What is inflammation?

Inflammation
Inflammation is a complex reaction in tissues that

consists mainly of responses of blood vessels and

leukocytes
Protective response intended to eliminate the initial
cause of cell injury and the necrotic cells and tissues
arising from the injury

History
Egyptian papyrus - 3000 B.C.
Celsus (Roman in 1st century A.D.)
Rubor - Tumor - Calor - Dolor

redness - swelling - heat pain

Rudolf Virchow added loss of function later
Elie Metchnikoff -Phagocytosis

 Acute
Rapid in onset, lasting for min/hrs/days

Exudation of fluid and plasma proteins (edema)

Emigration of leukocytes predominantly

neutrophils
Chronic
Longer duration

Lymphocytes and macrophages

Proliferation of blood vessels, fibrosis and tissue

necrosis

Etiologies
Microbial infections: bacterial, viral, fungal,parasitic

etc.-Toll like receptors

Physical agents: burns, trauma--like cuts, radiation
Chemicals: drugs, toxins, or caustic substances like

battery acids
Immunologic reactions: rheumatoid arthritis

Microbial infections
One of the commonest causes of inflammation
Bacteria release specific exotoxins or endotoxins
In parasitic infections hypersensitivity plays an

important role

Physical agents
Tissue damage leading to inflammation may occur
through physical trauma, ultraviolet or other ionizing
radiation, burns or excessive cooling
Irritant and corrosive chemicals
Corrosive chemicals (acids, alkalis, oxidizing agents)
provoke inflammation through tissue damage

Five classic local signs of acute

inflammation
Heat

Calor vasodilatation

Redness

Rubor vasodilatation

Swelling

Tumor vascular permeability

Pain

Dolor mediator release

Loss of function Functio laesa

Components of Inflammation

 Acute inflammation is a rapid response to an injurious

agent that serves to deliver mediators of host defenseleukocytes and plasma proteins- to the site of injury
Alterations in vascular caliber
Structural changes in microvasculature
Emigration and activation of leukocytes

Vascular changes
Transient vasoconstriction
Vasodilation
Exudation of protein rich fluid
Blood stasis
Margination
Transmigration

Vasodilatation
Vascular
permeability

Stasis
Leukocyte
Adhesion
Transmigration
Chemotaxis
Phagocytosis

Termination

Vasodilation
Earliest manifestation
First involves arterioles
Important mediators- Histamine and NO

Histamine
Causes dilatation of arterioles first
Increases the permeability of the venules
Principal mediator of the immediate transient phase

of increased vascular permeability, causing venular

gaps

 Swelling (tumor)
Swelling result from edema, the accumulation of
fluid(exudate) in the extra vascular space

Exudate

Transudate

vascular permeability Normal vascular

High protein & cell

debris
Specific gravity >
1.020

permeability
Low protein (mostly
albumin)
Specific gravity <
1.012

Triple response

How do endothelial cells become permeable?

Endothelial cell contraction
Direct endothelial injury (immediate sustained
response)
Leukocyte-dependent endothelial injury
Increased transcytosis of fluid

Slowing

Margination

Concentration

Rolling

Adhesion

Transmigration

Margination
Normal flow - RBCs and
WBCs flow in the center
of the vessel
A cell poor plasma is
flowing adjacent to
endothelium
As blood flow slows,
WBCs collect along the
endothelium

Rolling
Selectins transiently bind to

receptors
Some selectins are present on
endothelial cells (E-Selectin)
Some selectins are present on
leukocytes (L-Selectin)
Some selectins are present on
platelets (P-Selectin)
Weak & transient binding
Results in rolling

Adhesion
Mediated by integrins ICAM-1 and VCAM-1

Transmigration
Mediated by PECAM-1
Primary in venules
Collagenases degrade BM

 Locomotion oriented along a chemical gradient

Both exogenous and endogenous substances can act as
chemoattractants

Exogenous agents are bacterial products, including

peptides that possess an N-formylmethionine terminal
amino acid, and some lipids
Endogenous chemoattractants
(1) cytokines, particularly those of the chemokine
family (e.g., IL-8)

(2) components of the complement system,

particularly C5a
(3) arachidonic acid (AA) metabolites, mainly

leukotriene B4 (LTB4)

 The nature of the leukocyte infiltrate varies with the

age of the inflammatory response and the type of
stimulus
Neutrophils predominate in the inflammatory infiltrate
during the first 6 to 24 hours and are replaced by
monocytes in 24 to 48 hours
they are more numerous in the blood
respond more rapidly to chemokines
they may attach more firmly to the adhesion

molecules that are rapidly induced on endothelial

cells, such as P- and E-selectins

 After entering tissues, neutrophils are short-lived; they

undergo apoptosis and disappear

Monocytes not only survive longer but may

proliferate in the tissues, and thus become the
dominant population in chronic inflammatory
reactions
Pseudomonas infection-neutrophils for several days
In viral infections-lymphocytes
In hypersensitivity reactions- eosinophils

Phagocytosis
Destroy
Degranulation and the oxidative burst destroy the
engulfed particle
Recognition & attachment
Opsonins coat target and bind to leukocytes

Engulfment
Killing/degradation
O2 dependent
O2 independent

 Oxygen independent mechanisms

BPI-bactericidal/permeability increasing protein
Lysozyme
Lactoferrin
Major basic protein-in esinophils
Defensins

Defects in Leucocyte function

Chemical mediators of inflammation

Plasma-derived
Circulating precursors
Have to be activated

Cell-derived
Sequestered intracellular
Synthesized de novo

Most mediators bind to receptors on cell surface

but some have direct enzymatic or toxic activities

Mediators of Acute Inflammation

Mediator

Vasodilation

Immediate

Sustained

Chemotaxis

Opsonin

Pain

Histamine

+++

Serotonin (5HT)

Bradykinin

++

Complement 3a

Complement 3b

+++

Complement 5a

+++

Prostaglandins

+++

+?

Leukotrienes

+++

+?

+++

Lysosomal proteases

++1

Oxygen radicals

++1

Injury

Acute inflammation
Abscess

Chronic inflammation

Resolution

Repair

Beneficial effects
Beneficial effects of the fluid exudate are as follows:

1) Dilution of toxins produced by bacteria, allows them

to be carried away in lymphatics
2) Entry of antibodies- Increased vascular permeability
allows antibodies to enter the extracellular space,
where they may lead either to lysis of microorganisms, through the participation of complement,
or to their phagocytosis by opsonisation
3) Drug transport

4) Fibrin formation -Fibrin formation from exuded

fibrinogen may impede the movement of microorganisms trapping them and so facilitating
phagocytosis
5) Delivery of nutrients and oxygen
6) Stimulation of immune response -The drainage of
this fluid exudate into lymphatics allows particulate
and soluble antigen to reach the local lymph nodes
where they may stimulate the immune response

Harmful effects
1) Digestion of normal tissue -Enzymes such as
collagenases and proteases may digest normal tissues,
resulting in their destruction
2) Swelling - of cervical lymph nodes may lead to
obstruction of the airway resulting in death;
inflammatory swelling is especially serious when it
occurs in an enclosed space as the cranial cavity
resulting in ischemic damage/herniations

 When a host encounters an injurious agent,

phagocytes that reside in all tissues try to eliminate
these agents by liberating inflammatory mediators
Some of these mediators act on small blood vessels in
the vicinity and promote the efflux of plasma and the
recruitment of circulating leukocytes to the site where
the offending agent is located
As the injurious agent is eliminated and antiinflammatory mechanisms become active, the process
subsides and the host returns to a normal state of

health
If the injurious agent cannot be quickly eliminated,
the result may be chronic inflammation

Complement system
Role in immunity (C5-9 complex)
Membrane Attack Complex (MAC C5-9)
Punches a hole in the membrane

Role in inflammation (c3a and c5a)

Vascular effects

Increase vascular permeability and vasodilation

Similar to histamine

Activates lipoxygenase pathway of arachidonic acid

metabolism (c5a)
Leukocyte activation, adhesion and chemotaxis (c5a)
Phagocytosis

c3b acts as opsonin and promotes phagocytosis by cells

bearing receptors for c3b

Inflammatory Mediators from Complement

Anaphylatoxins:
C3a, C5a, & C4a trigger mast cells to release
histamine and cause vasodilatation
C5a also activates the lipoxygenase system in

PMNs and monocytes release of inflammatory

mediators
Leukocyte activation, adhesion, & chemotaxis:
C5a activates leukocytes, promotes leukocyte
binding to endothelium via integrins and is
chemotactic for PMNs, monocytes, eosinophils, &
basophils

 Genetic deficiency of regulatory proteins

PNH : mutations in the gene coding the enzyme
required to synthesize phasphatidylinnositol linkages
for membrane proteins resulting in defective
expression of such proteins including DAF & CD59
which results in uncontrolled complement activation
Def of C1 INH : Hereditary angioneurotic edema :
Increased breakdown of C2 & C4 leading to
proteolytic fragments of called C2 kinin & bradykinin
C1 INH also inhibits kallikrein & coagulation factor
XII which promote increased formation of bradykinin

Acute-phase proteins
Protein

Immune system function

C-reactive protein

Opsonin on microbes

D-dimer protein

Fibrin degradation product

Mannose-binding protein Mannan-binding lectin pathway

Alpha 1-antitrypsin

Serpin, downregulates inflammation

Alpha 1antichymotrypsin

Serpin, downregulates inflammation

Alpha 2-macroglobulin

Inhibitor of coagulation by inhibiting thrombin

Inhibitor of fibrinolysis by inhibiting plasmin

Protein

Immune system function

Fibrinogen, prothrombin,
factor VIII, von Willebrand
factor, plasminogen

Coagulation factors

Complement factors

Complement system

Ferritin

Binding iron, inhibiting microbe iron uptake

Serum amyloid Pcomponent

Opsonin

Serum amyloid A

Recruitment of immune cells to inflammatory sites

Induction of enzymes that degrade extracellular matrix

Orosomucoid (Alpha-1-acid
glycoprotein, AGP)

Steroids carrier

Ceruloplasmin

Oxidizes iron, facilitating for ferritin, inhibiting microbe iron

uptake

Haptoglobin

Binds hemoglobin, inhibiting microbe iron uptake

Regulation of complement activation

Regulation of C3 & C5 convertases:

Decay-accelerating factor (DAF) or by proteolytically

cleaving C3b (factor I)
Binding active complement components by specific
proteins in the plasma:
- C1 inhibitor (C1INH) inhibits C1 complex

- proteins that inhibit MAC formation (CD59, also called

membrane inhibitor of reactive lysis)