2 Inflammation and Repair

Acute Inflammation
Transient and early response to injury that involves release of chemical
mediators, causing stereotypic vessel and leukocyte responses
Acute
Inflammation
Transient and early response to injury that involves release of chemical
mediators, causing stereotypic vessel and leukocyte responses
Cardinal
signs of
inflammation
1. Rubor (redness) and calor (heat)
o istamine!mediated vasodilation of arterioles
". Tumor (s#elling)
o istamine!mediated increase in permeability of venules
$. %olor (pain)
o &rostaglandin (&') (" sensiti)es speciali)ed nerve endings to the
effects of bradykinin and other pain mediators.
*timuli for
acute
inflammation
1. +nfections (e.g., bacterial or viral infection)
". +mmune reactions (e.g., reaction to a bee sting)
$. ,ther stimuli
o Tissue necrosis (e.g., acute myocardial infarction), trauma, radiation,
burns
*e-uential
vascular
events
1. .asoconstriction of arterioles
o /eurogenic refle0 that lasts only seconds
". .asodilation of arterioles
a. istamine and other vasodilators (e.g., nitric o0ide) rela0 vascular
smooth muscle, causing increased blood flo#.
b. +ncreased blood flo# increases hydrostatic pressure.
". +ncreased permeability of venules
a. istamine and other mediators contract endothelial cells producing
endothelial gaps.
b. 1 transudate (protein and cell!poor fluid) moves into the interstitial
tissue.
$. *#elling of tissue (edema)
o /et outflo# of fluid surpasses lymphatic ability to remove fluid.
$. Reduced blood flo#
o 1 decrease in hydrostatic pressure is caused by outflo# of fluid into
the interstitial tissue.
*e-uential
cellular
events
Chronic granulomatous disease (C'%), an 2!linked recessive
disorder, is characteri)ed by deficient /1%& o0idase in the cell
membranes of neutrophils and monocytes. The reduced production
of
results in an absent respiratory burst. Catalase!positive organisms
that produce "," (e.g., Staphylococcus aureus) are ingested but
not killed, because the catalase degrades ",". 3yelopero0idase is
present, but ,Cl
4
is not synthesi)ed because of the absence of
",". Catalase!negative organisms (e.g., Streptococcus species)
are ingested and killed #hen myelopero0idase combines "," #ith
Cl
!
to form ,Cl
4
. The classic screening test for C'% is the nitroblue
tetra)olium test (/5T). +n this test, leukocytes are incubated #ith a
colorless /5T dye, #hich is converted to a blue color if the
respiratory burst is intact. This test has been replaced by other more
sensitive tests.
3yelopero0idase (3&,) deficiency, an autosomal recessive
disorder, differs from C'% in that both
and "," are produced (normal respiratory burst). The absence of
3&, prevents synthesis of ,Cl
4
.
The events described #ill emphasi)e neutrophil events in acute inflammation
due to a bacterial infection (e.g., Staphylococcus aureus).
1. /eutrophils are the primary leukocytes in acute inflammation
". 3argination
a. R5Cs aggregate into rouleau0 (6stacks of coins6) in venules.
b. /eutrophils are pushed from the central a0ial column to the periphery
(margination).
$. Rolling
a. %ue to activation of selectin adhesion molecules on the surface of
neutrophils and endothelial cells
b. /eutrophils loosely bind to selectins and 6roll6 along the endothelium.
7. 1dhesion
a. 1dhesion molecules firmly bind neutrophils to endothelial cells.
b. /eutrophil adhesion molecules
i. 8"!+ntegrins (C%11a9C%1:)
ii. 1dhesion molecule activation is mediated by C;a and
leukotriene 57 (<T57).
iii. Catecholamines, corticosteroids, and lithium inhibit activation
of adhesion molecules.
This causes an increase in the peripheral blood
neutrophil count (neutrophilic leukocytosis).
iv. (ndoto0ins enhance activation of adhesion molecules.
This causes a decrease in the peripheral blood
neutrophil count (neutropenia).
c. (ndothelial cell adhesion molecules
i. +ntercellular adhesion molecule (+C13) and vascular cell
adhesion molecule (.C13) bind to integrins on the surface of
neutrophils.
ii. +C13 and .C13 activation is mediated by interleukin 1 (+<!1)
and tumor necrosis factor (T/=).
d. <eukocyte adhesion deficiency (<1%)
i. 1utosomal recessive disorders
ii. <1% type 1 is a deficiency of C%11a9C%1:.
iii. <1% type " is a deficiency of a selectin that binds neutrophils.
iv. Clinical findings
%elayed separation of the umbilical cord (>1 month)
/eutrophil en)ymes are important in cord
separation.
*evere gingivitis, poor #ound healing, peripheral
blood neutrophilic leukocytosis
;. Transmigration (diapedesis)
a. /eutrophils dissolve the basement membrane and enter interstitial
tissue.
b. =luid rich in proteins and cells (i.e., e0udate) accumulates in
interstitial tissue.
c. =unctions of e0udate
i. %ilute bacterial to0ins
ii. &rovide opsonins (assist in phagocytosis), antibodies, and
complement
?. Chemota0is
a. /eutrophils follo# chemical gradients that lead to the infection site.
b. Chemotactic mediators bind to neutrophil receptors.
3ediators include C;a, <T57, bacterial products, and +<!:.
b. 5inding causes the release of calcium, #hich increases neutrophil
motility.
22 &hagocytosis
a. 3ultistep process9
i. ,psoni)ation
ii. +ngestion
iii. @illing
b. ,psoni)ation
i. ,psonins attach to bacteria.
,psonins include +g', C$b fragment of complement,
and other proteins (e.g., C!reactive protein).
/eutrophils have membrane receptors for +g' and
C$b.
ii. ,psoni)ation enhances neutrophil recognition and
attachment to bacteria.
iii. 5rutonAs agammaglobulinemia is an opsoni)ation defect.
c. +ngestion
i. /eutrophils engulf (phagocytose) and then trap bacteria in
phagocytic vacuoles.
ii. &rimary lysosomes empty hydrolytic en)ymes into phagocytic
vacuoles producing phagolysosomes.
+n ChBdiak!igashi syndrome (see a defect in
membrane fusion prevents phagolysosome
formation.
d. 5acterial killing
i. ,"!dependent myelopero0idase (3&,) system
,nly present in neutrophils and monocytes (not
macrophages)
&roduction of supero0ide free radicals

/1%& o0idase converts molecular ," to
, #hich releases energy called the
respiratory, or o0idative, burst.
&roduction of pero0ide (",")
*upero0ide dismutase converts
to ",", #hich is neutrali)ed by glutathione
pero0idase.
&roduction of bleach (,Cl
4
)
3&, combines "," #ith chloride (Cl
!
) to
form hypochlorous free radicals (,Cl
4
),
#hich kill bacteria.
Chronic granulomatous disease and 3&, deficiency
are e0amples of diseases that have a defect in the
,"!dependent 3&, system.
%eficiency of /1%& (e.g., glucose!?!phosphate
dehydrogenase deficiency) produces a microbicidal
defect.
ii. ,"!independent system
Refers to bacterial killing from substances located in
leukocyte granules
(0amples!lactoferrin (binds iron necessary for
bacterial reproduction) and major basic protein
(eosinophil product that is cytoto0ic to helminths)
Chemical
mediators
Table 2-1. Sources and Functions of Chemical Mediators
Mediator Source(s Function(s
Arachidonic Acid
Metabolites

&rostaglandins 3acrophages, endothelial cells,
platelets
&'"9 major precursor of &'s
and thrombo0anes
&'("9 vasodilation, pain, fever
&'+"9 vasodilationC inhibition of platelet
aggregation
Thrombo0ane 1" &latelets
Converted from &'" by
thrombo0ane synthase
.asoconstriction, platelet aggregation,
bronchoconstriction
<eukotrienes (<Ts) Converted from arachidonic
acid by lipo0ygenase!mediated
hydro0ylation
<T579 chemota0is and activation of
neutrophil adhesion molecules
<TC7, <T%7, <T(79 vasoconstriction,
increased vessel permeability,
bronchoconstriction
!rad"#inin &roduct of kinin system
activation by activated factor 2++
.asodilation, increased vessel permeability,
pain, bronchoconstriction
Chemo#ines <eukocytes, endothelial cells 1ctivate neutrophil chemota0is
Complement *ynthesi)ed in liver C$a, C;a (anaphylato0ins)9 stimulate mast
cell release of histamine
C$b9 opsoni)ation
C;a9 activation of neutrophil adhesion
molecules, chemota0is
C;!CD (membrane attack comple0)9 cell
lysis
C"to#ines
+<!1, T/= <ymphocytes, macrophages,
endothelial cells
+nitiate &'(" synthesis in anterior
hypothalamus, leading to production of
fever
1ctivate endothelial cell adhesion molecules
+ncrease liver synthesis of acute!phase
reactants, such as ferritin, coagulation
factors (e.g., fibrinogen), and C!reactive
protein
+ncrease release of neutrophils from bone
marro#
+<!? +ncrease liver synthesis of acute phase
reactants
+<!: Chemota0is
$istamine 3ast cells (primary cell),
platelets, enterochromaffin cells
.asodilation, increased vessel permeability
%itric &'ide (%& 3acrophages, endothelial cells
=ree radical gas released
during conversion of arginine to
citrulline by /, synthase
.asodilation, bactericidal
Serotonin 3ast cells, platelets .asodilation, increased vessel permeability
+<, interleukinC &', prostaglandinC T/=, tumor necrosis factor.
1. They derive from plasma, leukocytes, local tissue, bacterial products.
o (0ample!arachidonic acid mediators are released from membrane
phospholipids in macrophages, endothelial cells, and platelets
". They have short lives (e.g., seconds to minutes).
$. They may have local and systemic effects.
o (0ample!histamine may produce local signs of itching or systemic
signs of anaphyla0is.
7. They have diverse functions.
a. .asodilation
(0amples!histamine, nitric o0ide, &'+"
b. .asoconstriction
(0ample!thrombo0ane 1" (T21")
c. +ncrease vessel permeability
(0amples!histamine, bradykinin, <TC7!%7!(7, C$a and C;a
(anaphylato0ins)
d. &roduce pain
(0amples!&'(", bradykinin
e. &roduce fever
(0amples!&'(", +<!1, T/=
f. Chemotactic
(0amples!C;a, <T57, +<!:
Conse-uences of acute inflammation
1. Complete resolution
a. ,ccurs #ith mild injury to cells that have the capacity to enter the cell
cycle (e.g., labile and stable cells)
b. (0amples!first!degree burn, bee sting
". Tissue destruction and scar formation
a. ,ccurs #ith e0tensive injury or damage to permanent cells
b. (0ample!third!degree burns
$. &rogression to chronic inflammation
Types of acute inflammation
<ocation, cause, and duration of inflammation determine the morphology of
an inflammatory reaction.
1. &urulent (suppurative) inflammation
a. <ocali)ed proliferation of pus!forming organisms, such as
Staphylococcus aureus (e.g., skin abscessC
b. S. aureus contains coagulase, #hich cleaves fibrinogen into fibrin
and traps bacteria and neutrophils.
". =ibrinous inflammation
a. %ue to increased vessel permeability, #ith deposition of a fibrin!rich
e0udate
b. (0ample!fibrinous pericarditis
$. &seudomembranous inflammation
a. 5acterial to0in!induced damage of the mucosal lining, producing a
shaggy membrane composed of necrotic tissue
b. (0ample!pseudomembranes associated #ith Clostridium difficile in
pseudomembranous colitis
Corynebacterium diphtheriae produces a to0in causing
pseudomembrane formation in the pharyn0 and trachea.
Role of fever in inflammation
1. Right!shifts o0ygen!binding curve
o 3ore ," is available for the ,"!dependent 3&, system.
". &rovides a hostile environment for bacterial and viral reproduction
Chronic
Inflammation
+nflammation of prolonged duration (#eeks to years) that most often results
from persistence of an injury!causing agent
Causes of
chronic
inflammation
1. +nfection
o (0amples!tuberculosis, leprosy, hepatitis C
". 1utoimmune disease
o (0amples!rheumatoid arthritis, systemic lupus erythematosus
$. *terile agents
o (0amples!silica, uric acid, silicone in breast implants
3orphology
1. Cell types
o 3onocytes and macrophages,
lymphocytes and plasma cells,
eosinophils
". /ecrosis
o Not as prominent a feature as in
acute inflammation
$. %estruction of parenchyma
o <oss of functional tissue, #ith
repair by fibrosis
7. =ormation of granulation tissue
a. ighly vascular tissue composed
of ne#ly formed blood vessels
(i.e., angiogenesis) and activated
fibroblasts
i. (ssential for normal
#ound healing
ii. Converted into scar tissue
b. =ibronectin is re-uired for
granulation tissue formation.
i. Cell adhesion glycoprotein
located in the e0tracellular
matri0 ((C3)
5inds to collagen,
fibrin, and cell
surface receptors
(e.g., integrins)
ii. Chemotactic factor that
attracts fibroblasts
(synthesi)e collagen) and
endothelial cells (form ne#
blood vessels,
angiogenesis)
.ascular
endothelial gro#th
factor (.('=) and
basic fibroblast
gro#th factor
(='=) are
important in
angiogenesis.
". 'ranulomatous inflammation
o *peciali)ed type of chronic
inflammation
a. Causes
i. +nfections
(0amples!
tuberculosis and
systemic fungal
infection (e.g.,
histoplasmosis)
Esually
associated #ith
caseous necrosis
(i.e., soft
granulomas)
Caseation
is due to
lipid
released
from the
cell #all of
dead
pathogen
s.
ii. /oninfectious causes
(0amples!
sarcoidosis and
CrohnAs disease
/oncaseating
(i.e., hard
granulomas)
b. 3orphology
i. &ale, #hite nodule #ith or
#ithout central caseation
ii. Esually #ell!circumscribed
iii. Cell types
(pithelioid cells
(activated
macrophages),
mononuclear
(round cell)
infiltrate (C%7
helper T cells, or
T cells of the T1
type)
3ultinucleated
giant cells formed
by fusion of
epithelioid cells
/uclei
usually
located at
the
periphery
iv. &athogenesis of a
tuberculous granuloma
!&( 2-1 S)*+)%C) &F F&RMATI&% &F A T+!)RC+,&+S
-RA%+,&MA
The tubercle bacillus Mycobacterium tuberculosis
undergoes phagocytosis by alveolar macrophages
(processing of bacterial antigen).
3acrophages present antigen to C%7 T cells in association
#ith class ++ antigen sites.
3acrophages release interleukin (+<) 1" (stimulates
formation of T1 class cells) and +<!1 (causes feverC
activates T1 cells).
T1 cells release +<!" (stimulates T1 proliferation), F!
interferon (activates macrophages to kill tubercle bacillusC
epithelioid cells), and migration inhibitory factor (causes
macrophages to accumulate).
<ipids from killed tubercle bacillus lead to caseous necrosis.
1ctivated macrophages fuse and become multinucleated
giant cells.
Tissue
Repair
=actors involved in tissue repair
1. &arenchymal cell regeneration
". Repair by connective tissue (fibrosis)
=actors
involved
in tissue
repair
1. &arenchymal cell regeneration
". Repair by connective tissue (fibrosis)
&arenchymal
cell
regeneration
Table 2-2. Factors In.ol.ed in Tissue Repair
Factor Function(s
-ro/th Factors
.ascular endothelial cell gro#th
factor (.('=)
*timulates angiogenesis
5asic fibroblast gro#th factor
(5='=)
*timulates angiogenesis
(pidermal gro#th factor (('=) *timulates keratinocyte migration
*timulates granulation tissue formation
&latelet!derived gro#th factor
(&%'=)
*timulates proliferation of smooth muscle, fibroblasts,
endothelial cells
$ormones
+nsulin gro#th factor!1 (+'=!1) *timulates synthesis of collagen
&romotes keratinocyte migration
Interleu#ins (I,
+<!1 Chemotactic for neutrophils
*timulates synthesis of metalloproteinases (i.e., trace metal
containing en)ymes)
*timulates synthesis and release of acute phase reactants
from the liver
1. %epends on the ability of cells to replicate
a. <abile cells (e.g., stem cells in epidermis) and stable cells (e.g.,
fibroblasts) can replicate (see
b. &ermanent cells cannot replicate.
Cardiac and striated muscle are replaced by scar tissue
(fibrosis).
". %epends on factors that stimulate parenchymal cell division and migration
o *timulatory factors include loss of tissue and production of gro#th
factors
2. Cell cycle (
a. &hases of the cell cycle
22 'G phase
Resting phase of stable parenchymal cells
222 '1 phase
*ynthesis of R/1, protein, organelles, and cyclin %
2222 * (synthesis) phase
*ynthesis of %/1, R/1, protein
2v2 '" phase
*ynthesis of tubulin, #hich is necessary for formation
of the mitotic spindle
v2 3 (mitotic) phase
T#o daughter cells are produced.
b. Regulation of the '1 checkpoint ('1 to * phase)
22 3ost critical phase of the cell cycle
222 Control proteins include cyclin!dependent kinase 7 (Cdk7)
and cyclin %
'ro#th factors activate nuclear transcribing proto!
oncogenes to produce cyclin % and Cdk7.
Cyclin % binds to Cdk7, forming a comple0 causing
the cell to enter the * phase.
2222 RB (retinoblastoma) suppressor gene
R5 protein product arrests the cell in the '1 phase.
Cdk7 phosphorylates the R5 protein causing the cell
to enter the * phase.
2v2 TP53 suppressor gene
T&;$ protein product arrests the cell in the '1 phase
by inhibiting Cdk7.
&revents R5 protein phosphorylation and, if
necessary, provides time for repair of %/1 in
the cell
+n the event that there is e0cessive %/1 damage,
the BA gene is activated.
BA gene inhibits the BC!" antiapoptosis
gene (Chapter 1) causing release of
cytochrome c from the mitochondria and
apoptosis of the cell.
". Restoration to normal
a. Re-uires preservation of the basement membrane
b. Re-uires a relatively intact e0tracellular matri0 ((C3C i.e., collagen,
adhesive proteins)
<aminin, the key adhesion protein in the basement
membrane, interacts #ith type +. collagen, cell surface
receptors, and components in the (C3.
Repair by connective tissue (fibrosis)
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(hlers!%anlos syndrome ((%*) consists of a group of mendelian
disorders characteri)ed by defects of type + and type +++ collagen
synthesis and structure. Clinical findings include hypermobile joints,
aortic dissection (most common cause of death), bleeding into the
skin (ecchymoses), and poor #ound healing
!&( 2-2
0&+%1
$)A,I%- !2
3RIMAR2
A%1
S)C&%1AR2
I%T)%TI&%
3rimar" Intention
%ay 19 fibrin clot (hematoma) develops. /eutrophils infiltrate
the #ound margins. There is increased mitotic activity of
basal cells of s-uamous epithelium in the apposing #ound
margins.
%ay "9 s-uamous cells from apposing basal cell layers
migrate under the fibrin clot and seal off the #ound after 7:
hours. 3acrophages emigrate into the #ound.
%ay $9 granulation tissue begins to form. +nitial deposition of
type +++ collagen begins but does not bridge the incision site.
3acrophages replace neutrophils.
%ays 7!?9 granulation tissue formation peaks, and collagen
bridges the incision site.
Heek "9 collagen compresses blood vessels in fibrous
tissue, resulting in reduced blood flo#. Tensile strength is
1GI.
3onth 19 collagenase remodeling of the #ound occurs, #ith
replacement of type +++ collagen by type + collagen. Tensile
strength increases, reaching :GI #ithin $ months. *car
tissue is devoid of adne0al structures (e.g., hair, s#eat
glands) and inflammatory cells.
Secondar" Intention
Typically, these #ounds heal differently from primary
intention9
3ore intense inflammatory reaction than primary healing
+ncreased amount of granulation tissue formation than in
primary healing
Hound contraction caused by increased numbers of
myofibroblasts
1. ,ccurs #hen injury is severe or persistent
o Tissue in a third!degree burn cannot be restored to normal o#ing to
loss of skin, basement membrane, and connective tissue
infrastructure.
". *teps in repair
a. Re-uires neutrophil transmigration to li-uefy injured tissue and then
macrophage transmigration to remove the debris
b. Re-uires formation of granulation tissue
1ccumulates in the (C3 and eventually produces dense
fibrotic tissue (scar)
c. Re-uires the initial production of type +++ collagen
22 Collagen is the major fibrous component of connective tissue.
222 +t is a triple heli0 of cross!linked J!chains.
<ysyl o0idase cross!links points of hydro0ylation
(vitamin C!mediated) on adjacent J!chains.
2222 Cross!linking increases the tensile strength of collagen.
Type + collagen in skin, bone, and tendons has the
greatest tensile strength.
b. %ense scar tissue produced from granulation tissue must be
remodeled.
22 Remodeling increases the tensile strength of scar tissue.
222 3etalloproteinases (collagenases) replace type +++ collagen
#ith type + collagen, increasing tensile strength to
appro0imately :GI of the original.
". &rimary and secondary intention #ound healing
a. ealing by primary intention
22 1ppro0imation of #ound edges by sutures
222 Esed for clean surgical #ounds
b. ealing by secondary intention
22 Hound remains open
222 Esed for gaping or infected #ounds
=actors
that
impair
healing
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1. &ersistent infection
a. 3ost common cause of impaired #ound healing
b. Staphylococcus aureus is the most common pathogen.
". 3etabolic disorders
o (0ample!diabetes mellitus increases susceptibility to infection by
decreasing blood flo# to tissue and increasing tissue levels of
glucose.
2. /utritional deficiencies
a. %ecreased protein (e.g., malnutrition)
b. .itamin C deficiency
%ecreased hydro0ylation of proline and lysine causes
decreased tensile strength in collagen o#ing to loss of
linkage sites bet#een J!chains.
c. Trace metal deficiency
22 Copper deficiency leads to decreased cross!linking of J!
chains in collagen.
222 Kinc deficiency leads to defects in removal of type +++ collagen
in #ound remodeling.
". 'lucocorticoids
a. +nterfere #ith collagen formation and decrease tensile strength
b. ,ccasionally used along #ith antibiotics to prevent scar formation
(e.g., bacterial meningitis)
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@eloids, the raised scars caused by e0cessive synthesis of type +++
collagen, are common in 1frican 1mericans and may occur as the
result of third!degree burns. 3icroscopically, keloids appear as
irregular, thick collagen bundles that e0tend beyond the confines of
the original injury
Repair
in other
tissues
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1. <iver
a. 3ild injury (e.g., hepatitis 1)
i. Regeneration of hepatocytes
ii. Restoration to normal is possible if cytoarchitecture is intact.
b. *evere or persistent injury (e.g., hepatitis C)
i. Regenerative nodules develop that lack sinusoids and portal
triads.
ii. +ncreased fibrosis occurs around regenerative nodules.
&otential for cirrhosis
". <ung
a. Type ++ pneumocytes are the key repair cells of the lung.
b. They replace damaged type + and type ++ pneumocytes.
$. 5rain
a. 1strocytes proliferate in response to an injury (e.g., brain infarction).
This is called gliosis.
b. 3icroglial cells (macrophages) are scavenger cells that remove
debris (e.g., myelin).
22 &eripheral nerve transection
a. %istal degeneration of the a0on (called #allerian degeneration) and
myelin sheath
b. &ro0imal a0onal degeneration up to the ne0t node of Ranvier
c. 3acrophages and *ch#ann cells phagocytose a0onalMmyelin debris.
d. 3uscle undergoes atrophy in 1; days.
e. /erve cell body undergoes central chromatolysis.
i. /erve cell body s#ells.
ii. /issl bodies (composed of rough endoplasmic reticulum and
free ribosomes) disappear centrally.
iii. /ucleus is peripherali)ed.
b. *ch#ann cells proliferate in the distal stump.
c. 10onal sprouts develop in the pro0imal stump and e0tend distally
using *ch#ann cells for guidance.
d. Regenerated a0on gro#s " to $mmMday.
e. 10on becomes remyelinated.
f. 3uscle is eventually reinnervated.
7. eart
g. Cardiac muscle is permanent tissue.
h. %amaged muscle is replaced by noncontractile scar tissue.
,aborator"
Findin4s
Associated
/ith
Inflammation
<eukocytes
page $:
page $D
Table 2-5. Cells in Inflammation
Cell Characteristics
/eutrophil @ey cell in acute inflammation
Receptors for +g' and C$b9 important in phagocytosis of opsoni)ed bacteria
5one marro# neutrophil pools
3itotic pool9 myeloblasts, promyelocytes, myelocytes
&ostmitotic pool9 metamyelocytes, band neutrophils (stabs), segmented
neutrophils
&eripheral blood neutrophil pools
3arginating pool9 adherent to the endothelium (account for ;GI of
peripheral blood pool)
Circulating pool9 measured in complete blood cell count (C5C)
Causes neutrophilic leukocytosis
+nfections (e.g., acute appendicitis)
*terile inflammation #ith necrosis (e.g., acute myocardial infarction)
%rugs inhibiting neutrophil adhesion molecules9 corticosteroids,
catecholamines, lithium
3onocytes and
macrophages
@ey cells in chronic inflammation
Receptors for +g' and C$b
3onocytes become macrophages9 fi0ed (e.g., macrophages in red pulp),
#andering (e.g., alveolar macrophages)
=unctions9 phagocytosis, process antigen, enhance host immunologic
response (secrete cytokines like +<!1, T/=)
Causes of monocytosis9 chronic inflammation, autoimmune disease,
malignancy
5 cells and T cells &eripheral blood lymphocyte count9 T cells ?G!LGI, 5 cells 1G!"GI of the
total
5 cell function9 become plasma cells #hen antigenically stimulated
T cell functions9 cellular immunity (type +. *R), cytokines regulate 5 cells,
defense against intracellular pathogens (e.g., tuberculosis)
Causes of 5MT lymphocytosis9 viral infections
&lasma cells 1ntibody!producing cells derived from 5 cells
3orphology9 #ell!developed rough endoplasmic reticulum (site of protein
synthesis)C bright blue cytoplasm under Hright!'iemsa stainC nucleus
eccentrically located and has perinuclear clearing
3ast cells and
basophils
Release mediators in acute inflammation and allergic reactions (type + *R)
Receptors for +g(
(arly release reaction9 release of preformed mediators (i.e., histamine,
chemotactic factors, proteases)
<ate phase reaction9 ne# synthesis and release of &'s and <Ts, #hich
enhance and prolong the acute inflammatory process
(osinophils Receptors for +g(
Red granules contain crystalline materialC become Charcot!<eyden crystals in
the sputum of asthmatics
&reformed chemical mediators in granules
3ajor basic protein (35&) kills invasive helminths
istaminase neutrali)es histamine
1rylsulfatase neutrali)es leukotrienes
=unctions
3odulate type + *R by neutrali)ing histamine and leukotrienes
%estruction of invasive helminths9 +g( receptors interact #ith +g( coating the
surface of invasive helminths antibody!dependent cytoto0icity reaction (type
++ *R) causes the release of 35& kills helminth
Causes of eosinophilia
Type + *R reactions9 allergic rhinitis, bronchial asthma
+nvasive helminthic infections e#cludin$ pin#orms and adult #orms in
ascariasis, #hich are not invasive
*R, hypersensitivity reactionC +<, interleukinC &', prostaglandinC <T, leukotrieneC T/=, tumor necrosis factor.
1. 1cute inflammation (e.g., bacterial infection)
a. 1bsolute neutrophilic leukocytosis
i. 1ccelerated release of neutrophils from the bone marro#
ii. 3ediated by +<!1 and T/=
b. <eft shift
%efined as greater than 1GI band (stab) neutrophils or the
presence of earlier precursors (e.g., metamyelocytes)
b. To0ic granulation
&rominence of a)urophilic granules (primary lysosomes) in
neutrophils
c. +ncrease in serum +g3
i. &eaks in L to 1G days
ii. +sotype s#itching (N heavy chain replaced by F heavy chain)
in plasma cells to produce +g' peaks in 1" to 17 days.
". Chronic inflammation (e.g., tuberculosis)
b. 1bsolute monocytosis
c. +ncrease in serum +g'
$. summari)es cells involved in inflammation.
7. &eripheral blood effects of corticosteroid therapy
d. 1bsolute neutrophilic leukocytosis
+nhibits activation of neutrophil adhesion molecules
b. <ymphopenia
i. *e-uesters 5 and T lymphocytes in lymph nodes
ii. *ignal for apoptosis of lymphocytes
e. (osinopenia
*e-uesters eosinophils in lymph nodes
<eukocytes
page $D
Table 2-5. Cells in Inflammation
Cell Characteristics
/eutrophil @ey cell in acute inflammation
Receptors for +g' and C$b9 important in phagocytosis of opsoni)ed bacteria
5one marro# neutrophil pools
3itotic pool9 myeloblasts, promyelocytes, myelocytes
&ostmitotic pool9 metamyelocytes, band neutrophils (stabs), segmented
neutrophils
&eripheral blood neutrophil pools
3arginating pool9 adherent to the endothelium (account for ;GI of
peripheral blood pool)
Circulating pool9 measured in complete blood cell count (C5C)
Causes neutrophilic leukocytosis
+nfections (e.g., acute appendicitis)
*terile inflammation #ith necrosis (e.g., acute myocardial infarction)
%rugs inhibiting neutrophil adhesion molecules9 corticosteroids,
catecholamines, lithium
3onocytes and
macrophages
@ey cells in chronic inflammation
Receptors for +g' and C$b
3onocytes become macrophages9 fi0ed (e.g., macrophages in red pulp),
#andering (e.g., alveolar macrophages)
=unctions9 phagocytosis, process antigen, enhance host immunologic
response (secrete cytokines like +<!1, T/=)
Causes of monocytosis9 chronic inflammation, autoimmune disease,
malignancy
5 cells and T cells &eripheral blood lymphocyte count9 T cells ?G!LGI, 5 cells 1G!"GI of the
total
5 cell function9 become plasma cells #hen antigenically stimulated
T cell functions9 cellular immunity (type +. *R), cytokines regulate 5 cells,
defense against intracellular pathogens (e.g., tuberculosis)
Causes of 5MT lymphocytosis9 viral infections
&lasma cells 1ntibody!producing cells derived from 5 cells
3orphology9 #ell!developed rough endoplasmic reticulum (site of protein
synthesis)C bright blue cytoplasm under Hright!'iemsa stainC nucleus
eccentrically located and has perinuclear clearing
3ast cells and
basophils
Release mediators in acute inflammation and allergic reactions (type + *R)
Receptors for +g(
(arly release reaction9 release of preformed mediators (i.e., histamine,
chemotactic factors, proteases)
<ate phase reaction9 ne# synthesis and release of &'s and <Ts, #hich
enhance and prolong the acute inflammatory process
(osinophils Receptors for +g(
Red granules contain crystalline materialC become Charcot!<eyden crystals in
the sputum of asthmatics
&reformed chemical mediators in granules
3ajor basic protein (35&) kills invasive helminths
istaminase neutrali)es histamine
1rylsulfatase neutrali)es leukotrienes
=unctions
3odulate type + *R by neutrali)ing histamine and leukotrienes
%estruction of invasive helminths9 +g( receptors interact #ith +g( coating the
surface of invasive helminths antibody!dependent cytoto0icity reaction (type
++ *R) causes the release of 35& kills helminth
Causes of eosinophilia
Type + *R reactions9 allergic rhinitis, bronchial asthma
+nvasive helminthic infections e#cludin$ pin#orms and adult #orms in
ascariasis, #hich are not invasive
*R, hypersensitivity reactionC +<, interleukinC &', prostaglandinC <T, leukotrieneC T/=, tumor necrosis factor.
1. 1cute inflammation (e.g., bacterial infection)
a. 1bsolute neutrophilic leukocytosis
i. 1ccelerated release of neutrophils from the bone marro#
ii. 3ediated by +<!1 and T/=
b. <eft shift
%efined as greater than 1GI band (stab) neutrophils or the
presence of earlier precursors (e.g., metamyelocytes)
b. To0ic granulation
&rominence of a)urophilic granules (primary lysosomes) in
neutrophils
c. +ncrease in serum +g3
i. &eaks in L to 1G days
ii. +sotype s#itching (N heavy chain replaced by F heavy chain)
in plasma cells to produce +g' peaks in 1" to 17 days.
". Chronic inflammation (e.g., tuberculosis)
b. 1bsolute monocytosis
c. +ncrease in serum +g'
$. summari)es cells involved in inflammation.
7. &eripheral blood effects of corticosteroid therapy
d. 1bsolute neutrophilic leukocytosis
+nhibits activation of neutrophil adhesion molecules
b. <ymphopenia
i. *e-uesters 5 and T lymphocytes in lymph nodes
ii. *ignal for apoptosis of lymphocytes
e. (osinopenia
*e-uesters eosinophils in lymph nodes
(rythrocyte
sedimentation
rate ((*R)
(*R is the rate (mmMhour) of settling of R5Cs in a vertical tube.
1. (*R is increased in acute and chronic inflammation (e.g., rheumatoid
arthritis).
". &lasma factor or R5C factors that promote rouleau0 formation increase the
(*R.
a. +ncrease in fibrinogen (acute!phase reactant) in plasma decreases
negative charge in R5Cs, promoting rouleau0 formation.
b. 1nemia promotes rouleau0 formation.
1bnormally shaped R5Cs (e.g., sickle cells) do not produce
rouleau0.
C!
reactive
protein
(CR&)
1. 1cute!phase reactant
". Clinical usefulness
a. *ensitive indicator of necrosis associated #ith acute inflammation
CR& is increased in inflammatory (disrupted) atherosclerotic
pla-ues and bacterial infections.
b. (0cellent monitor of disease activity (e.g., rheumatoid arthritis)
*erum protein electrophoresis in inflammation
Clinical correlation9 &roteins in serum are separated into individual
fractions by serum protein electrophoresis (*&(). Charged proteins
placed in a buffered electrolyte solution #ill migrate to#ard one or
the other electrode #hen a current is run through the solution.
&roteins #ith the most negative charges (e.g., albumin) migrate to
the positive pole, or anode, and those #ith the most positive
charges (e.g., F!globulins) remain at the negatively charged pole, or
cathode. 5eginning at the anode, proteins separate into five major
peaks on cellulose acetate!albumin, follo#ed by J1!, J"!, 8!, and F!
globulins. The F!globulins in decreasing order of concentration are
+g', +g1, and +g3 (+g% and +g( are in very lo# concentration).
1. 1cute inflammation
a. *light decrease in serum albumin
i. Catabolic effect of inflammation
ii. 1mino acids are used by the liver to synthesi)e acute phase
reactants.
b. /ormal F!globulin peak
*erum +g3 is increased in acute inflammationC ho#ever, it
does not alter the configuration of the F!globulin peak.
22 Chronic inflammation (see
a. 'reater decrease in serum albumin than in acute inflammation
b. +ncrease in F!globulins due to increase in +g'
%iffuse increase in the F!globulin peak is due to many clones
of benign plasma cells producing +g' (i.e., polyclonal
gammopathy).