ACUTE AND CHRONIC INFLAMMATION

..

(inflammation)


(systemic effect)

2
fibroblasts

2 (acute inflammation)
(chronic inflammation)
2 3 1
(edema) (exudate)
neutrophils

(fibrosis)
macrophages lymphocytes


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..

4
(pain, dolor), (swelling, tumor), (redness, rubor) (heat, calor)

ACUTE INFLAMMATION
OVERVIEW OF ACUTE INFLAMMATION

3
1)

2)


3)


permeability

(intercellular
space)
(pericardial
cavity)
(pleural cavity) (peritoneal cavity)

exudate exudate
neutrophils
(pus) purulent exudate

transudate

(Kumar V, Abbas
AK, Fausto N, eds. Robbins and Cotran Pathologic
Basis of Disease. 7th ed. Philadelphia: Elsevier
Saunders, 2005: 51.)

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..

STIMULI FOR ACUTE INFLAMMATION

-
-
-
- (tissue necrosis)
- (foreign body)
- (immune reaction) hypersensitivity reactions
VASCULAR CHANGES


CHANGE IN VASCULAR FLOW AND CALIBER


- (vasodilation)
(transient
vasoconstriction)
arteriole (capillaries)
histamine nitric oxide

- permeability

(stasis)
- neutrophils

(intercellular space)
INCREASED VASCULAR PERMEABILITY (VASCULAR LEAKAGE)
permeability
(intravascular osmotic pressure)
(interstitial osmotic pressure)
(intravascular hydrostatic pressure)
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(edema)

- Formation of endothelial gaps in venules
venule
histamine, bradykinin, leukotriene neuropeptide substance P
30
cytokines interleukin-1 (IL-1), tumor necrotic
factor (TNF), interferon-N (IFN-N)
24
- Direct endothelial injury

arteriole venule

- Delayed prolonged leakage

venule 2 12
- Leukocyte-mediated endothelial injury venule

- Increased transcytosis vesiculovacuolar organelle

vascular endothelial growth factor
(VEGF), histamine
- Leakage from new blood vessels

receptor
histamine, substance P VEGF

CELLULAR EVENTS: LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

extravasation

extravasation
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1) Margination stasis

2) Rolling
3) Adhesion
4) Transmigration (diapesis) (pseudopod)

5) Migration

(Kumar V, Abbas AK,

Fausto N, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 53.)

LEUKOCYTE ADHESION AND TRANSMIGRATION

adhesion transmigration
adhesion molecules
adhesion molecule adhesion molecule 4
Selectins E-selectin Pselectin L-selectin
Immunoglobulin family 2 ICAM-1 (intercellular adhesion molecule 1)
VCAM-1 (vascular cell adhesion molecule 1)
integrin
Integrins integrin ligand (ICAM-1, VCAM-1)
extracellular matrix
Mucin-like glycoprotein heparan sulfate extracellular matrix
CD44 adhesion molecule
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..

adhesion molecules histamine, thrombin platelet activating

factor (PAF) Weibel-Palade body P-selectin
macrophages, mast cells
tumor necrotic factor (TNF) interleukin-1 (IL-1)
E-selectin selectin ligand
selectin
TNF IL-1 integrin ligand
VCAM-1 ICAM-1 integrin
integrin VCAM-1 ICAM-1
(adhesion)
adhesion molecule
platelet endothelial cell adhesion molecule (PECAM-1 CD31)
extracellular matrix integrin CD44
extracellular matrix

6 24 neutrophils
monocytes macrophages neutrophils
neutrophils
apoptosis 24 48 monocytes
Pseudomonas
neutrophils 4 lymphocytes
(hypersensitivity reaction) eosinophils
CHEMOTAXIS


(chemotactic stimuli) (exogenous stimuli) (endogenous stimuli)
1) Complement C5a
2) lipoxygenase pathway leukotriene B4 (LTB4)
3) Cytokine
Chemotactic stimuli receptors
actin
LEUKOCYTE ACTIVATION
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leukocyte activation
- arachidonic acid
- (lysozomal enzyme)
- cytokines
- adhesion molecule

receptors
- Toll-like receptors (TLRs) receptor
bacterial lipopolysaccharide bacterial proteoglycans
receptor cytokines
(microbicidal substance)
- Different seven-transmembrane G-protein-coupled receptors receptor
chemokine, C5a, platelet activating factor (PAF), prostaglandin E (PGE)
leukotriene B4 (LTB4)
migration
- Receptors for cytokines phagocytes receptor cytokine
IFN-N lymphocytes natural killer
cells (NK cell) T lymphocytes macrophages
- Receptors for opsonins opsonin antibody, complement proteins
lectin phagocytes
receptor FcN receptor phagocytes
IgG antibody complement receptor type 1 (CR1) complement protein C3

(499303) 2552 Acute and Chronic Inflammation

..

8
receptor (Kumar V, Abbas AK, Fausto N, eds.
Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 58.)

PHAGOCYTOSIS
3
Recognition and attachment
receptors
mannose receptors scavenger receptors opsonin

Engulfment
pseudopods phagosome
phagosome lysosome phagolysosome lysosome
phagolysosome actin
receptors chemotaxis
Killing and Degradation (oxygen-dependent
mechanism) reactive oxygen intermediates (ROIs) reactive oxygen species
phagolysosome
(oxygen-independent mechanism) bactericidal
permeability increasing protein (BPI)

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9
phagocytosis (Kumar V, Abbas AK, Fausto N, eds. Robbins
and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 60.)

RELEASE OF LEUKOCYTE PREDUCTS AND LEUKOCYTE-INDUCED TISSUE INJURY

phagolysosome
lysosomal enzymes,
reactive oxygen intermediates arachidonic acid

DEFECT IN LEUKOCYTE FUNCTION



- Defects in leukocyte adhesion leukocyte
adhesion deficiency type 1 (LAD1) integrin leukocyte adhesion
deficiency type 2 (LAD2) sialyl-Lewis X-modified glycoprotein
receptor E-selectin
- Defect in phagolysosome function Chdiack-Higashi syndrome
degranulation lysosomal
enzyme phagosome
autosomal recessive
- Defect in bactericidal activity chronic granulomatous disease
NADPH oxidase reactive oxygen intermediate
- Bone marrow suppression

CHEMICAL MEDIATORS OF INFLAMMATION

(chemical mediator)

- Chemical mediator
complement proteins kinin
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10

histamine, prostaglandins cytokines

fibroblasts
Chemical mediators
chemical mediators
Chemical mediators (receptor)

Chemical mediators chemical mediators
chemical mediators
Chemical mediators

chemical mediators

VASOACTIVE AMINES
histamine serotonin histamine

HISTAMINE
mast cells basophils
histamine
1) (physical injury) (trauma)

2) mast cells
3) Anaphylatoxins C3a C5a
4) mast cells histamine
5) Neuropeptide substance P
6) Cytokine interleukin-1, interleukin-8
Histamine H1 receptor arteriole
vascular permeability venule
SEROTONIN
Serotonin enterochromaffin cells
serotonin platelet-activating factors (PAF) platelet aggregation serotonin serotonin histamine
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11

PLASMA PROTEINS
3 complement, kinin
clotting systems
COMPLEMENT SYSTEM
Complement system complement proteins C1 C9
(inactive form) C3
3
- Classical pathway C1
classical pathway C3 convertase
C3
- Alternative pathway lipopolysaccharide (LPS)
C3 alternative pathway C3 convertase
- Lectin pathway lectin
C1 C3 convertase
C3 C3 convertase C3a C3b C3b
complement proteins C5 convertase C5 C5a C5b C5b
complement proteins C6 C9 membrane attack complex (MAC)

complement protein (Kumar V, Abbas AK, Fausto N, eds. Robbins and

Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 66.)

(499303) 2552 Acute and Chronic Inflammation

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C3a C5a mast cells histamine C5a

neutrophils monocytes arachidonic acid
lipoxygenase
- C5a chemotactic stimuli
leukocyte adhesion, chemotaxis activation
- C3b opsonin phagocytosis
complement system C3 C5

lysosomal enzyme plasmin neutrophils complement system
neutrophils

complement system (Kumar V, Abbas AK, Fausto N, eds.

Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 65.)

KININ SYSTEM
kininogen
kallikreins kinin system bradykinin
permeability
bradykinin kininase
CLOTTING SYSTEM
thrombin fibrin fibrin
thrombin thrombin protease-activated
receptors (PARs)
thrombin receptor
P-selectin, chemokines, integrins, PAF, nitric oxide cyclooxygenase-2
prostaglandins
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13

fibrin fibrin (fibrinolytic system)

(clot)
plasminogen activator plasminogen plasmin
complement protein C3
clotting factors thrombin fibrin

complement , kinin, clotting fibrinolytic sytem

(Kumar V, Abbas AK, Fausto N, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier
Saunders, 2005: 67.)

ARACHIDONIC ACID METABOLITES: PROSTAGLANDINS, LEUKOTRIENES AND LIPOXINS

Arachidonic acid (AA) phospholipids
phospholipase phospholipase
C5a arachidonic acid
cyclooxygenases prostaglandins thromboxanes
lipoxygenases leukotrienes lipoxin arachidonic acid
eicosanoids

Action
Vasoconstriction
Vasodilatation
Increased vascular permeability
Chemotaxis and Leukocyte adhesion

Eicosanoids
Thromboxane A2, Leukotrienes C4, D4, E4
Prostacyclin (PGI2), Prostaglandins E1, E2, D2
Leukotrienes C4, D4, E4
Leukotrienes B4, HETE, lipoxins

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arachidonic acid cyclooxygenases prostaglandins

(PG) PGE2, PGD2, PGF2H, PGI2 (prostacyclin)
TxA2 (thromboxane) PGE2
PGE2,
PGD2 PGF2H permeability
lipoxygenase 5-lipoxygenase (5-LO)
neutrophils 5-hydroxyeicosatetraenoic acid (5-HETE) chemotactic stimuli
neutrophils 5-HETE leukotrienes
LTB4 chemotactic stimuli neutrophils
leukocyte adhesion and aggregation oxygen free radicals lysosomal enzyme
leukotriene LTC4, LTD4 LTE4 permeability
LTA4 12lipoxygenase (12-LO) lipoxin A4 (LXA4) lipoxin B4 (LXB4)

archidonic acid (Kumar V,

Abbas AK, Fausto N, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders,
2005: 69.)

PLATELET-ACTIVATING FACTORS
PAF phospholipid arachidonic acid
(bronchoconstriction)
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permeability PAF leukocyte

adhesion, chemotaxis phagocytosis chemical mediators
PAF basophils, mast cells, neutrophils,
macrophages
CYTOKINES AND CHEMOKINES
Cytokine lymphocytes
macrophages
TUMOR NECROSIS FACTOR AND INTERLEUKIN-1
Tumor necrotic factor (TNF) interleukin-1 (IL-1) macrophages
fibroblasts acutephase reactions endotoxin
(immune complexes)

TNF IL-1 acute phase reaction (Kumar V, Abbas AK, Fausto N, eds.
Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 71.)

CHEMOKINES
(chemoattractant) 4

-

H chemokines interleukin-8 macrophages

IL-8 TNF, IL-1

IL-8 activation chemotaxis
neutrophils

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I chemokines monocyte chemoattractant protein (MCP-1), eotaxin, macro-

phage inflammatory protein-1H (MIP-1H) RANTES (regulate and normal T cell

expressed and secreted) chemoattractant monocytes, eosinophils,
basophils lymphocytes
N chemokines lymphotaxin lymphocytes
CX3C chemokines fractalkine monocytes lymphocytes

NITRIC OXIDE
Nitric oxide (NO) macrophages

NO
LYSOSOMAL CONSTITUENTS OF LEUKOCYTES
neutrophils monocytes lysosomal granules
neutrophils granules 2
- Specific (secondary) granules lysozyme, collagenase,
gelatinase, lactoferrin, plasminogen activator, histamine alkaline phosphatase
- Azurophil (primary) granules myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolase, neutral protease
phagolysosome
extracellular matrix
neutral protease C3 C5
lysosomal granules
antiprotease H1-antitrypsin
neutral protease H1-antitrypsin (H1-antitrypsin deficiency)
protease

OXYGEN-DERIVED FREE RADICALS

free radicals
chemokine (immune
complexes) oxygen-derived free radicals chemokines, cytokines,
adhesion molecules
antiprotease

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NEUROPEPTIDES
vasoactive amines eicosanoids
neuropeptide substance P neurokinin A

SUMMARY OF CHEMICAL MEDIATORS OF ACUTE INFLAMMATION

chemical mediators
Action
Mediator
Vascular
Chemotaxis
Others
leakage
Histamine and
+
Sertonin
Bradykinin
+
Pain
C3a
+
Opsonin
C5a
+
+
Leukocyte adhesion, activation
Prostaglandins
Potentiate
Vasodilation, pain, fever
others
Leukotriene B4
+
Leukocyte adhesion, activation
Leukotriene C4, D4, E4
+
Bronchoconstriction, vasoconstriction
Oxygen metabolites
+
Epithelial and tissue damage
PAF
+
+
Bronchoconstriction and leukocyte priming
IL-1 and TNF
+
Acute-phase reactions, endothelial activation
Chemokines
+
Leukocyte activation
Nitric oxide
+
+
Vasodilation, cytotoxicity
mediators
Effect
Mediators
Vasodilatation
Prostaglandin
Nitric oxide (NO)
Histamine
Increased vascular permeability
Vasoactive amines
C3a and C5a
Bradykinin
Leukotriene C4, D4, E4
Platelet activating factor (PAF)
Substance P
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Chemotaxis, leukocyte recruitment and activation C5a

Leukotriene B4
Chemokine
Tumor necrotic factor (TNF)
Interleukin-1 (IL-1)
Bacterial products
Fever
Tumor necrotic factor (TNF)
Interleukin-1 (IL-1)
Prostaglandins
Pain
Prostaglandins
Bradykinin
Tissue damage
Neutrophil and macrophage lysosomal enzymes
Oxygen metabolite
Nitric oxide (NO)

OUTCOME OF ACUTE INFLAMMATION

3
1. (complete
resolution)
permeability
neutrophils apoptosis
macrophages
2. (healing by connective tissue replacement or fibrosis)

(fibrin)

3. (chronic inflammation)

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(Kumar V, Abbas AK, Fausto N, eds.

Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 75.)

MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION

SEROUS INFLAMMATION
(serous fluid)

mesothelium (pericardial cavity) (pleural
cavity) (peritoneal cavity) effusion
FIBRINOUS INFLAMMATION

fibrinogen fibrin fibrinous exudate


procoagulant stimulus
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(resolution)

(fibrosis)

SUPPURATIVE OR PURULENT INFLAMMATION
(pus purulent exudate)
neutrophils pyogenic
bacteria (acute appendicitis)
(abscess)
neutrophils
(hyperemia)
ULCERS

neutrophils

lymphocytes, macrophages plasma cells

CHRONIC INFLAMMATION
OVERVIEW OF CHRONIC INFLAMMATION

1. Mycobacterium,
Treponema pallidum
delayed type hypersensitivity
granulomatous inflammation
2.
silicosis

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21

atherosclerosis
3. (autoimmune reaction)
autoimmune diseases rheumatoid arthritis systemic lupus
erythematosus (SLE)

MORPHOLOGIC FEATURES OF CHRONIC INFLAMMATION

neutrophils

1. mononuclear cells macrophages, lymphocytes
plasma cells
2. (tissue destruction)

3. (connective tissue replacement)

MONONUCLEAR CELL INFILTRATION
macrophages mononuclear phagocyte system (blood monocytes)
Kupffer cells sinus histiocytes alveolar macrophages osteoclasts


macrophages
48
neutrophils macrophages IFN-N T lymphocytes
NK cells macrophages
macrophages
lysosomal enzyme

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macro-phages
macrophages
macrophages
- adhesion molecules chemotactic stimuli monocytes
C5a,
platelet-derived growth factor (PDGF) transforming growth factor-H (TGF-H)
- macrophages (local proliferation)
- macrophages
(immobilization of macrophages)
macrophages
reactive oxygen and nitrogen intermediates protease
fibroblasts

macrophages (Kumar V, Abbas AK, Fausto N, eds. Robbins

and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 80.)

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OTHER CELLS IN CHRONIC INFLAMMATION

macrophages
Lymphocytes
Lymphocytes macrophages
macrophages cytokines interleukin-12 T lymphocytes
T lymphocytes cytokines IFN-N
macrophages
B lymphocytes plasma cells
macrophages, lymphocytes plasma cells lymphoid follicle synovium
rheumatoid arthritis

macropahges lymphocytes (Kumar V, Abbas AK, Fausto N,

eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005: 82.)

Eosinophils
IgE
eosinophils major basic protein
eosinophils
eosinophils eotaxin
Mast cells

mast cells histamine arachidonic acid metabolites
cytokines
GRANULOMATOUS INFLAMMATION
macrophages
(epithelial-like or epithelioid appearance)

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24

tuberculosis, cat-scratch disease, leprosy, syphilis, lymphogranuloma venereum

granuloma macrophages
epithelioid histiocytes epithelioid histiocytes
multinucleated giant cells
lymphocytes plasma cells
Granuloma 2
1. Foreign-body granulomas
granuloma giant
cell giant cells
foreign body-type giant cell
2. Immune granulomas
cell-mediated macrophages
T lymphocytes T lymphocytes IL-2 T
lymphocytes IFN-N macrophages
epithelioid histiocytes giant cells
Langhans-type giant cells granulomas
tuberculosis
caseous necrosis granuloma
central caseous necrosis
LYMPHATICS IN INFLAMMATION
basement membrane



lymphangitis lymphadenitis

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SYSTEMIC EFFECTS OF INFLAMMATION

acute phase responses systemic
inflammatory response syndrome (SIRD) cytokine

FEVER
1 4
pyrogens 2
exogenous pyrogens lipopolysaccharide
endogenous pyrogens interleukin-1 tumor necrotic factor
cyclooxygenases arachidonic acid prostaglandins prostaglandin
E2 hypothalamus
ACUTE-PHASE PROTEIN

C-reactive protein (CRP), fibrinogen serum amyloid A protein (SAA)
interleukin-6 C-reactive protein
fibrinogen serum amyloid A protein interlukin-1 tumor necrotic factor
Acute-phase protein CRP SAA opsonins
complement proteins fibrinogen
(sedimentary rate)
erythrocyte sedimentary rate (ESR)

SAA
amyoidosis
LEUKOCYTOSIS
10,000
( 5,000 10,000 )
cytokines IL-1 TNF

40,000
100,000 leukemoid reaction
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26

leukemia

Neutrophilia neutrophils

Lymphocytosis lymphocytes

Eosinophilia eosinophils
(bronchial asthma)
leukopenia
rickettsiae

OTHER MANIFESTATIONS
(anorexia)
(somnolence) (malaise) cytokines

CONSEQUENCES OF INFLAMMATION
DEFECTIVE INFLAMMATION



EXCESSIVE INFLAMMATION

autoimmune diseases

(atherosclerosis) (ischemic heart disease)
(degenerative diseases) Alzheimer disease

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REFERENCE
Fantone JC, Ward PA. Repair, Inflammation. In: Rubin E, eds. Essential pathology. 3rd ed.
Philadelphia: Lippincort Williams & Wilkins, 2001: 23-46.
Kumar V, Abbas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease. 7th ed.
Philadelphia: Elsevier Saunders, 2005.
Kumar V, Cotran RS, Robbins SL. Robbins basic pathology. 7th ed. Philaldelphia: W.B. Saunders,
2003.
Murphy HS, Ward PA. Inflammation. In: Rubin E, et al, eds. Rubins Pathology: Clinicopathologic
Foundation of Medicine. 4th ed. Philadelphia: Lippincort Williams & Wilkins, 2005: 40-83.

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