LM 202

Dr. Hassan Kofahi

Lungs: Structure
• Each lung is divided into lobes
• The right lung is divided into three lobes
• The left lung is divided into two lobes.
• The trachea branches into two main
bronchi.
• Each bronchus branches into smaller
bronchi which branches further to give
rise to progressively smaller airways,
termed bronchioles.
Lungs: Structure
• Bronchioles are distinguished from
bronchi by the lack of cartilage in
their walls.
• Additional branching of bronchioles
gives terminal bronchioles.
• Structures distal to the terminal
bronchiole form the acinus.
• The acinus is composed of:
• Respiratory bronchioles which
branches from the terminal
bronchioles.
• Alveolar ducts
• Alveolar sacs
• Alveoli
The wall of normal airways
The wall of a normal airway contains the
following layers:
• Mucosa:
• Mucus: forms a sticky blanket that traps
microorganisms.
• Epithelium: contains
• Ciliated pseudostratified columnar epithelial cells.
• The cilia is important for pushing the mucus and
microorganisms out of the lungs.
• Goblet cells: produce mucus
• Basement membrane.
• Lamina propria: connective tissue layer
• Submucosa: contains the following layers
• Smooth muscles
• Connective tissue layer: contains mucus glands
that secrets most of the mucus
• Cartilage: only in bronchi not in bronchioles
Lung structure: alveoli
• Alveoli are the sites of gas exchange between
the blood and the air.
• The alveolar walls consist of the following
components:
• The capillary endothelium and basement
membrane.
• The pulmonary interstitium: composed of fibers
and few cells (fibroblast-like cells, smooth muscle
cells, mast cells, and rare mononuclear cells).
• Alveolar epithelium: composed of a continues
layer of two types of cells:
• Type I pneumocytes: cover 95% of the alveolar walls
• Type II pneumocytes: synthesize pulmonary
surfactant and important for the repair of damaged
type I cells.
Lung diseases
Atelectasis (collapse)
• Atelectasis is a loss of the lung volume.
• Develops when the alveoli within the lung become
deflated.
• Atelectasis may affect part of the lung or the entire
lung.
• Results in an inadequate oxygenation of the blood
thus giving rise to hypoxia.
• Atelectasis is potentially reversible (except
contraction atelectasis).
Atelectasis: Forms
• Based on the underlying mechanism and the distribution
of collapse, atelectasis is classified into three forms:
• Resorption atelectasis:
• Occurs as a result of airways obstruction.
• The trapped air, distal to the site of obstruction, gradually becomes
absorbed leading to alveolar collapse.
• Causes: postoperative intrabronchial mucus, foreign body aspiration
(particularly in children), bronchial asthma, chronic bronchitis, or
intrabronchial tumor.
• Compression atelectasis:
• Results from the accumulation of fluids, blood or air in the pleural
cavity.
• Causes: pleural effusion (edema) in congestive heart failure and leakage
of air into the pleural cavity (pneumothorax).
• Contraction atelectasis:
• Occurs when local or diffuse fibrosis of the lungs prevents full expansion
of the lung.
Acute Respiratory Distress Syndrome (ARDS)
• ARDS is a respiratory failure occurs within one week of a known
clinical insult.
• Caused by severe inflammation in the lungs.
• lead to extensive bilateral injury to alveoli.
• Can be triggered by:
• Direct lung injury:
• e.g., aspiration, pneumonia, COVID-19
• Severe systemic inflammation, such as:
• Sepsis
• Pancreatitis
• Transfusion reactions
• Severe ARDS is characterized by rapid onset of life-threatening
respiratory insufficiency, cyanosis and severe arterial hypoxemia.
ARDS: Pathogenesis
• ARDS is caused by an acute inflammatory reaction in the alveoli.
• Pathogenesis:
• The insult triggers the alveolar macrophages to produce chemokines (e.g., IL-8) and
cytokines (IL-1 and TNF).
• The chemokines and cytokines recruit neutrophils to the interstitium and to the
alveoli.
• The neutrophils is stimulated to produce harmful products, such as proteases and
reactive oxygen species.
• Neutrophils’ products, cytokines and chemokines cause the following:
• Damage to alveolar epithelium and endothelium
• Increasing the vascular permeability, leading to edema.
• Inactivation of the surfactant which render the alveolar unit unable to expand.
• Stimulation of fibroblast growth and collagen deposition.
• The characteristic microscopic morphology of ARDS is alveolar edema,
epithelial necrosis, accumulation of neutrophils, and presence of hyaline
membranes lining the alveolar wall.
ARDS: Clinical features
• The mortality rate of ARDS is high (38%).
• Some ARDS survivors recover normal respiratory function within 6 to
12 months.
• The rest develop diffuse interstitial fibrosis leading to chronic respiratory
insufficiency.

Note: ARDS should not be confused with the respiratory distress

syndrome of the newborn, which is caused by the reduced
production of surfactant due to the prematurity.
Chronic Obstructive Pulmonary Disease (COPD)
• COPD is an umbrella term used to describe
progressive lung diseases including emphysema
and chronic bronchitis.
• In most of the cases, emphysema and chronic
bronchitis co-exist, because cigarette smoking is the
main cause of both.
• COPD is a progressive, irreversible disease (there is
no cure for COPD).
• The main causes of COPD are:
• Cigarette smoking (the leading cause of COPD).
• Long term exposure to air pollution.
• Genetic disorders: α1- antitrypsin deficiency.
Respiratory infections may worsen COPD.
• COPD affects 10% of the population and is the third
leading cause of death in the USA.
Emphysema
• Emphysema is caused by pathological changes in
the acini.
• Characterized by:
1. Destruction of the alveolar walls (septa) leading
to permanent enlargement of the air spaces in
the acini.
• The destruction of the walls results in merging normal
alveoli into larger dysfunctional airspaces.
• This reduces the surface area for gas exchange, thus
reduces the oxygenation of blood.
2. Loss of external support for respiratory
bronchioles.
• This results in a premature collapse of the respiratory
bronchioles during expiration leading to airflow
obstruction.
Types of emphysema
• Centriaciner emphysema:
• Affects respiratory bronchioles in the
central or proximal parts of the acini.
• Distal alveoli are not affected except in
severe centriacinar emphysema.
• More common in the upper lobes of
the lungs.
• Caused by cigarette smoking.
• Panacinar emphysema:
• The acini are uniformly enlarged.
• Occurs more commonly in the lower
lung zones.
• Associated with α1 antitrypsin
deficiency.
Emphysema: Pathogenesis
• Inhaled cigarette smoke and other noxious particles cause emphysema by
inducing inflammation which, particularly in patients with a genetic
predisposition, result in the pathological changes in the acini.
• Alveolar wall destruction in emphysema is caused by the following:
• Inflammatory cells activation and the production of inflammatory mediators.
• Imbalance between proteases and anti-proteases:
• Inflammatory cells release proteases, which break down the connective tissue.
• Anti-proteases, such as α1-antitrypsin, inhibit the proteases and protect against tissue
damage.
• Patients with emphysema may have a relative deficiency in the protective anti-proteases.
• Oxidative stress: Reactive oxygen species (ROS) cause tissue damage in the lungs:
• ROS is generated by cigarette smoke
• ROS is released from activated inflammatory cells.
Emphysema: Clinical features
The classic presentation of emphysema (without
chronic bronchitis) is:
• Dyspnea: difficulty in breathing
• Prolonged expiration with pursed lips
• Hyperinflation of the lungs and Barrel chest
• Weight loss
• Until very late in the disease, gas exchange is
adequate and blood gas values are relatively
normal.
Emphysema patients are often called “pink
puffers.”
• Progression of the disease results in pulmonary
hypertension, cor pulmonale and right sided heart
failure.
Expiration with pursed-lips
Chronic bronchitis
• Chronic  lasts for long time
• Bronchitis inflammation of the bronchi
• Chronic bronchitis Is defined clinically as: the presence of a
persistent productive cough (i.e., a cough that produces mucus)
for at least 3 consecutive months in at least 2 consecutive years.
• Often, coexist with emphysema.
• Caused by cigarette smoking or air pollution.
• Characterized by the excessive production of mucus in the
airways.
Chronic bronchitis: Pathogenesis
• Cigarette smoking and air pollution induces
• Inflammation
• Hypertrophy of the mucous glands
• An increase in the number of the goblet cells
• Destruction of the cilia
• Excessive mucus production results in a persistent productive cough
and it leads to airflow obstruction.
• The airflow obstruction in chronic bronchitis results from:
• Small airway disease, induced by mucous plugging of the bronchiolar lumen,
inflammation, and bronchiolar wall fibrosis.
• Coexistent emphysema.
Chronic bronchitis: clinical features
• Course of chronic bronchitis disease varies between individuals.
• Patients experience the following symptoms:
• High body weight
• Persistent productive cough.
• Wheezing
• Recurrent infections.
• Hypercapnia (elevated CO2 levels in the blood), hypoxemia, and cyanosis.
• Pulmonary hypertension leading to cor pulmonale and right-sided heart failure.
• Chronic bronchitis patients are often referred to as “ blue bloaters”.
COPD patients die due to right-sided heart failure or respiratory failure.
Blue bloaters Pink puffers
Asthma
• Asthma is a chronic inflammatory disorder of the airways.
• It causes recurrent episodes of severe and reversible
bronchoconstriction that develops in response to various stimuli
including cold, exogenous allergens, and some chemicals such as
aspirin.
• Caused by a combination of genetic and environmental factors.
• Affect people at all ages, but usually starts during childhood.
• The incidence of asthma is increasing in the western world. Why?
The hygiene hypothesis is a possible explanation.
• The hygiene hypothesis states that a lack of exposure to microorganisms in early
childhood results in defects in immune tolerance and subsequent hyperreactivity to
stimuli later in life.
Hallmarks of asthma:
• Accumulation of mucus in the
bronchial lumen.
• Increase in the number of mucus-
secreting goblet cells in the mucosa
• Thickened basement membrane.
• Recruitment of eosinophils,
macrophages, and other
inflammatory cells in the lamina
propria.
• Hypertrophy and hyperplasia of
smooth muscle cells.
• An increase in size of the
submucosal glands.
Types of Asthma
• Atopic asthma: (Allergic)
• The most common type.
• Caused by an allergic reaction.
• Attacks may be triggered by allergens in dust, pollen, animal dander, food, or by infections.
• Non-atopic asthma:
• No evidence of allergic reaction
• Triggered by viral infections and inhaled air pollutants.
• Drug-induced asthma
• No evidence of allergic reaction.
• Triggered by drugs (such as aspirin).
• The pathogenesis is unknown
• Occupational asthma
• Triggered after an extended period of exposure to chemicals in the work environment.
Asthma: Clinical features
• Bronchoconstriction and mucus plugging during asthma attacks result in
the following symptoms:
• Severe dyspnea
• Wheezing
• Cough
• Hyperinflation of the lungs.
• The episodes lasts for 1 hour or several hours and subside spontaneously
or in response to therapy.
• Occasionally, some patients may develop a severe attack that lasts for days
or weeks (a condition known as status asthmaticus) and can be fatal.
• In most of the cases asthma is not fatal.
• Treatment: anti-inflammatory drugs such as glucocorticoids and
bronchodilators such as beta-adrenergic drugs.
Bronchiectasis
• Bronchiectasis refers to the presence of a
permanent dilation of bronchi or
bronchioles.
• Caused by the destruction of the smooth
muscles and the supporting elastic tissue in
the walls of the bronchi.
• As a result, mucus accumulate in the
enlarged area causing a chronic productive
cough.
• Occurs secondary to persistent infection or
obstruction.
Bronchiectasis: causes
• Bronchiectasis can be caused by the following conditions:
• Bronchial obstruction:
• By tumors, foreign bodies or mucus.
• Causes localized bronchiectasis.
• Congenital or hereditary conditions:
• Cystic fibrosis: causes a widespread severe bronchiectasis that results from the
obstruction of airways with an abnormally thick mucus.
• Congenital Immunodeficiency: localized or widespread bronchiectasis develop as a
result of recurrent bacterial infections.
• Necrotizing, or suppurative, pneumonia
• e.g., infections with Staphylococcus aureus or Klebsiella pneumonia.
Bronchiectasis: Pathogenesis
1. Accumulation of mucus or foreign body aspiration results in the obstruction
of airways.
2. This blocks the clearance of secretions.
3. Results in a favorable environment for superimposed bacterial infection and
induces inflammation.
4. The inflammation causes damage to the bronchial walls and results in the
accumulation of exudate which further distend the airways leading to a
permanent dilation.
Bronchiectasis: Clinical features
• Symptoms:
• Persistent cough associated with purulent
sputum.
• Dyspnea
• Coughing up blood
• Chest pain
• Severe, widespread bronchiectasis may
lead to:
• Hypoxemia
• Hypercapnia (elevated carbon dioxide (CO2)
levels in the blood)
• Pulmonary hypertension, and cor pulmonale.
Pulmonary infections: Pneumonia
• Pneumonia can be broadly defined as any infection of the lung.
• Pneumonias are classified according to the following criteria:
• Cause:
• Infectious:
• Viral
• Bacterial
• Non-infectious: (aspiration pneumonia)
• Source:
• Community acquired
• Hospital acquired
• Pattern:
• Bronchopneumonia
• Lobar pneumonia
Pneumonia: Patterns
• Pneumonia has two patterns of
anatomic distribution:
• Bronchopneumonia: characterized by a
patchy consolidation of the lung.
• lobar pneumonia: characterized by the
consolidation of a large portion of a
lobe or of an entire lobe.
• In pneumonia, the term
“consolidation,” refers to
“solidification” of the lung due to
replacement of the air by exudate in
the alveoli.
Bronchopneumonia Lobar pneumonia
Community-acquired viral pneumonia
• The most common causes of community-acquired viral pneumonias are
influenza virus, respiratory syncytial viruses, adenovirus, rhinoviruses,
varicella virus and coronavirus.
• Viruses infect and damage respiratory epithelium causing an inflammatory
response.
• Outpouring of exudate into alveolar spaces may occur.
• This replaces the air with fluids (exudate) and leads to the consolidation of the lungs.
• Damage and necrosis of the respiratory epithelium inhibits mucociliary
clearance and predispose to secondary bacterial infections.
• Severe complications of viral infection are more likely to occur in infants,
older adults, malnourished patients, alcoholics, and immunosuppressed
individuals.
Viral pneumonia: Clinical Features
• Symptoms:
• Fever
• Headache
• Malaise
• Later, cough with minimal sputum.
Influenza virus
• Single stranded RNA virus (8 segments of RNA).
• The surface of influenza virus contains two types of antigens: hemagglutinin (H) and
neuraminidase (N).
• H and N determines the subtype of the virus (e.g., H1N1, H5N1, H3N2).
• Influenza virus can infect humans, pigs, horses and birds.
• The virus undergo two types of genetic changes:
• Antigenic drift: caused by mutations in the H and N and allow the virus to escape most of the host
antibodies and cause epidemics every year.
• Antigenic shift: occur when H or N are replaced through recombination of RNA segments with
those of animal influenza viruses. Generates a new virus that can cause pandemics.
• In 1918, influenza pandemic (the Spanish flu, H1N1 of swine origin) killed 20-100 million
people globally.
• In 2009, the same strain of virus (Swine H1N1) caused severe infections in young adults.
• H5N1 (avian flu) caused 400 deaths in humans and is a potential threat to cause the next
pandemic.
Community-acquired bacterial pneumonia
• Bacterial pneumonias often follow a viral upper-respiratory tract
infection.
• The most common cause of community acquired bacterial
pneumonia is Streptococcus pneumoniae.
• Spread by airborne droplets.
• The inflammatory response results in acute inflammatory exudate filling the
alveolar spaces.
• Tends to produce a bronchopneumonia.
• If untreated, bronchopneumonia may progress to lobar pneumonia.
Bacterial pneumonia: clinical features
• Symptoms of typical community-acquired acute bacterial pneumonia
are:
• Sudden onset of high fever
• Shaking
• Chills
• Cough, producing mucopurulent sputum
• Treatment: antibiotics
Hospital-Acquired (Nosocomial) Pneumonias
• Nosocomial pneumonia is defined as pulmonary infections acquired
in the course of a hospital stay.
• Patients on mechanical ventilators are at high risk of acquiring
nosocomial pneumonia.
• The most common causes of hospital acquired pneumonia are the
gram-negative bacteria (Enterobacteriaceae and Pseudomonas spp)
and Staphylococcus aureus.
• Hospital-acquired bacterial pneumonia is harder to treat than
community-acquired bacterial pneumonia. Why?
• Because the bacteria tend to be more aggressive and more resistant to
antibiotic treatment in hospitals.
Aspiration pneumonia
• Usually, caused by the aspiration of gastric contents into the airways.
• The gastric contents introduces bacteria and foreign material into the lungs.
• Gastric acid causes direct injury to lungs, which also disrupts normal host
defenses, facilitating bacterial growth.
The resultant pneumonia is partly chemical, due to the extremely irritating
effects of the gastric acid, and partly bacterial.
• More common in debilitated or unconscious patients. Why?
• The gag reflux is diminished in these cases.
• Aspiration pneumonia causes severe damage to the lungs and
frequently progress to lung abscess.
• Aspiration pneumonia is a frequent cause of death in predisposed
individuals.
Tuberculosis (TB)
• Tuberculosis is a chronic granulomatous disease.
• Caused by an infection with Mycobacterium tuberculosis.
• Affects mainly the lungs, but other organs might also be affected.
• Epidemiology:
• Tuberculosis is the most common cause of death resulting from a single infectious
agent.
• It is estimated that 1.7 billion individuals are/were infected with M. tuberculosis
worldwide (≈1/3 of the world population).
• In most of the cases, the infection is self-limiting, asymptomatic and does not cause
disease.
• Transmission: direct person-to-person by inhalation of airborne droplets
containing the organisms.
TB: Pathogenesis
• Sequence of events:
1. Entry of the Mycobacterium into the macrophages by phagocytosis:
Mycobacteria are recognized by macrophage surface receptors and as a result, the
bacteria are phagocytosed.
2. Replication in macrophages: once internalized, Mycobacteria inhibit the fusion of
lysosome with the phagosome. Thus, they persist and replicate inside the
macrophages.
3. Development of cell-mediated immunity (TH1 response): 3 weeks after the
infection, a subclass of T lymphocyte, called TH1, become activated. TH1 cells
produce cytokines (IFN-γ) that activate the macrophages. Activated macrophages
kill the internalized Mycobacteria.
4. Granulomatous inflammation and tissue damage: In addition to stimulating
macrophages to kill mycobacteria, the TH1 response orchestrates the formation of
granulomas and caseous necrosis (discussed in chapters 1&2).
Primary tuberculosis
• Refers to a disease that develops in a previously unexposed patient.
• In the majority of the cases (95%), the only consequence of primary TB
is the formation of foci of scarring and calcification (asymptomatic).
• Most individuals who develop primary TB have the so-called Ghon
complex consisting of granulomatous lesions in lung tissue in
conjunction with granulomas in draining hilar lymph nodes.
• The foci may harbor dormant viable organisms that might be reactivated
later in life causing secondary TB.
• In 5% of the cases, primary infection may result in progressive primary
tuberculosis.
• This occurs usually in immunocompromised patients, such as:
• HIV-positive patients
• Malnourished patients
Secondary tuberculosis
• Arises in a previously infected (sensitized) patient.
• May appear shortly or, in most of the cases, years (or even decades) after
the primary TB.
• Causes of secondary TB:
• Reactivation of a dormant primary lesion, particularly when the host immune system
is weakened.
• Reinfection
• Secondary TB is often associated with more caseous necrosis and with
cavitation (formation of cavities) in the lung tissues.
In progressive primary and in secondary TB, the bacteria may spread via
the blood vessels to other organs in the body causing a life-threatening
form of disease, called Miliary TB.
TB: Clinical features
• Symptoms:
• Anorexia
• Weight loss
• Fever (low grade).
• Night sweats
• Increasing amounts of sputum
• Coughing up blood