypoxia of tissues can result from low inspired O2 (in an Alveolar hypoventilation is a state in which the breath-
airplane or at high altitude), anemia (due to lack of blood ing depth, rate, or both are inadequate to meet the
oxygen-carrying capacity), lack of perfusion (due to body’s needs, and, for our purposes, it is useful to dis-
thromboembolic vascular occlusion), or poisoning that tinguish generalized hypoventilation due to neurolog-
prevents cells from using O2. Here, we focus on hypox- ical or neuromuscular disorders as a category separate
emia, specifically on the relationship between lung dis- from hypoventilation in lung disease. It is important
ease and decreased arterial O2 partial pressure. to note here that not all of the Vt reaches alveoli to
Although healthy lungs efficiently exchange O2 and refresh alveolar air composition. The conducting air-
CO2, hypoxemia can indicate failure of the lungs to pro- ways of the lungs have no alveoli and are unable to con-
vide adequate gas exchange to sustain life. An under- duct gas exchange; thus, they are collectively known
standing of how gas exchange occurs and the causes of as dead space. As a general rule, a person’s dead space
insufficient gas exchange are vital to caring for patients (in milliliters) is about the same as his or her weight (in
with lung diseases. Like hypoxia, hypoxemia may occur pounds); thus, a man with average body composition
at high altitudes, as a result of lowered inspired Po2. The and weighing 150 pounds would have about 150 mL of
short-term adaptation is through increased rate and depth dead space. The Vt during inspiration, then, consists of
of breathing, whereas long-term adaptation to high alti- the sum of air entering the dead space and air entering
tude is via increased red blood cell production (polycy- alveoli. Calculation of minute ventilation is thus:
themia) and increased 2,3-DPG. For extreme elevations
(e.g., climbing Mount Everest and similar peaks), O2 sup-
( VT × Respiratory rate ) =
plementation is required. Individuals with healthy lung
function are able to make these adaptations, but people ( VD × Respiratory rate ) + ( VA × Respiratory rate )
with preexisting lung disease may not be able to adapt
well to high altitude. The common pathological mecha- where VD refers to the dead space portion of Vt, and Va
nisms of hypoxemia that will be discussed in this book refers to the alveolar portion of Vt. Minute ventilation
are generalized hypoventilation, ventilation/perfusion is then made up of dead space ventilation plus alveolar
mismatch, shunt, and diffusion limitation (Table 11.2).23 ventilation.
. .
An extreme case of hypoventilation is exemplified by Ventilation/Perfusion ( V/Q) Mismatch
a traumatic high spinal cord injury that disrupts neural Optimal gas exchange depends on both the rate of ven-
pathways between the medullary respiratory pattern gen- tilation reaching the alveoli and the rate of blood flow
erators and the spinal cord motor neurons of the phrenic (perfusion) traveling through the alveolar capillaries
and intercostal nerves. This leaves the accessory muscles (Figure 11.27). Atmospheric air has a Po2 of about
of the upper chest as the only inspiratory muscles, while 160 mm Hg at sea level, and has minimal CO2. Upon enter-
the diaphragm and external intercostals cease activity. ing the airways, water vapor is added, humidifying the
In such a case, the Vt is dramatically decreased, perhaps air and reducing O2 and CO2 partial pressures slightly. As
falling from 500 mL to 200 mL.
the air is breathed in, it meets air in the dead space that
Table 11.3 shows data that would be consistent
was depleted in O2 and enriched in CO2 from the previous
with this condition. Immediately after such a traumatic
expiration. At the level of the alveoli, the approximate par-
neurological injury, suppose that respiratory rate does
tial pressures are Po2 = 100 mm Hg and Pco2 = 40 mm Hg.
not change. That drops minute ventilation by more
Blood traveling in the pulmonary arteries to the alve-
than half, and alveolar ventilation drops to one-seventh
olar capillaries has the average composition similar to
of its previous value. CO2 retention will be extreme
mixed systemic venous blood, with Po2 = 40 mm Hg and
at this level, and arterial O2 will rapidly drop. These
Pco2 = 46 mm Hg. As soon as the blood is exposed to
changes will stimulate chemoreceptors, quickly driv-
alveolar air, it normally equilibrates to the composition
ing an increase in respiratory rate (depth of breathing
cannot change because of spinal cord injury). Despite of alveolar air, leaving the lungs through the pulmonary
increasing respiratory rate, alveolar ventilation will still veins with the composition shown in Figure 11.27.
be inadequate to meet the body’s O2 needs, even at rest. In clinical situations, imbalance between ventilation
Furthermore, supplementing O2 will have only limited and perfusion of the alveoli (ventilation/perfusion
usefulness, as CO2 will continue to build up in the alve- mismatch) is the most common cause of hypoxemia in
olar spaces and in the blood. The only treatment that chronic lung disease as well as in acute conditions such
will be effective is mechanical ventilation. as pulmonary edema and pneumonia. Rather than gen-
Clinical manifestations of other, less dramatic eralized hypoventilation, as described earlier for certain
hypoventilation syndromes can be nonspecific and neurological disorders, hypoventilation in many lung
variable, depending on factors such as the underlying disorders is often regional and patchy and blood flow
disorder as well as severity of hypoventilation and can also be variable, depending on the disease process.
the rate at which hypercapnia develops. These syn- Pneumonia, for example, may cause inflammatory exu-
dromes include acute disorders such as acute neuro- date in many alveoli of one lung lobe, while the remain-
logical injury, rapid-onset Guillain–Barré syndrome, ing lung may have relatively normal function. Similar
or the much more common opioid overdose. Chronic uneven pathology can occur in COPD. In these sce-
hypoventilation is seen in obesity-related hypoventila- narios, perfusion of alveoli in underventilated regions
tion syndrome, restrictive thoracic disorders and rib results in the incomplete oxygenation of exiting blood
injuries, degenerative neurological and neuromuscu- (Figure 11.28). When mixed with . . oxygenated blood
lar disorders such as amyotrophic lateral sclerosis and coming from areas with a higher V/Q ratio, the partially
myasthenia gravis, and central sleep apnea syndromes. oxygenated blood decreases final . P.o2 of blood leaving
Symptoms can include daytime somnolence and the lungs. Hypoxemia caused by V/Q mismatch is typi-
fatigue, poor-quality sleep, and snoring; these are com- cally responsive to oxygen therapy as inhalation of sup-
mon among patients with sleep-disordered breathing. plemental O2 raises the Po2, shown in Figure 11.29.24
TABLE 11.3 Hypoventilation Example: Data From a Hypothetical Patient With Spinal Cord Injury
Ventilation:
Volumes (mL) Volume × Rate (mL/min)
Respiratory
Rate Alveolar Alveolar
Variables (breaths/min) Tidal Dead Space Space Total Dead Space Space
Before injury 12 500 150 350 6,000 1,800 4,200
Immediately 12 200 150 50 2,400 1,800 600

after injury
Shortly after 30 200 150 50 6,000 4,500 1,500

injury
PO2 = 160
PCO2 = 0
PO2 = 40 PO2 = 40 PO2 = 40 PO2 = 40

PCO2 = 46 PCO2 = 46 PCO2 = 46 PCO2 = 46
PO2 = 100 PO2 = 100 PO2 = 55 PO2 = 100

PCO2 = 40 PCO2 = 40 PCO2 = 43 PCO2 = 40
PO2 = 100 PO2 = 81

PCO2 = 40 PCO2 = 42
. . . . . .
FIGURE 11.27 Arterial blood gases with ideal V/Q matching. FIGURE 11.28 Ventilation/perfusion ( V/Q) mismatch. V/Q mis-
All blood gas pressures are in units of mm Hg. Air entering match can be unevenly distributed in different lung regions. All
alveoli from the atmosphere continually replenishes alveolar blood gas pressures are in units of mm Hg. Here, the airway on
O2 and removes CO2. Blood flowing through alveolar capillaries the left is partially blocked, providing a region of low ventila-
initially has essentially the same gas composition of O2 and tion, whereas adjacent regions have normal ventilation. Blood
CO2 as mixed systemic venous blood, but equilibrates with flowing through the underventilated region is unable to pick up
alveolar air. Alveolar gas exchange results in the average blood sufficient O2 or remove sufficient
. . CO2. When mixed with blood
gas composition shown leaving the alveolar region to join the perfusing units with better V/Q matching, the resulting pulmo-
pulmonary veins, with Po2 = 100 and Pco2 = 40. If ventilation nary venous blood has lower O2 and higher CO2 than normal.
increases in rate or depth while perfusion stays the same, Po2
will rise and Pco2 will fall, with a corresponding change in blood
gases leaving the lungs. If ventilation decreases in rate or depth PO2 = 320
while perfusion stays the same, Po2 will fall and Pco2 will rise. PCO2 = 0
If both ventilation and perfusion change simultaneously and
in the same direction, there will be little effect on alveolar and
arterial blood gas levels.
Po2, partial pressure
. . of the oxygen; Pco2, partial pressure of PO2 = 40 PO2 = 40
carbon dioxide; V/Q ventilation/perfusion. PCO2 = 46 PCO2 = 46
PO2 = 100 PO2 = 200

Shunt
PCO2 = 43 PCO2 = 40
In the lungs, shunt . is. usually considered to be an
extreme degree of V/Q mismatch in which blood is
flowing by alveoli that are receiving no ventilation at
all (Figure 11.30). Shunted venous blood decreases
the arterial partial pressure of O2 when mixed with PO2 = 160
fully oxygenated blood leaving other well-ventilated PCO2 = 42
lung areas. As shunt represents areas where no gas
exchange occurs, such hypoxia cannot be treated with FIGURE 11.29 Oxygen administration improves oxygenation
100% inspired O2. In fact, a poor response to oxygen . .
in ventilation/perfusion ( V/Q) mismatch with regional hypo-
therapy is a hallmark feature that differentiates shunt ventilation. All blood gas pressures are in units of mm Hg.
from other mechanisms of hypoxemia. Clinically, if Increasing the fraction of inspired oxygen
. . (FIo2) generally
giving pure O2 at 100% for 5 to 10 minutes does not improves hypoxemia in patients with V/Q mismatch. The
improve arterial O2 levels, it is evidence that the defect effects on CO2 levels vary with the degree of regional
in hypoventilation, but CO2 and pH levels may remain relatively
. .the lung is due to a pulmonary shunt in contrast with
V/Q mismatch.24 normal due to stimulation of respiratory rate and depth by
As described next, a physiological response to regional CO2-sensitive central chemoreceptors.
hypoxia within the lung is constriction of the pulmonary
vasculature. This response is known as hypoxic vaso- matching toward normal. Without this hypoxic pulmo-
constriction, and it helps to compensate for areas of nary vasoconstriction, the effects of shunt and regional
shunt and regional hypoventilation by reducing blood . . hypoventilation would cause progressively greater
flow to the affected areas. This essentially improves V/Q hypoxemia. This principle is not able to compensate for
other situations of anatomical shunting; for example, the

type of shunting that occurs in infants with cyanotic con-
genital heart defects, allowing blood to bypass the lungs
and flow to the systemic circulation instead.
Diffusion Limitation
PO2 = 40 PO2 = 40
Diffusion limitation is a cause of hypoxemia in which PCO2 = 46 PCO2 = 46
O2 transport across the alveolar–capillary membrane is
impaired. Based on Fick’s law of diffusion, gas move- PO2 = 40 PO2 = 100
ment down a concentration gradient is dependent on PCO2 = 46 PCO2 = 40
the properties of the gas, the surface area and thick-
ness of the barrier to movement, and the magnitude of
the concentration gradient:
∆c
J ∝ − DA PO2 = 55
∆x PCO2 = 44
where
FIGURE 11.30 In shunt, one region of lung is receiving
J = the rate of movement of the gas, which is a no airflow at all, due to atelectasis, mucus plugging, or
negative value because it moves from higher flooding due to pneumonia or pulmonary edema. All blood
to lower concentration, thus decreasing the gas pressures are in units of mm Hg. Blood flowing through
amount on the side with higher concentration these lung regions has no addition of O2 or removal of CO2,
from which there is net loss creating more severe hypoxemia and hypercapnia of the
D = the diffusing constant of the molecule that mixed pulmonary venous blood. Oxygen administration is
reflects the unique properties making it easier ineffective at improving blood gases, as inspired air can never
or harder to move through a barrier reach the affected regions.
A = the surface area for diffusion, maximized in the
lungs by the millions of alveoli reduced in emphysema, severe fibrotic lung disease,
∆c = the concentration difference across the barrier and pulmonary hypertension. Although diffusion lim-
∆x = the thickness of the barrier, optimized in the itation can result in hypoxemia, normally it is rare in
lungs by the thin layers of alveolar epithelium, humans at rest. It is more common in individuals with
minimal extracellular matrix, limited intersti- interstitial lung disease, particularly when they attempt
tial fluid, and endothelial cells making up the to increase physical activity. As O2 demands increase,
alveolar–capillary walls respiratory rate and heart rate increase to optimize O2
delivery. However, this also decreases transit time for
Diffusion limitation has several potential mechanisms red blood cells in the alveolar capillaries, and O2 trans-
and causes. Decreased surface area can occur with fer cannot be completed before the blood leaves the
capillary. Diffusion limitation responds well to supple-
• Alveolar loss as in emphysema mental O2. As oxygen therapy raises the alveolar Po2,
• Removal of all or part of a lung for cancer surgery the partial pressure difference across the membrane
• Atelectasis (complete alveolar collapse) barrier increases and promotes greater diffusion rate,
• Complete alveolar flooding due to pulmonary edema as predicted by the Fick equation.
or inflammatory fluid in pneumonia
Thickness of the alveolar–capillary interface may

increase due to Thought Questions
• Fibroblast accumulation and collagen deposition 8. Describe the path of an O2 molecule entering the
due to idiopathic pulmonary fibrosis nose, traveling down the airways to an alveolus,
• Fluid accumulation along the alveolar walls in early and traveling in a blood cell for delivery to the
pulmonary edema or pneumonia tissues. What factors influence that path and the
ease of oxygen movement at each transition?
Diffusing capacity of the lung is measured during pul-
monary function testing, usually by giving a single 9. What causes of hypoxemia can be treated
breath of carbon monoxide and measuring its uptake. simply with supplemental O2? How do those
The result is reported as DLCO (diffusing capacity of the causes compare with hypoxemia treatment that
lung for carbon monoxide). This measurement can be requires other measures?
normal in asthma and chronic bronchitis, and is usually
resistance rises, creating secondary pulmonary hyper-

LUNG VASCULAR CONSIDERATIONS tension. Elevated pulmonary artery pressures increase
afterload on the right ventricle, which ultimately
The pulmonary circulation provides lung perfusion
responds by developing right ventricular hypertro-
that eliminates CO2 produced by tissue metabolism and
phy and, in many cases, right-sided heart failure.
provides O2 for tissue metabolism. It is astonishing to
Enlargement of the heart secondary to chronic lung
realize that the lungs, weighing about 850 g, receive the
disease with pulmonary hypertension is termed cor
entire output of the right side of the heart, with a flow
pulmonale. Obstructive and restrictive lung diseases
rate averaging 5 L/min. This cardiac output is equal to
commonly associated with the development of cor
that pumped by the left side of the heart through the
pulmonale are COPD, CF, kyphoscoliosis, sarcoidosis,
rest of the body! The blood vessels of the lungs branch
interstitial pulmonary fibrosis, obesity hypoventilation
extensively, ending in dense plexuses of capillaries that
syndrome, and sleep apnea syndrome.26 Primary pul-
surround each alveolus. Deoxygenated blood is ejected
monary hypertension, discussed later in this section,
by the right ventricle into the pulmonary arteries, even-
is highly associated with cor pulmonale. The progres-
tually reaching the pulmonary capillary beds where
sion to right-sided heart failure favors development
gas exchange occurs. Oxygenated blood then returns
of increased systemic venous pressures and can pre-
to the left atrium via pulmonary veins. Pulmonary vas-
cipitate left-sided heart failure as well. Treatments for
cular resistance is substantially lower than systemic
the underlying lung condition (β2-receptor agonists,
resistance, so pulmonary vascular pressures are much
inhaled corticosteroids to reduce airway inflamma-
lower than systemic vascular pressures, despite receiv-
tion) are administered to improve lung oxygenation
ing an equal cardiac output. Mean pulmonary artery
and relieve hypoxic bronchoconstriction. Other treat-
pressure averages 15 to 20 mm Hg in adults younger
ments can include diuretics, directed to the fluid-
than 50 years.25 Owing to lower pressures, gravity has
retaining aspects of heart failure.
a substantial effect on blood flow distribution from
the top to the bottom of the lungs, with the smallest
amount of blood flow reaching the apex of each lung, PULMONARY EMBOLISM
and the greatest amount of flow to the bases when in
Pulmonary embolism (PE) occurs when a clot or
the upright posture.
other particulate matter moves from the systemic
In addition to gravity, lung blood flow is modified
veins into the pulmonary circulation, causing vascu-
by local tissue Po2. As previously noted, optimal oxy-
lar obstruction. The result is a focal loss of pulmonary
genation is achieved when blood flow (perfusion)
blood flow distal to the blockage. Potential causes of
matches ventilation at each level of the lung. A vas-
PE include thromboembolism, fat, air, amniotic fluid,
cular adaptation to lung regions that are hypoxic due
tumor cells, and septic emboli related to bacteremia.
to poor ventilation is vasoconstriction. This hypoxic
Venous thromboembolism due to deep vein throm-
vasoconstriction limits blood flow to poorly ventilated
bosis is the most common cause of PE, accounting
alveoli and maximizes blood flow to well-ventilated
for 90% of cases. There are an estimated 500,000 to
alveoli.
600,000 cases of PE each year in the United States,
Although this mechanism is protective in patients
resulting in 100,000 deaths.27 Risk factors related to
with limited, focal areas of consolidation, it is prob-
venous thromboembolism are described in Chapter 8,
lematic in patients with progressive, generalized lung
Blood and Clotting, so this section focuses on the
disease. In such disorders, widespread hypoxia and
consequences of PE for function of the lungs and
hypoxic vasoconstriction may be present, leading to
right side of the heart.
chronic elevations in pulmonary arterial pressures,
PE is subdivided clinically with respect to ana-
termed pulmonary arterial hypertension. Increased
tomical location and presence or absence of hemo-
pressures in the pulmonary vasculature damage vessel
dynamic stability. Depending on the size of a clot,
integrity, stress the heart, and spill over into negative
blood fl ow may be blocked to a lung subsegment,
effects on the systemic circulation that empties into the
segment, lobe, or the whole lung. Very large clots
right side of the heart.
called saddle emboli may lodge at or near the bifur-
cation of right and left pulmonary arteries; patients
CARDIAC CONSEQUENCES OF with these clots have a 5% mortality rate. The greater
PULMONARY DISEASE the degree of vessel occlusion, the more likely it is
Diffuse lung diseases with low levels of ventilation that the right side of the heart will be unable to pump
throughout the lungs have the greatest potential for effectively against the increased vascular resistance
damaging the right side of the heart. As the lungs and the left side of the heart will receive inadequate
become generally hypoxic, pulmonary vascular fi lling, resulting in systemic hypotension. Recent
clinical guidelines include the following stratified hydrostatic pressure. Although acute decompensated
definitions of PE: heart failure is the most common cause of pulmo-
nary edema, additional causes of edema include vol-
• Massive PE, characterized as persistent hypotension ume overload secondary to blood transfusion, severe
lasting more than 15 minutes or necessitating ino- hypertension, renal artery stenosis, and severe renal
tropic support, with systolic blood pressure <90 mm disease in patients with no evidence of heart d isease.
Hg, heart rate <40 beats/min, or absence of pulse Transfusion-associated circulatory overload
• Submassive PE without hypotension, but with right (TACO) is a form of volume overload related directly to
ventricular dysfunction based on pulmonary angiog- the amount of volume administered during transfusion
raphy, transthoracic echocardiogram, or biomarker of blood products.
elevation (brain natriuretic peptide, troponin) Noncardiogenic pulmonary edema is classified
• Low-risk PE without hypotension or right ventricu- based on the radiographic evidence of fluid accumula-
lar dysfunction tion without clinical evidence of a cardiac cause. The
most common cause is acute respiratory distress
The lung region affected by the embolism will syndrome (ARDS), which is caused by damage to the
receive no perfusion, but will still continue to be ven- alveolar–capillary membrane that greatly increases
tilated. This constitutes additional dead space, and if alveolar–capillary permeability, alters normal alveo-
enough lung tissue is affected, it will lead to hypoxia lar osmotic balance, and promotes capillary filtration
and consequently tachypnea to compensate. The typi- at any level of Starling force imbalance. The lung lym-
cal patient presentation includes dyspnea, which may phatic system normally clears fluid that leaks out of
be accompanied by chest pain, cough, and hemoptysis. alveolar capillaries, but in ARDS, the rate of capillary
Diagnosis of PE can be difficult and is typically done via filtration overwhelms the capacity of lung lymphatics
imaging (CT angiogram, chest radiograph, and echo- to remove the edema fluid. Disease processes most
cardiogram). Treatment modalities include anticoag- likely to precipitate ARDS are (in descending order
ulation, hemodynamic stabilization, catheter-directed of prevalence) sepsis, pneumonia, aspiration, trauma,
administration of thrombolytics, and thrombectomy.28 transfusion, pancreatitis, and drug overdose.29
The pathological changes contributing to pul-
PULMONARY EDEMA monary edema in ARDS begin with an escalating
inflammatory response that is promoted by alveolar
Pulmonary edema is defined as the accumulation of
macrophage cytokine production. Neutrophils are
fluid in the alveoli. Pulmonary edema can be due to
recruited into alveoli and become activated, releas-
cardiac or noncardiac causes. An excess of filtration
ing proteases and reactive oxygen species that dam-
over reabsorption by alveolar capillaries can be due
age both the primary alveolar epithelial cells (type
to alterations in the capillary Starling forces (capillary
1 cells) and type 2 cells that manufacture surfactant
hydrostatic pressure, capillary oncotic pressure, tissue
(Figure 11.31). The inflammatory cascade promotes
hydrostatic pressure, tissue oncotic pressure), as noted
alveolar–capillary permeability, favoring filtration
in Chapter 9, Circulation. Pulmonary edema occurs

of fluid into the narrow interstitial space around the
in three distinct stages, based on the degree of fluid
alveoli, while loss of type 1 alveolar cells leaves gaps
accumulation:
that allow edema fluid to enter and flood the alveoli.
Surfactant production stops, increasing alveolar sur-
• During stage 1, fluid moves from the capillaries into face tension and promoting collapse. As the numbers
the interstitial space but is still able to be removed
of collapsed and fluid-filled alveoli increase, there is
via lymphatic drainage.
increasing shunt, producing severe hypoxemia despite
• Stage 2 is characterized by maximum lymphatic
O2 administration.30 Estimates of ARDS mortality rate
drainage and increased fluid accumulation in the
range from 35% to 46%, depending on severity and
interstitial space, creating crescentic filling along
patient characteristics.29
the alveolar margins.
• Flooding of the alveoli occurs in stage 3, with fill-
ing of the air space and disruption of the alveolar PULMONARY HYPERTENSION
membrane. Pulmonary hypertension—defined as the mean pul-
monary artery pressure >25 mm Hg and pulmonary
Cardiogenic pulmonary edema secondary to heart capillary wedge pressure <15 mm Hg31—is a complex
failure or other cardiac pathology is associated with disorder having five major subdivisions and many
protein-poor fluid accumulation in the alveoli. The causes. Common causes are left-sided heart failure
increased capillary filtration is caused by an increase (although typically that is associated with increased
in left ventricular filling pressures and left atrial pulmonary capillary wedge pressure) and chronic lung
pressures, ultimately increasing alveolar capillary disease with hypoxic vasoconstriction, as described
Normal ARDS
Bronchiole
epithelium
NET
Damage/death of type 1 AEC,

type 2 AEC increases alveolar
Surfactant permeability
layer
Fibroblast
Type 2
AEC Alveolar
macrophage
Type I Neutrophil
AEC
Edema fluid
enters interstitium
and alveolus
CEC
Surfactant layer
lost
Neutrophil Endothelial permeability
FIGURE 11.31 ARDS produces pulmonary edema due to macrophage and neutrophil recruitment
and activation that greatly increase alveolar capillary permeability and damage type 1 and type 2
AECs. Loss of surfactant contributes to alveolar flooding and atelectasis.
AECs, alveolar epithelial cells; ARDS, acute respiratory distress syndrome; CEC, capillary
endothelial cell; NET, neutrophil extracellular trap.
earlier. A detailed discussion of other forms of pulmo- production. Prostacyclin may be administered intra-
nary hypertension is beyond the scope of this chapter, venously, and prostacyclin-related drugs are avail-
but it is useful to describe the pathophysiology of idio- able in oral and inhaled forms. Endothelin-1 (ET-1)
pathic pulmonary hypertension (IPH). is a potent vasoconstrictor, and its action is blocked
IPH is a rare disorder of the small muscular arter- by ET-1 receptor antagonists. These are currently
ies in the pulmonary circulation. Resistance increases the most commonly used management approaches
as the smooth muscle layer of the blood vessels and have a common endpoint of increasing vasodila-
become thickened, for reasons that are still unknown. tion and lowering pulmonary pressures.32 The patho-
Additional pathological findings can include intimal physiology of pulmonary hypertension, along with its
thickening and complex lesions of both arteries and management, is an important example of the interde-
arterioles. Early symptoms include dyspnea on exer- pendence of cardiovascular and lung function.
tion, chest pain, tachycardia, fatigue, and decreased
appetite. Later symptoms may include fainting, lower
extremity edema, and cyanosis. Thought Questions
Management of IPH is based on the pharmacol-
ogy of vascular smooth muscle (VSM) constriction.
Nitric oxide and prostacyclins are potent vasodila-
10. What is the major mechanism differentiating
heart failure–associated pulmonary edema
tors, inhibit platelet activation, and are antiprolifer-
and ARDS?
ative. Nitric oxide activates vascular smooth muscle
cyclic guanosine monophosphate (cGMP) production, 11. What is the effect of a relatively large
producing vasodilation. Phosphodiesterase-5 (PDE-5) pulmonary embolism on lung ventilation/
inhibitors decrease degradation of cGMP, whereas perfusion relationships?
guanylyl cyclase stimulators directly increase cGMP
PEDIATRIC CONSIDERATIONS
Randall L. Johnson
LUNG DEVELOPMENT stronger than those of the intercostal muscles, so as the

diaphragm moves down, making the pleural pressure
During embryonic development, the trachea and more negative, the chest wall moves inward, rather than
esophagus are divisions of the foregut that soon outward. This is referred to as paradoxical movement.
diverge. The primordial trachea and lung buds begin The diameter of the peripheral airways is much smaller
to differentiate and later develop into the bronchial than that of adult airways until 5 years of age, when air-
tree. Airway branching continues during fetal develop- way diameter begins to increase and airway resistance
ment, and all airway generations are present by about decreases. For this reason, children younger than 5 years
25 weeks of gestation. Maturation of type 1 and type 2 old have more airway resistance in small airways and
alveolar epithelial cells at this time contributes to the have greater respiratory difficulties with small airway dis-
beginning of airway surfactant production. Formation eases such as bronchiolitis, as well as greater vulnerability
and expansion of the gas exchange surface area begin to airway obstruction due to inhaled small objects such as
before birth and grow through childhood in the process nuts, candies, and toys.35
of alveolarization. Pulmonary vascular development
parallels alveolar development, with the alveolar cap-
illary bed continuously developing during childhood33
(Figure 11.32). Fetal and early life influences on lung RESPIRATORY PROBLEMS ASSOCIATED
health can have lasting effects on vulnerability to con- WITH PRETERM BIRTH
ditions such as asthma, pulmonary fibrosis, and other
chronic lung conditions.34 Premature birth is associated with a variety of respi-
Relative to adults, infants and children have significant ratory problems that are most severe in those with the
differences in lung structure and function. Respiratory greatest prematurity. As noted, surfactant production
rate is high at birth (averaging about 40 breaths/min), begins between 25 and 26 weeks, so very premature
decreasing throughout childhood to approximate adult infants may develop neonatal respiratory distress
rates during the teen years. In early childhood, elastin syn- syndrome and require administration of exogenous
thesis is just beginning, so there is reduced elastic recoil, surfactant, as well as oxygen and CPAP or mechanical
less airway support, and greater tendency to develop air- ventilation. Of infants born at or before 28 weeks of
way collapse. The chest wall is more flexible and com- gestational age, about 40% go on to develop broncho-
pliant in young children. Diaphragmatic contractions are pulmonary dysplasia (BPD).
Birth and
Embryonic period Fetal period postnatal
growth
38 weeks
3–6 weeks 7–17 weeks 17–27 weeks 27–36 weeks
to 8 years
Embryonic Pseudoglandular Canalicular Saccular Alveolar
* → Formation of lung bud * → Branching of * → Formation of * → Formation of * → Formation of
* → Differentiation into bronchial tree lung periphery alveolar saccules mature alveoli
trachea and bronchi * → Formation of * → Increased * → Detectable surfactant * → Proliferation
respiratory parenchyma vascularization in amniotic fluid and expansion
* → Type II pneumocytes * → Type 1 pneumocytes
appear appear
* → Air–blood
interface formed
FIGURE 11.32 Milestones of prenatal lung development. Note that surfactant production does not
begin until 25 to 27 weeks, after which the level of surfactant production increases in parallel with
alveolar saccule formation. Formation of alveoli begins late, at 36 weeks, and continues after birth.
Source: From Hameed A, Sherkheli MA, Hussain A, Ul-haq R. Molecular and physiological determinants
of pulmonary developmental biology: a review. Am J Biomed Res. 2013;1(1):13–24. https://doi.
org/10.12691/ajbr-1-1-3.
416
Understanding of the pathology of BPD has evolved incomplete, so an individual may have more than one
over the years since it was first described in the 1960s. RSV infection, and there is currently no RSV vaccine.
At that time, infants with neonatal respiratory distress Laboratory pathogen identification is by rapid antigen
syndrome were treated with positive pressure ventilation testing or nucleic acid amplification.
and relatively high O2 pressures, resulting in subsequent Bronchiolitis is diagnosed by history and physical
lung damage with marked fibrosis. As the standard of examination, based on a history of symptoms of upper
care has evolved to focus on surfactant treatment and respiratory infection (rhinorrhea, fever) followed
protective ventilation, including CPAP, BPD is becoming by development of increased respiratory effort and
less common in infants born after 32 weeks of gestational wheezing. Tissues around the bronchioles are swollen
age, whereas it remains common in infants born sooner, with white blood cells and inflammatory secretions,
at 26 to 28 weeks of gestational age. This “new” BPD is obstructing the small, delicate airways. Thus, the main
associated with the development of abnormally large and airflow defect in bronchiolitis is obstructive, with air
simplified alveoli, altered pulmonary capillary develop- trapping and atelectasis. Nutrition suffers as infants are
ment, and some interstitial fibroproliferative changes. unable to feed normally. Care is supportive, and usually
BPD is graded as mild, moderate, or severe, depending only brief hospitalizations are needed, with recovery
on gestational age at birth, oxygen dependency, and need in about 2 weeks. Preexisting conditions such as BPD,
for pressure-assisted ventilation. As previously noted, congenital heart disease, and family history of asthma
alveoli are developing both before and after term birth; or smoking all are associated with greater risk of bron-
thus, extremely premature birth disrupts that process chiolitis infection. Bronchiolitis in early life can also be
much earlier in alveolar development. Exposure before a risk factor for later development of asthma, particu-
birth to stressors such as intrauterine growth retarda- larly in those with a family history of asthma.38
tion, steroid treatments, and infections can initiate the
lung damage of BPD. After premature birth, exposures
to ventilator-induced lung injury, oxidative stress, steroid CHILDHOOD ASTHMA
treatments, infections, fluid overload, and nutritional
deficits all can produce lung injury and prevent normal Asthma is a common childhood illness; in the United
lung development. Long-term outcomes of BPD include States one in 12 children from birth to 17 years had
greater risk for other lung disorders such as severe lung asthma in 2016. Of these children, asthma is seen more
infections, reactive airway disease and asthma, and frequently in boys, non-Hispanic black children, Puerto
impaired physical and neurological development.36,37 Rican children, and children from lower-income house-
holds. Although asthma prevalence is high, the number
of asthma attacks per year decreased significantly from
LUNG CONCERNS IN INFANCY 2001 to 2016. This may be attributed to the finding that
50.8% of children with asthma had an asthma action
Growth of the lungs and supporting structures during plan that included education about asthma and early
early infancy and into adolescence provides the capacity interventions.39

for full recovery from lung injuries in early life.33 Within As previously noted, many cases of asthma result from
the first year of life, respiratory infections are the most allergy associated with IgE production. Although this is
common lung insult because of the relative immaturity true for children older than 5 years of age, below that
of the immune system. Viral infections are the most com- age infections are the most common causes of asthma.
mon, particularly in younger children in daycare settings. Other nonallergic causes of asthma in children from
Respiratory syncytial virus (RSV) is the most com- birth to 4 years are drug sensitivity to aspirin and other
mon cause of pneumonia and bronchiolitis in infants. nonsteroidal antiinflammatory drugs and environmental
The pathophysiology of RSV infection involves the irritants such as air-polluting particulates, smoke, and
surface expression of fusion proteins that cause host cold air. Neutrophils are the main airway white blood
cells to cluster, forming giant cells that lose normal cell in nonallergic asthma. Rates of wheezing are high,
function. Severe cases cause respiratory failure requir- probably due to the fact that airways are smaller and
ing hospitalization, and the virus is highly contagious, more easily obstructed in children. Bronchial smooth
requiring careful precautions to prevent spread to muscle may develop hypertrophy and hyperreactivity,
other hospitalized infants. Older children and adults as in adults. Although recurrent RSV infections may
generally develop colds from RSV, rather than lower trigger asthma and airway obstruction, they may also
respiratory infections. Another point of vulnerability strengthen Th1 lymphocyte responses and ultimately
comes at the end of life: Older adults and adults with reduce the incidence of allergic asthma. Treatment of
chronic diseases may also develop lower respiratory asthma in children is similar to that in adults, with par-
infections and pneumonia from RSV. Although some ticular emphasis on an asthma action plan that involves
adaptive immunity is stimulated by RSV infection, it is parents and school nurses as well as the child.40
GERONTOLOGICAL CONSIDERATIONS
Ingrid Deming and Alison Fife
Respiratory changes in older adults include greater vul- aging is usually little change in TLC, accompanied by a
nerability to lung disease and decreased lung capacity decrease in VC.
(functional reserve) to adapt to challenges such as exer- Decreased elastic recoil and structural airway sup-
cise, altitude, and disease processes. Sustaining a life- port contributes to a modest but progressive decline
time of insults arriving with the inhaled air takes its toll in airway patency. This is manifested as an increase in
in terms of oxidative stress, smoking, occupational and alveolar units that are distal to blocked airways, increas-
other environmental exposures, and sporadic respiratory ing RV and decreasing surface area for gas exchange.
infections. Advancing age is associated with progressive FEV1 is reduced and the expiratory flow/volume curve
changes to the structures of the lungs and the chest wall assumes more of the convex “scooped out” appear-
that alter compliance, resistance, gas exchange, and neu- ance associated with obstructive disorders (see Figure
ral control. In addition, prevalence of many chronic and 11.21). With increased air trapping, FRC also increases
acute lung disorders—including COPD, pulmonary fibro- and FVC decreases. FEV1 decreases to a greater extent
sis, and pneumonia—increases with advancing age. than FVC, so the FEV1/FVC ratio decreases with aging,
Alveolar changes with aging are similar to those consistent with a modest obstructive defect. Loss
observed in emphysema, but without the inflammatory of alveolar surface area also changes the area of gas
infiltrate and elastin destruction. Pertinent age-related exchange, which decreases with aging and limits the
changes include increased alveolar size and modestly overall diffusing capacity of the lungs.40 Structural and
reduced alveolar elastic recoil. Increased lung compli- functional alterations in the pulmonary system with
ance means that the chest wall can exert greater pull aging are summarized in Box 11.3 and Table 11.4.
in the outward direction, resulting in air space enlarge- There are moderate decreases in respiratory muscle
ment and greater TLC. Contrasting with the lung tissue’s strength with aging, but it appears that in healthy older
greater compliance, the chest wall becomes stiffer with adults the continuous activity of breathing maintains a
aging from the calcification of the ribs and ossification good degree of overall respiratory muscle function. Age-
of cartilage. This causes a stiffening of the thoracic related calcification and stiffening of the chest wall, ribs,
cavity and inhibits the ability for expansion during and muscles, and kyphosis, may prevent full lung expan-
inspiration. These changes, along with vertebral distor- sion with inspiration (because of decreased chest wall
tion by kyphosis, can increase the anterior–posterior compliance), altering the curvature of the diaphragm,
diameter, producing a characteristic barrel-shaped thereby inhibiting the diaphragm from having an optimal
thorax. Decreased muscle strength and increased force of contraction. The pulmonary system may func-
chest stiffness promote an overall decrease in TLC, tion normally at rest but may be impaired in its ability to
whereas the loss of elastic recoil and alveolar enlarge- increase rate and depth of breathing to enable increased
ment promote increased TLC. The result in healthy physical activity. Some of these structural changes can
BOX 11.3
Normal Age-Related Pulmonary Physiological Changes in Older Adults
Loss of lung elastic recoil, increased airway resistance → Decreased expiratory flow
Premature airway closure → Reduced functional alveolar surface area

Reduced gas exchange
Calcification of ribs and ossification of cartilage → Increased chest anterior–posterior diameter

Flattened diaphragm
Decreased overall pulmonary compliance
Muscle atrophy/sarcopenia → Decreased strength of diaphragm, intercostal muscles,

and accessory muscles
Decreased endurance and exercise tolerance
418
TABLE 11.4 Age-Related Changes in Pulmonary Function Tests

Pulmonary Function Parameter Changes With Age Mechanisms, Observations
FRC Increase Premature airway closure, air trapping
RV Increase Premature airway closure, air trapping
TLC Unchanged
Lung compliance Increase Alveoli and airway increase in diameter
FEV1 Decrease Peaks around 20–36 years old and declines with age
FVC Decrease Declines later in life and at slower rate than FEV1
Lung dif fusing capacity Decrease Loss of alveolar surface area
Diaphragm strength Decreased 13% decrease in older adults
FEV1, volume of expired air in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.
also impair the ability to efficiently expectorate and clear serum leukocyte count, and mental status changes such
the airways during an acute or chronic infection.41,42 as acute confusion. Treatment includes appropriate anti-
Neural control of breathing is somewhat impaired biotic selection. The most common organism in aspira-
with aging, with decreased responsiveness to chemore- tion pneumonia is Pseudomonas aeruginosa.
ceptor activity signaling either hypoxemia or hypercap-
nia. Older adults are more likely to describe dyspnea at
rest and particularly with exertion. CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (CHRONIC BRONCHITIS
AND EMPHYSEMA)
PNEUMONIA
As noted earlier in the chapter, chronic obstructive
A more detailed discussion of pneumonia in older pulmonary disease (COPD) encompasses both chronic
adults appears in Chapter 5, Infectious Disease. Here, it bronchitis and emphysema, and refers to conditions with
is important to note that age-related changes in upper a resistance to airflow at any level by a partial or com-
airway tone, control, and cough and swallowing reflexes plete obstruction. The disease is common in older adults,
lead to increased frequency and severity of aspiration, particularly those with a history of smoking.44 The chem-
and subsequently aspiration pneumonia, with age. Lung icals and particles inhaled with smoking cause lung cell
factors contributing to the greater incidence of pneu- damage and chronic inflammation.
monia in older adults include decreased effectiveness of Although aging does not directly affect the under-
cough and mucociliary clearance, decreased secretory lying pathophysiology of COPD, the presentation in
IgA in airways, and decreased chest compliance and older adults may be complicated by some of the pre-
respiratory muscle strength.43 In addition, the present- viously described changes (e.g., diaphragmatic and
ing signs and symptoms of pneumonia may be blunted accessory muscle atrophy, ossification and calcifi-
or altered in older adults, obscuring the diagnosis. Above cation of ribs, loss of alveolar elastic recoil). As life
all, in clinical practice, it is important to reinforce the expectancy increases, the number of older adults
available vaccines for pneumococcal pneumonia and with chronic bronchitis also increases, and a lower
influenza, as these infections are the common causes of threshold for impaired lung function makes them
community-acquired pneumonia in older adults. more prone to exacerbations. These exacerbations
Older adults at risk for aspiration include those who can be significantly worse, especially in patients who
are immobile or have alterations in posture (cervical continue to smoke or those exposed to environmental
hyperextension due to degenerative spine disease) or toxins. COPD may progress faster in older adults due
neuromuscular conditions. Additionally, older adults to physical deconditioning, decreased mobility, frag-
with dysphagia secondary to a new or previous stroke ile state, and immobility. These conditions, superim-
and poor oral health or dentition are also at risk. Clinical posed on the damage and chronic inflammation of the
manifestations of aspiration pneumonia appear within 24 lung parenchyma and loss of ciliary protection, place
to 48 hours after aspiration and include dyspnea, fever, older adults at an even greater increased risk of air-
tachycardia, decreased oxygen saturation, increased way infections.
CASE STUDY 11.1: A Child With Asthma
Stephanie L. Carper
Patient Complaint: An 8-year-old boy reports: “I Physical Examination: Findings are as follows:
had a runny nose and it felt like it was harder to temperature of 99.0°F, blood pressure of
take a breath 2 days ago, then yesterday I started 105/78 mm Hg, heart rate of 100 beats/min,
coughing.” His father adds, “My son has asthma, respirations of 36 breaths/min. O2 saturation is 93%
and he’s been coughing almost nonstop for the on room air. The patient is alert, afebrile, and well
last day. He brings up yellowish stuff most of the appearing. On examination, his skin is warm and
time, and I can hear him wheezing when he takes dry, with no lesions. Head is normocephalic and
a breath.” atraumatic. Sclerae and conjunctivae are clear, with
no active discharge; pupils are equal, round, and
History of Present illness: The patient is an 8-year- reactive to light and accommodation (PERRLA),
old boy who came to the clinic today with his father and extraocular movements are intact. Nasal cavity
because of respiratory symptoms. As reported by has a scant amount of clear rhinorrhea. Oral cavity
the child and his father, he has been afebrile, with no has moist mucous membranes, pharynx without
sore throat, chills, rash, abdominal pain, vomiting, injection, and no tonsillar hypertrophy or exudative
or diarrhea. He has had slightly decreased food and tonsils. The neck and upper extremity examination
fluid intake, but normal urine output. The boy and is normal. Lung examination reveals diffuse
father both feel that his respiratory symptoms are inspiratory and expiratory wheezes throughout,
worsening, and he stayed home from school today. positive tachypnea, and mild subcostal retractions.
The boy had been previously diagnosed with asthma Heart rate and rhythm are regular, S1 and S2 are
and his medications include daily fluticasone and present, and there are no murmurs. Abdomen
(as needed) albuterol. Over the last 24 hours, the is soft, nontender, and nondistended, with no
boy has been taking fluticasone as directed, and has hepatosplenomegaly. Lower extremities show full
been requiring albuterol every 4 hours for cough. range of motion. On neurological exam, the patient
His last dose of albuterol was 3 hours ago. The is alert and oriented appropriately for age and
father states that his son has asthma exacerbations development, and cranial nerves II to XII are intact,
with cold weather, strenuous physical activity, and with normal tone for developmental age and normal
illness, most notably upper respiratory infections. gait for development.
Review of Systems, Past Medical/Social History: The Additional Testing: Peak flow by handheld meter is
patient has moderate, persistent asthma that is reduced from previous visits; no other laboratory
currently being treated with fluticasone (44 mcg, tests are indicated in this case (stable asthma with a
two puffs twice daily via metered dose inhaler [MDI] superimposed respiratory infection).
with spacer, daily) and albuterol (90 mcg/actuation,
two puffs via MDI with spacer, every 4 hours, as CASE STUDY 11.1 THOUGHT QUESTIONS
needed). His father reports that his son is a curious • What factors contribute to decreased peak flow
and active child who has no health issues other in the context of a respiratory infection in a
than asthma. The patient is a second grader at a patient with chronic asthma?
nearby elementary school. He lives at home with his • What environmental factors in the home should
mother, father, two sisters, brother, and dog. be assessed in a child who has chronic asthma?
CASE STUDY 11.2: A Patient With Chronic Bronchitis
Linda W. Good
Chief Complaint: “I just can’t catch my breath influenza. He has had allergic rhinitis symptoms in
sometimes for all the coughing fi ts these last the spring and fall. He stopped smoking 6 months
4 months. I’m tired all the time because I wake ago after smoking a pack of cigarettes a day from
up at night coughing. I have trouble getting age 17, and has had work-related exposure to paint
through my workday as a painter because I’m fumes for almost 40 years.
exhausted. My work mates call me ‘old man’
Physical Examination: Findings are as follows:
even though I’m only 57. I stopped smoking 6
temperature of 98°F, blood pressure of
months ago and this is the thanks I get. I got this
150/85 mm Hg, heart rate of 88 beats/min, and
albuterol inhaler from the urgent care doctor
respirations of 20 breaths/min. Body mass index
and it’s worthless.”
(BMI) is 32 kg/m2. Throat exam revealed a red
History of Present Illness/Review of Systems: The oral pharynx with cobblestoning on the posterior
primary care provider observes an anxious man pharyngeal wall. Sinuses are nontender and nasal
appearing slightly older than his stated age, speaking turbinates are not enlarged. There is no cervical
in full sentences without laboring to breathe. The adenopathy or thyroid hypertrophy. Heart tones
interview is disrupted by several paroxysms of are slightly muffled but regular in rate and rhythm,
coughing that produce clear mucus. The patient without murmur or gallop. Lung fields are clear
comments that he has tried over-the-counter with symmetrical, slightly coarse breath sounds
remedies, including dextromethorphan, guanfacine, and no wheezes, rhonchi, or rales. When asked to
pseudoephedrine, and diphenhydramine. In addition, accentuate his exhalation, the patient develops a
he used various home remedies including hot tea prolonged coughing paroxysm and appears to have
and honey, cough drops, and gargles. He also stated difficulty catching his breath.
that he had a previous prolonged coughing episode
Additional Testing: Laboratory tests are normal
1 year ago that eventually was treated with several
except for an elevated eosinophil count in the
courses of antibiotics, which did not seem to help,
white blood cell differential. Chest radiograph is
but he gradually improved with codeine cough
within normal limits. Spirometry is significant for
syrup. The patient denies chest pains, palpitations,
mildly reduced FEV1, but otherwise normal flows
orthopnea, fevers, discolored sputum, wheezing, and
and volumes.
hemoptysis. He admits to gradually reduced exercise
tolerance, some achy chest tightness especially after
CASE STUDY 11.1 THOUGHT QUESTIONS
coughing spells, and low mood.
• What risk factors for chronic bronchitis does
Past Medical History: The patient states that he has this patient have?
sinus infections two to three times per year, and • What is the pathogenesis of chronic bronchitis
had one episode of pneumonia associated with in a patient with a smoking history?
FEV1, forced expiratory volume in 1 second.
BRIDGE TO CLINICAL PRACTICE
Ben Cocchiaro
PRINCIPLES OF ASSESSMENT visualizes the endobronchial tree and allows for
both bronchial and transbronchial biopsies to
History and Physical Examination
be obtained.
• Dyspnea: Ask about duration, triggers, co-occurring
symptoms, and functional limitations imposed by Laboratory Evaluation
shortness of breath. • Thoracentesis: This invasive procedure is used
• Cough: Note the duration of any cough, pres- to remove fluid from the intrapleural space.
ence of sputum, and any acute changes in spu- Laboratory evaluation of extracted fluid can
tum color. Ask about hemoptysis and clarify its differentiate malignant, infectious, and cardiac
amount and appearance. Examine the posterior causes.
oropharynx for signs of cobblestoning or postna- • D-dimer: This sensitive though nonspecific quan-
sal drip, which might indicate a diagnosis of upper titation of fibrin degradation products occasion-
airway cough syndrome. ally is used to rule out deep vein thrombosis and
• Physical appearance: Look for digital clubbing, pulmonary embolism when pretest probability
pallor, cyanosis, nicotine stains on the teeth or is low.
fingernails, use of accessory respiratory muscles, • Sputum culture: This test is used in the diagno-
tracheal deviation, jugular venous distention, sis of hospital-acquired lower respiratory tract
and large neck circumference. infections. Normal respiratory flora is often a
• Auscultation: Breath sounds are best auscultated contaminant, making diagnosis by culture of
in the posterior intercostal spaces over the api- expectorated sputum difficult unless samples are
ces, superior and inferior lobes, and the lung obtained by bronchoscopy.
bases. Unilateral inspiratory rales or crackles
MAJOR DRUG CLASSES AND THERAPEUTIC
may indicate pneumonia, whereas similar sounds
MODALITIES
found at both lung bases could indicate pulmo-
• Steroids: Both oral (e.g., prednisone) and inhaled
nary edema and fluid overload.
(e.g., fluticasone, mometasone) steroid prepara-
Diagnostic Tools tions are used in the treatment of inflammatory
• Spo2 (oxygen saturation): This test is an inexpen- lung conditions. Inhaled corticosteroids are
sive proxy for oxygenation. Notable shortcom- preferred due to the adverse effects associated
ings include failure to account for hypercapnia, with systemic corticosteroid therapy.
inability to distinguish between oxygen and car- • Bronchodilators: These medications include
bon monoxide hemoglobin binding, and limited long-acting (e.g., formoterol) and short-acting
correlation with arterial Po2. (e.g., albuterol) β-receptor agonists as well as

• PFTs: These tests include spirometry, which anticholinergic agents (e.g., tiotropium, ipratro-
measures respiratory flow loops, differentiating pium). They are mainstays in treating asthma and
obstructive lung diseases such as asthma and COPD, and are often administered in combina-
COPD from restrictive conditions such as inter- tion with inhaled corticosteroids.
stitial lung disease or sarcoidosis. • Antitussives: Both central (dextromethorphan,
• CXR: Quick and inexpensive, CXR is a useful first- codeine) and peripherally acting (benzonatate)
line study in the diagnosis of pneumonia, pleural agents have been employed in the symptomatic
effusion, pneumothorax, tuberculosis, and some treatment of cough.
malignancies. • Oxygen: Oxygen is used in the treatment of
• Lung CT: More sensitive than CXR (at the cost both acute and chronic hypoxemia second-
of exposing the patient to 70× more radiation), ary to pulmonary disease. The risks of oxygen-
chest CT with intravenous contrast agent is the induced hypercapnia in patients with COPD and
first-line test in the emergent evaluation of sus- oxygen-induced free radical damage are often
pected pulmonary embolism. overlooked.
• Bronchoscopy: This diagnostic and therapeu- • CPAP: This modality is used in the management of
tic procedure, performed by pulmonologists, obstructive sleep apnea.
COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; CXR, chest x-ray exam; PFTs, pulmonary
function tests.
KEY POINTS • Asthma is the principal acute obstructive dis-

order. It usually results from type 1 hypersen-
• The respiratory system encompasses lungs sitivity (IgE/mast cell mediated), with airway
and the surrounding structures of the pleural narrowing after antigen exposure caused by
space, chest wall, and diaphragm. Lung infla- mast cell degranulation, leukocyte recruit-
tion depends on an intact nervous system and ment, and prostaglandin and leukotriene pro-
connections with spinal and brainstem motor duction. Mucosal swelling, excess mucus
neurons innervating the muscles of respira- production, and bronchoconstriction cause
tion, particularly the diaphragm and external airway obstruction in the acute phase. A late
intercostal muscles. phase may be refractory to pharmacological
• Several mechanisms, including a mucus blan- management. Between asthma attacks, the
ket over the ciliated airway epithelium, protect airways may still be hyperresponsive to bron-
the lungs from inhaled particulate matter and choconstricting stimuli.
pathogens. • COPD is the principal chronic obstructive
• Lung and chest wall properties and neuro- disorder. In COPD with emphysema, airflow
muscular strength of respiratory muscles obstruction occurs from premature collapse
determine the capacity for airflow and volume of weak airways and loss of elastic tethering
inspired and expired. Pulmonary function test- by surrounding alveoli. In chronic bronchitis,
ing reports these volumes and capacities as bronchial mucus production is excessive, and
part of lung assessment. small airways have reactive bronchial smooth
• The lungs are highly compliant, easily expand- muscle.
ing during inspiration and recoiling during • First-line management strategies in obstruc-
expiration with appropriate volume changes tive diseases include inhaled corticosteroids
driven by relatively small pressure gradients. to suppress inflammatory responses and
• Pathophysiological loss of lung compliance long-acting bronchodilators.
limits the lungs’ ability to expand, requiring • OSA is the most common form of sleep-disor-
extra effort to inflate the lungs and decreasing dered breathing. It is more common in those
measured lung volumes. This is characteris- who are obese and in older adults. Repeated
tic of acute surfactant deficiency or chronic episodes of apnea and hypoxia during the night
fibrotic or infiltrative lesions of lung tissue. cause recurrent spikes of sympathetic nervous
• In emphysema, breakdown of lung elastin and system activity, blood pressure, and heart rate.
other connective tissue fibers increases lung These episodes, in turn, increase cardiovascu-
compliance and enlarges lung air spaces, ham- lar morbidity and mortality risks.
pering gas exchange. Inflation of the lungs is • Alveolar ventilation is the process of air entry
very easy, but elastic recoil is poor and empty- during inspiration, refreshing the alveolar Po2.
ing the lungs is difficult. Air trapping enlarges Air exit during expiration reduces the alve-
lung volumes. olar Pco2. The continual renewal of O2 and
• The airways are relatively low-resistance pas- removal of CO2 create a partial pressure gra-
sageways and only small pressure changes dient between alveolar air and blood perfus-
are needed to move air in and out with normal ing the alveolar capillaries. Diffusion of the
quiet breathing. The main measure of airway gases across the alveolar–capillary membrane
function is the volume of air exhaled in the causes the blood gas composition leaving the
first second of a maximal expiratory effort alveolar capillary to be higher in O2 and lower
(called a forced expiratory maneuver). The in CO2 as it leaves the lungs.
FEV1 stresses the airways by surrounding them • As oxygen diffuses from alveolar air to pul-
with positive pleural pressure. This tends to monary capillary blood, it binds to red blood
collapse the airways as lung volume decreases. cell Hb for transport to the tissues. The match
Disorders of airway resistance are known as of alveolar ventilation to blood perfusion
obstructive diseases. determines the alveolar Po2, which in term
• Airway smooth muscle is controlled by the determines the percent saturation of Hb with
autonomic nervous system, with sympathetic oxygen and the arterial Po2.
stimulation causing bronchodilation via β- • Lung disease can result in low blood O2 levels
adrenergic receptors, and parasympathetic in a variety of ways. Some of these are failure of
stimulation causing bronchoconstriction via adequate neuromuscular activation of muscles
muscarinic receptors. of respiration, alveolar–capillary membrane
thickness increasing and reducing gas diffu- underdeveloped lungs, and those born at or
sion, shunt-like regions of lung that receive before 25 weeks of gestational age will also
no ventilation but still receive blood flow, and lack surfactant, with very low lung compliance.
ventilation/perfusion mismatching, with some These infants have a high risk of BPD that can
alveolar units and lung regions receiving too predispose them to later life lung dysfunction.
little ventilation for the amount of blood flow • Infant bronchiolitis is generally infection-
they receive, and others having too much ven- related and usually resolves spontaneously.
tilation in poorly perfused alveoli. • Asthma often begins in childhood, and can
• The lung vasculature is a richly branched bed have greater airflow limitations owing to the
that accommodates the entire cardiac out- smaller airways in children.
put of the right side of the heart, surrounding • Older adults have normal age-related reduc-
each of the millions of alveoli with blood flow tions in compliance, resistance, alveolar
for oxygenation and CO2 removal. Regional recoil, and chest wall compliance. Those fac-
lung blood flow is sensitive to local Po2, with tors, combined with increased aspiration and
hypoxia leading to vasoconstriction, and to decreased mucociliary clearance and cough
gravity, with the greatest flow going to the efficacy, predispose to greater risk of pneumo-
dependent lung regions. nia and greater pneumonia-associated morbid-
• Pulmonary vascular pressures are substantially ity and mortality.
lower than systemic vascular pressures, and
the right side of the heart has a thinner wall
consistent with its lighter workload. Increased
pulmonary vascular pressures can result from
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11

carbon dioxide (CO2)—a gas that causes acidosis and

T he lungs have the central and critical function

To maintain homeostasis and accomplish movement STRUCTURES OF THE RESPIRATORY SYSTEM

output—the output of the right ventricle—via the right

Diaphragmatic contraction results in downward move-

FIGURE 11.3 Major muscles of inspiration. The

(Figure 11.6). The internal intercostal muscles pull

d, diameter. the brainstem, primarily from a pattern generator that

air and tissue; at this level, the inspired air is

tonsils and adenoids—lymphoid tissues able to con-

Other Respiratory Phrenic nerve (C3-C5)

Cerebral Contraction of diaphragm,

FIGURE 11.7 Overview of neural control of respiration.

poor digestion and nutrition, abnormalities of bile

known, additional measures can be calculated based

CFTR degradation Acidification and/or Airway obstruction Damage of Respiratory failure

BOX 11.2 (continued)

Inspiratory Inspiratory Vital Total

FIGURE 11.10 Lung volumes and capacities.

outward. At FRC, these two forces are balanced, tug-

Symptoms include shortness of breath, cough, and pain

1. How is the lung protected against the

needed, during inspiration, greater action potential fir-

Lung volume (normal) ↓ Compliance

Type I Surfactant layer

by increased RV and FRC, which is particularly evident

muscle hyperplasia consistent with pulmonary fibrosis.

Idiopathic Pulmonary Fibrosis

FIGURE 11.18 Spirometry flow/volume analysis. Airflow (with

Volume expired (L)

Normal FVC Airway obstruction FVC

all forms. In all three disorders, when airway resistance

and FVC are both reduced. FEV1 shows the greatest

Following inspiration, air is trapped behind closed air-

are readily apparent on graphical representations of spi-

parasympathetic branch of the autonomic nervous

Normal airway During asthma symptoms

Airway cross section Muscle

(elastance, or elastic recoil, is the inverse of compli- PA = 35

Simultaneously, CO2 diffuses in the opposite direction,

variable. When the surrounding Po2 is low, Hb is partially

Hb% saturation with O2

equilibrates to that level, as does the red blood cell cytoplasm.

affinity for O2, and O2 delivery at a lower level consistent

Cause of Hypoxemia Such as That Observed in:

Hypoxia refers to any deficiency of O2, whereas hypox-

Before injury 12 500 150 350 6,000 1,800 4,200

Immediately 12 200 150 50 2,400 1,800 600

Shortly after 30 200 150 50 6,000 4,500 1,500

PO2 = 40 PO2 = 40 PO2 = 40 PO2 = 40

PO2 = 100 PO2 = 100 PO2 = 55 PO2 = 100

PO2 = 100 PO2 = 81

PO2 = 100 PO2 = 200

other situations of anatomical shunting; for example, the

Thickness of the alveolar–capillary interface may

resistance rises, creating secondary pulmonary hyper-

42. Lalley PM. The aging respiratory system—pulmonary SUGGESTED RESOURCES