Pathophysiology of Inflammation
Miklós Molnár
Essentials of Inflammation
Inflammation is a complex defense
reaction in the vascularized connective
tissue in response to endogenous or
exogenous stimuli in order to destroy,
eliminate the injurious agents or
microorganisms and initiate a series of
events that heal and reconstitute the
damaged tissue
Subsequent Events
Alteration (tissue injury)
Vascular reaction
Proliferation (reconstitution)
Localization
The connective tissue and its
microcirculation including the
surrounding extracellular space.
Participants
 Plasmaproteins
– Proteolytic cascades:
coagulation, kinin,
fibrinolytic
 Blood cells
– Neutrophils, eosinophils,
basophils, monocytes,
lymphocytes, platelets
 Cells of the connective tissue
– Mast cells, fibroblasts,
macrophags, lymphocytes
 Blood vesels
– Endothelium, basement
membrane, smooth muscle
cells
Participants
 Extracellular matrix
– Fibronectin, laminin, collagen,
enactin, tenascin, proteoglikans
etc.
 Specific mediators
– Early mediators  positive,
amplification
– Late mediators  negative,
restitutio
Injury
Acute
Inflammation
or
Restitution
Chronic
Inflammation
or
Restitution
Proliferation
(granuloma)
Restitution
Types of Inflammatory
reactions
Type
Acute
Inflammation
Duration
max. 1 week
Characteristics exudation (edema)
emigration of leukocytes
Chronic
Inflammation
> 1 week
connective tissue
proliferation
lymphocytes and
macrophages
accumulation
Inflammation
Local reactions
Systemic reactions
Classical (cardinal)
Acute phase reaction,
fever, leukocytosis etc.
signs
Celsus described the four famous signs of
inflammation calor, rubor, tumor, and dolor(A.D. 30)
Systemic Effects of Inflammation
Acute-phase reaction
TNFa, IL-1 & IL-6
 fever




leukocytosis
Iron deficiency, anemia
proteolysis
activation of lymphocytes
g-INTERFERON
IMMUNCOMPLEX
NEUROPEPTIDES
MACROPHAGES
ENDOTOXIN
EXOTOXIN
Initiation of
Acute Phase IL-1
IL-6
Reaction
URATE SILICATE
CRISTALS
TNFα
Acute Phase proteins
 Ceruloplasmin
– Scavenges oxygen radicals generated by leukocytes
 Protease inhibitors
– α1-protease inhibitor, α1-antichymotrypsin and α2-macroglobulin
 C-reactive protein (CRP)
– binds to bacteria and produce capsular swelling, precipitation and
agglutination; binding also fixes complement, thus causing the
production of C3b (an opsonin) and chemotactic factors
 Fibrinogen
– may serve as opsonin by clumping bacteria together; breakdown
products of fibrinogen has anti-inflammatory activity
 Transferrin
– decreases, thus limiting the amount of iron available to meet bacterial
growth requirement
P
A
T
H
O
M
E
C
H
A
N
I
S
M
O
F
INFECTION, TOXINS, IMMUNCOMPLEXES, NEOPLASIA
IL-1/TNF
Hypothalamus
F
E
V
E
R
Prostaglandins (E2)
Vasomotor center ?
Sympathetic nerves
Skin vasoconstriction
↓ Heat dissipation
FEVER
IL-6
Local Effect of Acute
Inflammation
 Blood flow increases (alteration of vascular caliber)
 Increased vascular permeability (plasma proteins
and leukocytes leave the circulation, retraction of
endothelial cells, fenestration)
 Cellular events (emigration of leukocytes and
makrophages: margination, rolling, adhesion, emigration,
chemotaxis, phagocytosis)
Advantages of exudation
 Fluid exudation
(dilution of toxins)
 Increased protein content
Globulins (antibodies)
Fibrin precipitation
(Bacterial fixation, wound healing)
Acute-phase proteins
Mechanisms of Vascular Leakage
1. Endothelial contraction
widening of intercellular junctions (rapid , short-lived
action, histamine, bradykinin, leukotrienes etc. effects
only the small venules)
2. Junctional retraction
induced by IL-1, TNFα, IFNg, delayed (4-6 hours) effect
3. Leukocyte-dependent leakage
free radicals and proteolytic enzymes
4. Leakage from regenerating capillaries
angiogenesis, intercellular junction development
Leukocyte extravasation
 Margination, rolling and adhesion
 Transmigration across the endothelium
(diapedesis)
 Migration in interstitial tissues toward a
chemotactic stimulus
Adhesion receptors
 Selectins
– E-selectin (ELAM-1, endothelium)
– P-selectin (GMP140, platelets)
– L-selectin (LAM-1, leukocytes)
 Immunoglobulins
 endothelial adhesion molecules:
intercellular (ICAM-1), vascular cell ~ (VCAM-1)  both
interact with integrins found on leukocytes
 Integrins (transmembrane-adhesive heterodimeric
glycoproteins, α and β chains)
 2-integrins (LFA-1, MAC-1  ICAM-1)
 1-integrin (VLA-4  VCAM-1)
Cell Surface Adhesion Receptors
Roles and Mechanism of Adhesion
Molecules
1. Redistribution of adhesion
molecules to the cell surface
P-selectin (intracitoplasmatic granules of endothelial
cells - Weibel-Palabe granules
histamin, thrombin, PAF cell surface 
adhesion and rolling of leukocytes
Roles and Mechanism of Adhesion
Molecules
2.
Induction of adhesion molecules on
endothelium
(IL-1, TNF)  E-selectin, and ICAM-1, VCAM-1
3.
Increased avidity of binding
LFA-1 on leukocytes dose not adhere to its ligand ICAM1 on endothelium at resting condition. However, after
certain stimuli LFA-1 is converted from a state of low- to
high-affinity binding toward ICAM-1
Strong binding  Transmigration across endothelium
Migration of Leukocytes
Selectins
Integrins
Chemotaxis and Leukocyte Activation
 Exogenous substances
– bacterial products (N-formyl-methionine containing
peptides, lipids)
 Endogenous substances
Compounds of complement system ( C5a, C3a)
Products of the Lipoxygenase pathway (LTB4)
Cytokines (IL-8)
receptor bindings  PLC-Ca2+  actin-myosin  active locomotion and
activation of PLA2 AA, degranulation (lysosomal enzymes), modulation of
adhesion molecules
Chemotaxis
Phagocytosis 1.
Recognition and attachment
– opsonins mediated (Fc-fragment of IgG, C3b)
(via FcgR receptors)
– nonopsonic phagocytosis  recognition of LPS
Phagocytosis 2.
 Engulfment
Binding to FcgR  pseudopods  fusion of the
phagocytic vacules and the lysosomal granules
 Killing or Degradation
Oxygen dependent:
NADPH oxidase  superoxide ion  H2O2
MPO H2O2 + Cl-  HOCl
NO synthase  NO  peroxinitrite (CONO2- )
Oxygen independent:
lysozyme, lactoferrin, MBP –major basic protein-,
defensins, acid hydrolase
Phagocytosis
Defects in Leukocyte Functiom
Genetic
Disease
Defect
 Leukocyte adhesion deficiency 1  β chain of CD11/ CD18 integrins
 Leukocyte adhesion deficiency 2  Selectin receptors (Sialyated oligosacharide)
 Neutrophil specific granule
deficiency
 Absence of neutrophil specific
granules, defective chemotaxis
 Chronic granulomatosus disease  Decreased oxidative burst
– X-linked
– NADPH oxidase (membrane component)
– Autosomal recessive
– NADPH oxidase (cytoplasmic component)
 Myeloperoxidase deficiency
 Absent MPO-H2O2 system
 Chédiak-Higashi syndrome
 Multiple defect
Defects in Leukocyte Functiom
Acquired
Disease
 Thermal injury, diabetes,
malignancy, sepsis,
immunodeficiencies
 Hemodialysis, diabetes
 Leukemia, anemia, sepsis,
diabetes, neonates,
malnutrition
Defect
 Chemotaxis
 Adhesion
 Phagocytosis and
microbicidal activity
Plasma Proteases
Kinin system
Fibrinolytic system
Complement system
The Kinin system
 Bradykinin
1. Inducing arteriolar dilatation
2. Increasing the permeability
of venules
3. Causing pain
 Kallinkrein
1. Activation of plasminogen
2. Activation of C1q in the
complement system
3. Found in plasma , tissues
and secretions
The Fibrinolytic System
Plasminogen Activating
Factors
prourokinase  urokinase
Kallikrein
 Plasmin
1. Produce vasodilatation by generating FDP
2. Can digest fibrin, removes fibrin deposit
3. Can activate complement system by cleaving C3
Other Plasminogen Activators
Bacterial substances (eg. streptokinase)
Cell-derived activators (eg. trypsin)
Macrophage plasminogen activator
Hageman factor
Note:
Plasmin was formerly known as fibrinolysin, this old name
is still used for this system
The Complement System
 Consist of 20 interactive plasma and cell
membrane proteins
 Activated complement:
–
–
–
–
Mediating vascular responses (histamine release)
Requiting phagocytic leukocytes (chemotaxis)
Opsonizing target of phagocytic cells
Directly damaging target cells or tissue
 Activation:
– Classic pathway
– Alternative pathway
Classic Pathway
This pathway is activated by antibody-coated targets or antigenantibody complexes
Hageman Factor
C1 inhibitor
Alternative Pathway
Activated by: 1. LPS; 2. plasmin; 3. a factor from cobra venom;
4. aggregated IgM or IgG; 5. complexes of antigen with IgA
C3b inhibitor
The Role of Hageman Factor
C1 inhibitor
Chemical Mediators of
Inflammation
Vasodilatation
Prostaglandins, histamin
Vascular permeability
Vasoactiv amins
C3a and C5a
Bradykinin
Leukotrien C4, D4, E4, PAF
 Chemotaxis
C5a, Leukotrien B4 , lipids, bacterial products
Chemical Mediators of
Inflammation
 Fever
IL-1; TNF, Prosztaglandin E2
 Pain
Prosztaglandins, Bradykinin
 Tissue injury
Lysosomal enzymes (neutrophils, macrophages)
oxygen metabolites
Cyclo-oxygenase Hypothesis - 1990’s
membrane phospholipids
(-)
Phospholipase A2
glucocorticoids
(-)
arachidonic acid
COX-1
constitutive
(-)
Classical
NSAIDS
COX-2
(-)
Stomach
Kidney
Endothelium
PGE2/PGI2
PGE2/PGI2
PGI2
gastric
cytoprotection
renal blood
flow
inducible
Platelets
TXA2
haemostasis
Physiological Effects
INDUCTION:
mitogens
endotoxins
cytokines
(-)
selective
COX-2
inhibitors
Inflammatory Sites
PGE2
inflammatory
mediators
Inflammation
Hierarchies of cytokines
Stimulus
TNF a
IL-1
IL-6, IL-8, VEGF, GM-CSF
Effect of anti-TNFa Treatment
 Decreased synthesis of IL-1, IL-6
 Inhibition of the migration of leukocytes
 Decreased number of endothelial adhesion
molecules (VCAM-1, ICAM-1, E-selectin)
 Decreased endothelial chemotactic chemokins (IL-8)
 Decreased T-cell infiltration (T CD4 sup+, CD45
RO sup+)
Chronic Inflammation
Inflammation of prolonged duration (weeks,
months) in which active inflammation, tissue
destruction and attempts to healing are
proceeding simultaneously
–
–
–
–
infiltration with mononuclear cells
tissue destruction
attempt to repair by connective tissue (fibrosis)
angiogenesis
Causes of Chronic Inflammation
Persistent infection
Prolonged exposure to toxic agents
Immune reactions against own tissue 
autoimmune disease (SLE, RA)