Mechanism of inflammation

Dr. Subhash R. Yende
Assistant Professor
Gurunanak College of
Pharmacy, Nagpur
Mechanism of Inflammation

Defination
 a protective response against the initial cause of injury
 chemical agents
 cold, heat
 trauma
 invasion of microbes
 Inflammation accomplishes its missions by trying to
dilute, destroy or otherwise neutralize the affecting
agents.
2Dr. Subhash R. Yende

Cardinal signs of (acute) inflammation
 Rubor = redness
 Tumor = swelling
 Calor = heat
 Dolor = pain
 Functio laesa = loss of function

Components of the Inflammatory
Response
 Plasma protein
 Circulating cells – neutrophils, monocytes,
eosinophils, basophils & platelets
 Connective tissue – mast cells, macrophases and
lymphocyte
 Extracellular matrix – Fibrous proteins like
collagene, elastine. Adhesine glycoprotein like
fibronectine, laminine, tenascine etc. &
Proteoglycone

Basic Patterns of Inflammation
 Acute inflammation is of relatively short duration
(hours to days) and is rapid onset
Characterized by exudation of fluid and plasma
proteins
Activation of platelet and neutrophils
 Chronic inflammation is of longer duration (days
to years)
Characterized by mononuclear infiltration, vascular
proliferation and tissue necrosis.

Acute Inflammation
 Acute inflammation has two major mechanisms:
- Vascular changes
- Cellular (leukocytes) changes

Vascular changes
I. Changes in vascular flow
 Transient vasoconstriction
 Vasodilation ---increased blood flow
and blood pooling --- redness and
warmth
 Increase hydrostatic pressure Increased
permeability for plasma proteins and
cells creating swelling (tumor)
 Fluid loss leads to concentration of red
blood cells and slowed blood flow
(stasis)
 due to stasis leukocytes leads
mirgination
 Emigration of leukocytes from
microcirculation

Transudate
 ultrafiltrate of plasma
 Low protein content
 result in hydrostatic or
osmotic imbalance
Exudate
 vascular permeability
 high protein content
 result of inflammation
Increases interstitial osmotic
pressure contributing to edema
(water and ions)
II. Increased vascular permeability
and edema

Mechanism for vascular permeability and edema

Cellular changes
 Sequence for cellular events (Extravasation):
 Margination and rolling
 Adhesion and transmigration (diapedesis)
 Chemotaxis and activation
 They are then free to participate in:
 Phagocytosis and degranulation
 Leukocyte-induced tissue injury

Margination and Rolling
 Due to increase stasis, hydrostatic pressure and tearing of
endothelial layer------Margination
 Marginated leukocytes begin to roll on the endothelial surface by
forming transient adhesions via the selectin family of proteins:
–E-selectin on endothelial cells
–P-selectin on endothelial cells and platelets
–L-selectin on most leukocytes
 Selectins bind oligosaccharides that decorate mucin-like
glycoproteins
Dr. Subhash R. Yende 13

Adhesive Protein
Selectins
E-selectin (on endothelium)
P-selectin (on endothelium &
platelets; is preformed and stored in
Weible Palade bodies)
L-selectin (leukocytes)
Ligands for E-and P-Selectins are
sialylated glycoproteins (e.g
Sialylated Lewis X)
Ligands for L-Selectin are Glycan-
bearing molecules such as GlyCam-1,
CD34, MadCam-1 Immunoglobulin family
ICAM-1 (intercellular
adhesion molecule 1)
VCAM-1 (vascular adhesion
molecule 1)
Are expressed on activated
endothelium
Ligands are integrins on
leukocytes
Integrins (a + b chain)
Heterodimeric molecules
VLA-4 (b1 integrin) binds to
VCAM-1
LFA1 and MAC1 (CD11/CD18)
b2 integrin bind to ICAM
Expressed on leukocytes
Mucin-like glycoproteins
Heparan sulfate (endothelium)
Ligands for CD44 on
leukocytes
Bind chemokines

Adhesion and Transmigration
 Leukocytes firmly adhere to endothelial cells before
transmigration
 Adhesion is mediated by members of Ig superfamily on
endothelial cells (ICAM-1, VCAM-1) that interact with
leukocyte integrins (VLA-4, LFA-1)
 transmigration typically occurs in venules and is mediated
by PECAM-1 (CD31)

Chemotaxis and Activation
 Transmigrated leukocytes move to the site of injury along
chemical gradients of chemotactic agents
 Chemotactic agent can be:
–Soluble bacterial products
–Components of the complement system (C5a)
–Products of lipoxygenase pathway of arachidonic acid
metabolism (leukotrieneB4)
–Cytokines (chemokines such as IL-8)
 Chemotactic molecules bind cell-surface receptors,
resulting calcium mobilization and assembly of
cytoskeletal contractile elements as----

Phagocytosis and Degranulation
Phagocytosis and its outcome involves three distinct steps
 Recognition and attachment
 Engulfment and fusion of phagosome and lysosome
 Killing and degradation of ingested material

Recognition and Binding
 Occurred by serum protein called Opsonine,
eg. immunoglobulin G and Collectine
 Bind to corresponding receptors on leukocytes (FcR,
CR1, 2, 3)
Engulfment
Killing and degradation
 engulfment and formation of vacuole which fuses with
lysosomal granule membrane (phagolysosome)
 Granules discharge within phagolysosome and
extracellularly (degranulation)
 Triggers an oxidative burst

Degradation and Clean-up
 Reactive end-products only active within
phagolysosome
 Hydrogen peroxide broken down to water and oxygen
by catalase
 Dead microorganisms degraded by lysosomal acid
hydrolases

Summary of cellular events

CHEMICAL MEDIATORS

 Cell-derived:
 Preformed, sequestered and released (mast cell
histamine)
 Synthesized as needed (prostaglandin)
 Plasma-derived: (Sysytemic)
 Complement, kinins, coagulation factors
 Many in “pro-form” requiring activation (enzymatic
cleavage)

Cellular mediators
Mediators Source
I. From secretary
granules
Vasoactive Amine
* Histamine Mast cell, Basophils, platelets
* Serotonine platelets
Lysosomal enzyme Neutrophils, macrophases
II. Newly synthesized Prostaglandins All leukocytes, platelets and EC
Leukotrienes All leukocytes
Platelet activating factor All leukocytes, EC
NO and Oxygen radicals All leukocytes, EC, Macrophses
Cytokines Lymphocyte, EC, Macrophses
Dr. Subhash R. Yende
25

Plasma or Systemic Mediators
Plasma factors synthesized mainly in liver
Plasma proteins
Factor XII
coagulation system
(Hageman factor)
activation
Kinin system
(Bradykinin)
Coagulation
system
Complement
activation
C3a
C5a
C3b
C5b-C9
anaphylatoxins
opsonin
Membrane
Attack Complex

 May or may not utilize a specific cell surface
receptor for activity
 May also signal target cells to release other effector
molecules that either amplify or inhibit initial
response (regulation)
 Are tightly regulated:
 Quickly decay (AA metabolites), are inactivated
enzymatically (kininase), or are scavenged
(antioxidants)

Vasoactive amines
Histamine
• Mast cell is richest source of histamine
• located in connective tissue, adjacent to
blood vessels
• Degranulation through receptors for IgE-,
IgG, histamine, bacterial products and
anaphylatoxin C5a, physical injury, cold,
heat
• release of PAF (platelet activating factor)
leads to serotonin and histamine release
from activated platelets
• Mast cells are very important effector cells
in hypersensitivity reactions (anaphylactic
reactions)
• Function- vasodilation and venular
endothelial cell contraction, increased
vascular permeability
Serotonin (5-HT)
*Chromaffine cells of GIT,
spleen, nervous tissue, mast
cell ans platelete
*vasodilatory effects similar to
those of histamine;

Metabolites of Arachidonic Acid (eicosanoids)
• Membrane lipids of activated cells can be transformed into
biological active lipid mediators
• All mammalian cells except erythrocytes can produce
eicosanoids
• They are autocoids = short-range hormones (very short range and
half-life)
• Arachidonic acid is derived from conversion of linoleic acid

Action Metabolite
Vasoconstriction Thromboxane A2,
Leukotrien C4, D4, E4
Vasodilation PGI2, PGE1, PGE2,
PGD2
Increased vascul. permeab. LTC4, LTD4, LTE4
Chemotaxis, Leuko. adhesion LTB4, 5-HETE
Bronchospasm Leukotrien C4, D4, E4
Platelet aggregation Thromboxane A2
Pain mediation, Fever induction PGE2

 PAF (platelet activating factor)
 Derived also from cell membrane phospholipid,
 Release from IgE sensitised basoplils, and mast cell also
from endothelium and platelete.
 causes vasodilation, increased vascular permeability,
increases leukocyte adhesion (integrin conformation)
 Also increase synthesis of ecosinides.
 Cytokines
 Protein cell products that act as a message to other cells,
telling them how to behave.
 IL-1, TNF-a and -b, IFN- are especially important in
inflammation.
 Chemokines
IL8, PF4 (CxC) and MCP-1, MIP 1a, eotaxin (CC)

Nitric Oxide  short-acting soluble free-radical gas with many
functions
 NO is produce by many cells including:
endothelial cells,some neurons and phagocytes
 synthesized from L-arginine by: nitric oxide synthase
(NOS)
 Three different NOS: endothelial (eNOS), neuronal
(nNOS) and inducible (iNOS)
 Produced by endothelial cells, macrophages, causes:
 vasodilation
 Kills microbes in activated macrophages
 Counteracts platelet adhesion & aggregation

Lysosomal components
Release from activated neutrophils and
macrophages after demise, attempts at
phagocytosis, etc.
Neuropeptide

Plasma proteins
The mediators are derived from interaction of following
interrelated system
 Complement
 Kinins
 Clotting system

Complement system
 Components C1-C9 present in inactive form
 Activated via classic (C1) or alternative (C3) pathways to
generate MAC (C5 – C9) that punch holes in microbe
membranes
 In acute inflammation
 Vasodilation, vascular permeability, mast cell degranulation (C3a,
C5a)
 Leukocyte chemotaxin, increases integrin avidity (C5a)
 As an opsonin, increases phagocytosis (C3b, C3bi)

Kinin system
 Leads to formation of bradykinin from cleavage of
precursor (HMWK)
 Vascular permeability
 Arteriolar dilation
 Non-vascular smooth muscle contraction (e.g.,
bronchial smooth muscle)
 Causes pain
 Rapidly inactivated (kininases)

Clotting cascade
 Cascade of plasma proteases
 Hageman factor (factor XII)
 Collagen, basement membrane, activated platelets
converts XII to XIIa (active form)
 Ultimately converts soluble fibrinogen to insoluble
fibrin clot
 Factor XIIa simultaneously activates the “brakes”
through the fibrinolytic system to prevent continuous
clot propagation

Outcome of acute Inflammation
• Complete resolution
Little tissue damage
Capable of regeneration
• Scarring (fibrosis)
tissues unable to regenerate
Excessive fibrin deposition
organized into fibrous
tissue
• Abscess formation
• Progression to chronic
inflammation

Resolution

Chronic Inflammation

 Definition:
 Inflammation of prolonged duration in which active inflammation,
tissue injury and the healing proceed simultaneously
 Causes:
 Persistent Infections
 Ex. Treponema palladium (causative organism of syphilis)
 Organism of low toxicity and evoke an immune reaction = delayed
hypersensitivity
 Prolonged Exposure to toxic Agents,
 Exogenous (Silicosis)
 Endogenous (Atherosclerosis)
 Autoimmunity
 Ex. Autoimmune diseases

 Morphologic Features:
 Infiltration with mononuclear cells (macrophages,
lymphocytes & plasma cells)
 indicates persistent reaction to injury
 Tissue destruction
 Done by way of Inflammatory cells
 Repair involving angiogenesis and fibrosis
 Attempt to replace lost tissue

Mononuclear cell infiltration
 Mononuclear Phagocyte System
 Circulating blood monocytes →Tissue macrophages
↓
Kupffer cells (liver), Sinus Histiocytes (spleen), Microglia (CNS),
Alveolar Macrophages (lung)
 Maturation of Mononuclear Phagocytes

Mechanisms of macrophage accumulation
during Chronic Inflammation
 Continued recruitment of monocytes from the
circulation
 Most important source for macrophages
 Local proliferation of macrophages from the blood
stream
 Immobilization of macrophages within the site of
inflammation
 Cytokines and oxidized lipids can cause
immobilization

Role of activated macrophages in chronic inflammation

Other Cells of Chronic Inflammation
 Infiltration with mast cells, lymphocytes and plasma
cells
 Lymphocytes
 Mobilization in both antibody – mediated and
 Mast Cells
 Widely distributed in connective tissues and participate in both
acute and persistent inflammatory reactions
 Binds the Fc portion of the IgE antibody
 Plasma Cells
 Produce antibody directed either against persistent antigen in the
inflammatory site or against altered tissue components
 Eosinophils
 parasitic infections
 Mediated by IgE
 Eotaxin – a chemokine that has the ability to prime eosinophils for
chemotaxis

Reference
 Vinay Kumar, Abul K. Abas, Jon C. Aster; Robbins &
Cotran Pathologic Basis of Disease; Seventh edition.
 Harsh Mohan; Text book of Pathology; 6th edition;
India; Jaypee Publications.

Mechanism of inflammation

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