INFLAMMATION

Presented by Dr Lahari.A.S.R, 1st year P.G student, Department of public health dentistry.

CONTENTS:
Definition Types of inflammation Events in inflammation Mediators in inflammation Inflammatory cells Regulation of inflammation Fate of inflammation Systemic effects of inflammation

Inflammation : Defined as local response of living mammalian tissues to injury due to any agent. It is a body defense reaction to eliminate or limit the spread of injurious agent as well as to remove the consequent necrosed cells and tissues.

Inflammation is a complex reaction to injurious agents such as microbes, & damaged usually necrotic cells, that consists of vascular response, migration & activation of leucocytes & systemic reaction

CARDINAL SIGNS:

Rubor Calor Tumor Dolor Functio laesa Roman writer Celsus in 1st century AD

INFLAMMATION VS INFECTION

Inflammation is a protective response Infection is invasion of microorganisms in to the host Inflammation is helpful to body while infection is harmful Inflammation is followed by healing while infection is followed by damage to the host tissue

TYPES OF INFLAMMATION
Acute inflammation Rapid onset Short duration & lasts for minutes or several hours Characteristic finding Exudation of fluid & plasma proteins Emigration of leucocytes predominantly Neutrophils Intra vascular activation of platelets

Chronic inflammation Longer duration Occurs either after the causative agent of acute inflammation persists for long time or the stimulus is such that it induces chronic inflammation from the beginning Characteristic finding Infiltration of lymphocytes & macrophages Proliferation of blood vessels Fibrosis Tissue necrosis

GRANULOMATOUS INFLAMMATION:

Granulomatos inflammation is a distinctive pattern of chronic inflammatory reaction in which the predominant cell type is an activated macrophage with a modified epithelial-like ( epitheloid ) appearance.

ACUTE INFLAMMATION:
DEFINITION Acute inflammation is rapid response to injurious agent that serves to deliver mediators of host defense to the site of injury 3 components of Acute inflammation Alterations in vascular caliber leading to increased blood flow

Structural changes in microvasculature that permits plasma proteins & leucocytes from the microcirculation

Emigration of leucocytes from the microcirculation, their accumulation in focus of injury & their activation to eliminate the offending organism

STIMULI FOR ACUTE INFLAMMATION:

Infections bacterial, viral , microbial toxins, & parasites Trauma blunt & penetrating Physical agents & chemical agents e.g. thermal injury like burns or frost bite, irradiation & some environmental chemicals Tissue necrosis Foreign bodies Immune reactions (hypersensitivity)

EVENTS OF ACUTE INFLAMMATION:

The chief events of acute inflammation can be grouped in to: Vascular events Cellular events

VASCULAR CHANGES:
Changes in vascular flow & caliber Vasoconstriction for few seconds (transient) vasodilatation of arterioles increased vascular flow heat & redness

Increased permeability of microvasculature outpouring of protein rich fluid into tissues Loss of fluid conc. Of RBC in blood vessels increased viscosity of blood - STASIS

Formation of endothelial gaps in venules:

Is mediated by histamine, leucotrienes etc Fast & short lived (immediate transient response).

Binding of the mediators to receptors on endothelium Activates intracellular signaling pathway Phosphorylation of contractile & cytoskeletal proteins (myosin) Contraction of endothelial cells & separation of intercellular junctions Gaps in venular endothelium which are largely intercellular

Direct injury : Leads to cell necrosis Arterioles , capillaries & venules Due to Toxins , burns & chemicals Fast & may be long lived (hours to days)

Leucocyte dependent injury: Mostly venules , pulmonary capillaries & glomerular capillaries Late response & long lived (hours) Early stage leucocyte adhere to endothelium activated release toxic oxygen species & proteolytic enzymes endothelial injury & detachment increased permeability

Increased transcytosis:

It occurs across the channels consisting of clusters of interconnected & uncoated vesicles & vacuoles called vesico vacuolar organelles which are located near intercellular junctions

Increased vascular leakage by increasing the number & size of these channels

Leakage from new blood vessels:

New blood vessel formed are leaky until endothelial cells mature Factors causing angiogenesis also increase the vascular permeability

CELLULAR EVENTS:

This phase consists of two events: Exudation of leukocytes Phagocytosis

Sequence of events in the extravasations of leucocytes:

In the lumen Margination , Rolling & Adhesion to endothelium Diapedesis - transmigration across the endothelium (passive, RBC) Migration in the interstitial tissue towards chemotactic agent

Leucocyte adhesion & transmigration is regulated by binding of complementary adhesion molecules on the leukocyte & endothelial surfaces, & chemical mediators chemo attractants & certain cytokines affect these processes by modulating the surface expression or avidity of such adhesion molecules

ADHESION RECEPTOR MOLECULE:

Adhesion receptor molecules are Selectin Immunoglobulin form- a) ICAM - 1 b) VCAM 1 Integrins Mucin like glycoprotein Heparin sulphate

ADHESION RECEPTOR MOLECULE:

SELECTINS - Binding is calcium dependent - 3 types - a) L- selectin(CD62 L) b) E selectin( CD62 E) c) P selectin( CD62 P)

SELECTINS
L Selectin( CD62 L) Functions Homing receptor for lymphocyte Binding neutrophils to endothelial cells Located at tips of microvilli projection of leucocytes Binds to 3 ligands- a) Glycam 1 b) Madcam 1 c) CD34

E Selectins( CD62E) Recognizes a complex sialalated carbohydrate group related to Lewis X & Lewis A which are found on cell surface proteins of granulocytes, monocytes, & T cells Function homing of effector & memory T-cells to particular site of inflammation e.g. skin

P Selectin( CD62P ) Identified in secretory granules of platelets Present in secretory granules of endothelial cells Weibel palade bodies

Function is activation of endothelial cells & platelets

ADHESION RECEPTOR MOLECULE INTEGRINS:

These proteins promote cell-cell & cellmatrix interactions

They integrate signals from extra cellular ligand with cytoskeleton dependent motility , shape change & phagocytic responses

They are composed of two non covalently linked polypeptide chains i.e. Alpha & Beta

Extra cellular domains of two chains bind to various ligands such as extra cellular matrix glycoproteins, activated complement components & proteins on the surface of other cells

On the basis of Beta subunits, subfamilies of the integrins have been classified. They are Beta-1 integrins also called CD49a-h CD29

Beta 2 integrins also called CD11a-c CD18 or LFA-1 CD11b CD 18

Events in induction of adhesion molecules on endothelial cells by a number of mechanisms: Mediators such as Histamine , thrombin & PAF stimulate redistribution of P-selectin from its normal intracellular store (granule) to cell surface Resident tissue macrophages & mast cells secrete cytokines & chemokines

TNF & IL-1 act on Endothelial cells of post capillary venules adjacent to infection & induces the expression of several adhesion molecules

CHEMOTAXIS
Definition: Locomotion oriented along the chemical gradient Chemo attractants: They can be Exogenous Bacterial products Endogenous a) components of complement system e.g. C5a b) Products of Lipoxygenase pathway mainly Leukotrienes c) Cytokines

Chemotactic agents binds to 7 transmembrane Gcoupled receptors signals initiated by these receptors Recruitment of G-proteins Activation of several effector molecules like Phospholipase C (PLC gamma) Phosphoinositol 3 kinase (PI3K) & protein tyrosine kinase

PLC Gamma & PI3K Act on membrane inositol phospholipids Generating lipid second messengers increasing cytosolic calcium Activation of GTPases of Rac/Rho/cdc42 family as well as numerous kinases Polymerisation of actin at the leading edge of the cell

LEUCOCYTE ACTIVATION:
The functional responses that are induced on leucocyte activation:

Phospholipase A2 activation by intracellular calcium & other signals converts phospholipids into Arachidonic acid metabolites Degranulation & secretion of lysosomal enzymes & activation of oxidative burst Secretion of cytokines by macrophages leads to amplification of inflammatory response Modulation of leucocyte adhesion molecule

In the resting state G-protein form a stable inactive complex containing Guanine diphosphate bound to Galpha subunit Occupancy of the ligands leads to exchange of GTP for GDP GTP bound form of the G-protein activates numerous cellular enzymes including isoform of Phosphotidyl inositol specific phospholipase C degrades inositol phospholipids intracellular calcium activation of protein kinase C release of microbicidal substances

OPSONIZATION & OPSONINS:

The process of coating particle , such as a microbe , to target it for phagocytosis is called Opsonization & substances that coat are called Opsonins Efficient opsonins are IgG antibodies components of complement Mannose binding Lectin Fibronectin Fibronogen C- reactive protein

PHAGOCYTOSIS:

Cell Eating Engulfment Of Solid Particles By The Cell

Mainly Performed By: Leukocytes In The Firstline Macrophages In The Later Stages

Stages of phagocytosis:

Recognition and attachment stage(opsonins) Engulfment stage Degranulation stage Degradation stage

ENGULFMENT STAGE:

Formation of cytoplasmic pseudopods Activation of actin filaments Release in free cytoplasm Vacuolar envolopment Formation of phagolysosome

DEGRANULATION STAGE:

Release of stored granules in the leukocytes Fusion of Azurophilic granules Activation of arachidonic acid metabolites Superoxide formation

DEGRADATION STAGE:

Also called killing stage Complete digestion of foreign cells and their scavenging

Types: Oxygen dependent killing Oxygen independent killing Nitric oxide mechanism

MEDIATORS OF INFLAMMATION:
Also known as Permeability factors Endogenous mediators

Derived from:

Cells Plasma Damaged tissue itself

2 types:

From the cells From the plasma

Cell derived: Vasoactive amines Eicosinoids Lysosomal components PAF cytokines

Plasma derived:

They are the products of:

The kinin system The clotting system The fibrinolytic system The complement system

REGULATION OF INFLAMMATION:
Inflammation is a double edged sword In severe stages it may damage the host tissue, hence it should be regulated Regulation is carried out by:

Acute phase proteins Corticosteroids Free cytokine receptors Suppressor T cells Anti inflammatory mediators

FACTORS DETERMINING VARIATION OF INFLAMMATORY RESPONSE:

These factors are:

1) involving the organism 2) involving the host 3) type of exudation 4)cellular proliferation 5) necrosis

FACTORS INVOLVING THE ORGANISM:

Type of injury and infection Virulence Dose Portal of entry Product of the organism

FACTORS INVOLVING THE HOST:

General health of the host Immune status of the host Leucopenia Type of tissue involved Local host factors

TYPE OF EXUDATION:

Serous Purulent Fibrinous Heamorrhagic catarrhal

CELLULAR PROLOFERATION:
The chief variable factor Differs in

Bacterial infections Viral infections Progressive Glomerulonephritis In chronic inflammation

NECROSIS:

Extent of necrosis is variable

Gas gangrene- extensive necrosis with foul smell Appendicitis- necrosis due to vascular obtruction Chronic inflammation- Caseous necrosis

MORPHOLOGY OF ACUTE INFLAMMATION:

Morphologic varieties of acute inflammation:

Pseudomembranous inflammation Ulcer Suppuration Cellulites Bacterial infection of the blood

Bacterial infection of the blood: Bacteraemia Septicaemia Pyaemia pyaemic abscess septic infarct

SYSTEMIC EFFECTS OF INFLAMMATION;

Fever

Leucocytosis But in thyroid inflammation Leucopenia is seen Lymphangitis

Shock due to massiverelease cytokine and TNF Disseminated intravascular coagulation.

FATE O ACUTE INFLAMMATION;

Resolution: Complete return rto normal situation

Healing by scarring : Excessive tissue destruction leads to healing through fibrosis

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Suppuration: Due to pyogenic bacteria an abscess is formed and if it is not drained it leads to septicemia.

REFERENCES:

Robin E.R Text book general pathology, edition 3,95-124. Harsh Mohan. Essential pathology for dental students, edition 4, 89132 . Munford, R. S., J. M. Andersen, and J. M. Dietschy. 1981. Sites of tissue binding and uptake in vivo of bacterial density lipoprotein complexes: studies in the rat and monkey. J. Clin. Invest. 68: 1503 1513.

Read, T. E., H. W. Harris, C. Grunfeld, K. R. Feingold, M. C. Calhoun, J. P. Kane, and J. H. Rapp. 1993. Chylomicrons enhance endotoxin excretion in bile. Infect. Immun. 61: 34963502. Levine, D. M., T. S. Parker, T. M. Donnelly, A. Walsh, and A. L. Rubin. 1993. In vivo protection against endotoxin by plasma high density lipoprotein. Proc. Natl. Acad. Sci. USA. 90: 1204012044..

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