inflammation and repair rince

Inflammation PRESENTED BY DR.RINCE MOHAMMEDJ.R 1 O.M.F.S,G.D.C KOTTAYAM

Contents

Introduction Definition Cardinal Signs Types of inflammation Acute inflammation – Pathogenesis Chemical mediators of acute inflammation Systemic & laboratory manifestations Exudate Vs Transudate Out comes of Acute Inflammation

Chronic inflammation Chronic inflammatory cells Chronic inflammation types Summary and conclusion References

Introduction

Inflammation is the reaction of living tissue to injury or infection. It is a protective vascular connective tissue reaction or response

intended to remove injurious stimuli as well as the necrotic cells. Repair-causes the replacement of damaged tissues by

regeneration of parenchyma cells or by filling of any residual defect by fibrous scar tissues. (Healing)

jayalakshmi jayakumar

inflammation repair closly related.inflmn-response phase repair healing phase...

Definition

A local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissues.

(Websters medical dictionary)

Sometimes harmful – hypersensitivity reactions,immune diseses.

Repair also can cause scarring ,fibrosis that may lead to obstruction of movement.

Anti inflammatory drugs - enhance favourable effects of inflammation and controls its harmful sequelae.

The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “- itis ” e.g pancreatitis meningitis pericarditis arthritis


allergy to drugs insect bite,toxins.immune diseases like rhumatoid artritis,

Cardinal Signs (Celsus)

Rubor- redness due to increased blood flow and vasodilation Calor- or heat due to increase blood flow to the periphery Tumor- swelling from inflammatory edema Dolor-pain from swelling and presence of inflammatory

mediators Functio laesa-loss of function due to main and structural

necrosis (Virchow 1793)

:

Types of inflammation

Acute inflammation – immediate and early response to an injurious agent,short duration usually less than 48 hrs PMN as inflammatory cells

Chronic inflammation – longer duration,occurs either after the causative agent of acute inflammation persist for a long time or the stimulus induces chronic inflammation from the beginning Lymhocytes,plasma cells,macrophages –inflammatory cells

Acute inflammation

Stimuli for acute inflammation

Infections (bacterial, viral, fungal, parasitic) and microbial toxins. Tissue necrosis from any cause, including ischemia (as in a

myocardial infarct),trauma, and physical and chemical injury Foreign bodies Dirt, sutures etc Immune reactions (hypersensitivity reactions) are reactions in

which the normally protective immune system damages the individual's own tissues.


physical injury-thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals). Several molecules released from necrotic cells are known to elicit inflammation

Acute inflammation - Pathogenesis

3 major components:

1. Alteration of vascular flow and caliber (vasodilation leads to

increased blood flow)

2. Increased Vascular Permeability (Vascular Leakage)

3. Emigration of leukocytes from microcirculation (leukocyte activation

leads to elimination of offending agent)



1 and 2 vascular changes 3 cellular change

VASCULAR CHANGES

Major role in acute inflammation

Leukocyte Emigration AdhesionTransmigrationChemotaxisPhagocytosis

Termination

Stasis

↑ Vascular permeability

Vasodilation

1.Changes in Vascular Flow and Caliber

Transient constriction of arterioles – immediate vascular response after an injury.

Vasodilation Arterioles are involved, and leads to increased blood flow, which is

the cause of heat and redness at the site of inflammation. Induced by the action of mediators like histamine and nitric oxide,

on vascular smooth muscle.


events

Increased permeability of the microvasculature leads to exudation of protein rich fluid into the extravascular space causing swelling (tumor).

Stasis of the blood flow -Loss of fluid from the vessels leads to Concentration of red cells resulting in decreased velocity and stasis of the blood flow

Leukocytic margination-Neutrophils, accumulate along the vascular endothelium.At the same time endothelial cells are also activated by mediators produced at sites of injury, and express increased levels of adhesion molecules.

2.Increased Vascular Permeability 15

Hallmark of acute inflammation as it causes escape of protein rich exudate leading to edema.

loss of protein from plasma reduces intravascular osmotic pressure, and increases that of interstitium.

So marked outflow of fluid Edema



pathogenesis-3 components.1 vasodilation (Alteration of vascular flow and caliber) 2 Vascular Leakage)3 Emigration of leukocytes

Mechanism of vascular leakage

Contraction of endothelial cells

Resulting in gaps in endothelium. most common mechanism. Elicited by histamine, bradykinin, leukotrienes,and substance P. It is called the immediate transient response because it occurs

rapidly and is short-lived.

Endothelial retraction Structural reorganization of cytoskeleton of endothelial cells Reversibile retraction of intercellular junctions Delayed and prolongedDirect endothelial injury Resulting in endothelial cell necrosis.Eg:Burns,bacterial infections Immediate and sustained reaction.

Leukocyte-dependent endothelial cell injury Marginating leukocytes may damage the endothelium through

activation and release of toxic oxygen radicals and proteolytic enzymes making the vessel leaky.

Transcytosis occurs across cellular channels.


Shows the difference between normal and inflamed tissues....vasodilation

CELLULAR EVENTS

Leukocyte EmigrationAdhesionTransmigrationChemotaxisPhagocytosis

Termination

Stasis


Vasodialtion

3.Emigration of leukocytes

critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents.

Leukocytes leave the vasculature routinely through the following sequence of events:

1. Margination, rolling, and adhesion to endothelium

2. Diapedesis (trans-migration across the endothelium)

3. Migration toward a chemotactic stimuli from the source of tissue injury.

Margination and Rolling

With increased vascular permeability, fluid leaves the vessel causing leukocytes to settle-out of the central flow column and “marginate” along the endothelial surface

Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium until it adhire firmly.

Rolling and adhesion are mediated by selectins, integrins, Immunoglobulin superfamily adhesion molecules.



There are three types of selectins: one expressed on leukocytes (L-selectin), one on endothelium (E-selectin), and one in platelets and on endothelium (P-selectin).The expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury.

Transmigration (diapedesis)

After adhesion leukocytes insert their pseudopods into endothelial cell junction and squeeze through this layer into the extarvascular space..

It cross basement membrane by damaging it locally with Collagenases

Chemotaxis.

Once they have exited the capillary, the leukocytes move through the tissue guided by secreted cytokines, bacterial and cellular debris, and complement fragments (C3a, C5a),leukotrienes (LTB4).

Most chemotactic agents signal via G-protein-coupled receptors resulting in intracellular Ca2+ release and activation of small GTPases. This leads to actin/myosin polymerization and filopodia formation directed to the chemical agent.


The process by which leukocytes migrate in response to a chemical signal is called chemotaxis.

Phagocytosis and Degranulation

During the next and final stage of the cellular response, the neutrophils and macrophages engulf and degrade the bacteria and cellular debris in a process called phagocytosis.It involves

Recognition Engulfment Killing (degradation/digestion)

Recognition and Binding The phagocytic cells are recognized by chemotactic factors released

by bacterial products.It is made easier by opsonisation-coating with natural opsonins like C3b, IgG,lectins.

Engulfment After a particle is bound to phagocyte receptors,pseudopods flow

around it, and form a vesicle (phagosome) that encloses the particle.It fuses with lysosome-phagolysosome.


mpo myeloperoxidase

Killing (degradation/digestion) Triggers an oxidative burst which forms Reactive oxygen species.it

causes Increased oxygen consumption Glycogenolysis Increased glucose oxidation Formation of superoxide ion Killng by halogenation, or lipid/protein peroxidation

Chemical mediators

Cell derived or plasma derived Have “triggering” stimuli Usually have specific targets Can cause a “cascade” Are short lived

Cell Derived

• Histamine• Serotonin• Eicosanoids• Nitric oxide• Platelet activating factor (paf)• Cytokines• Lysosome constituents• Free radicals• Neuropeptides

Plasma Protein Derived

• Complement System• Coagulation & Kinin System• Fibrinolytic system

Histamine Vasoactive “amine” Mast Cells, basophils Vasodilatation, Increase vascular permeability,

Endothelial activation Produced in response to physical injury,immune

reactions, neuropeptides, C3a & C5a, Cytokines

Serotonin

(5HT, 5-Hydroxy-Tryptamine) Platelets and EnteroChromaffin Cells Also vasodilatation, Increase vascular

permeability Released during platelet aggregation

Eicosanoids (arachidonic acid derivatives)


When cells are activated by stimuli, such as microbial products and various mediators of inflammation, membrane AA is rapidly converted by the actions of enzymes to produce prostaglandins and leukotrienes.Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins


block leukotriene receptors (e.g. Montelukast) are useful in the treatment of asthma.

Cyclooxygenase pathway PGD2,PGE2,PGF2α

Causes Vasodilation,capillary permeability, and the pain and fever that accompany inflammation.

PGI2(prostacyclin) Produced by prostacyclin synthase in endothelial cell,Vasodilation,

Inhibits Platelet aggregation TxA2

Produced by Thromboxane synthase in platelets,Vasoconstriction & stimulates platelets aggregation



nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin. They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis;

Lipoxygenase PathwayLTB4

Produced by neutrophils & some macrophagesChemotactic agent for neutrophils

LTC4,LTD4 & LTE4 Produced by mast cellsVasoconstriction,bronchospasm

Lipoxins -Endogenous antagonists of Leukotrienes,Vasodilatation Inhibit chemotaxis,

Platelet-Activating Factor (PAF) Produced by WBCs & endothelial cells Activate platelets, induces platelet aggregation, Causes

Vasoconstriction, Bronchoconstriction It contributes to extravascularization of plasma proteins and so, to

edema.

Nitric oxide

Potent vasodilator Produced from the action of nitric oxide synthetase from arginine

Cytokines/chemokines Cytokines are proteins produced mainly by LYMPHOCYTES and

MACROPHAGES. Includes interferon, interleukin, TNF etc. Interferon -Activation of macrophages CHEMOKINES are small proteins which are attractants for PMN.

Plasma protein derived mediators

Complement System Coagulation & Kinin System Fibrinolytic system

Complement System Consists of Plasma proteins Upon activation different complement proteins(C3b) coat/opsonize

microbes for phagocytosis & destruction C3a & C5a cause mast cells to release histamine which inturn

causes Vasodilation thus increasing vascular permeability C5a activates lipoxygenase pathway causing release of more

inflammatory mediators C5a also helps in leukocyte activation, adhesion & chemotaxis

Coagulation SystemHageman factor/Factor12a

A protein synthesized by liver Activated factor12 further activates Kinin System,Clotting

System,Fibrinolytic System,Complement System

Kinin System Ultimately leads to formation of bradykinin Bradykinin causes arteriolar dilation, increases vascular

permeability & broncho constriction,also pain.

Fibrinolytic System Ultimately leads to formation of plasmin Plasmin

converts C3 to C3a Converts factor-12 to factor-12a Breaks down fibrin to fibrin degradation products which

further increases the vascular permeability

Morphological patterns of acute inflammation

Serous (watery) Fibrinous (hemorrhagic, rich in FIBRIN) Suppurative -Produce pus & purulent exudates- neutrophil, necrotic

cells & edema fluid Ulcerative

Systemic manifestations Fever lymphadenitis Myalgia Malaise shock

Laboratory manifestations Leukocytosis Increased ESR Elevated serum acute

phase proteins (C-reactive protein, fibrinogen, etc)

Hypercoagulability

51Acute inflammation

Exudate

Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction.

A filtrate of blood plasma. High protein concentration Contains cellular debris & High

specific gravity.

Transudate

It is an ultrafiltrate of plasma, resulting from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability.

A fluid with low protein content Little or no cellular material &

Low specific gravity.

52

OUT COMES OF INFLAMMATION

Acute Inflammation

Resolution

Chronic Inflammation

Abscess

SinusFistula

Fibrosis/Scar

Ulcer

Injury

FungusVirus

CancersT.B. etc.

CHRONIC INFLAMMATION

Chronic inflammation is the inflammation with prolonged duration usually from weeks to months and sometimes to years in which active inflammation, tissue injury and healing process proceed simultaneously.

Causes

Persisting infection or prolonged exposure to irritants Repeated acute inflamations (otitis, rhinitis) Primary chronic inflammation - low virulence, sterile inflammations

(silicosis),viral infections Autoimmune reactions (rheumatoid arthritis, glomerulonephritis,

multiple sclerosis)

Features:

Infiltration of mono-nuclear cells like lymphocytes, macrophages and plasma cells.

The dominant cellular player in chronic inflammation is the tissue macrophage

Destruction of tissue by inflammatory cells. Proliferation of new vessels leading to repair (angiogenesis &

fibrosis).

Chronic inflammatory cells

1) MACROPHAGES: Formed from monocytes. Activated by cytokines,endotoxins,Extra cellular matrix proteins and

cause tissue destruction, Neovascularisation, fibrosis. In liver _ Kupffer cells Spleen and lymph nodes _ Sinus histocytes Nervous system _ Microglial cells Lungs _ Alveolar macrophages

2) LYMPHOCYTES: Both T- & B-lymphocytes are involved. Activated macrophages release TNF & IL1 and activate lymphocytes

which then produce different antibodies that cause destruction of antigens at the inflammatory site.

3) EOSINOPHILS: Found in parasitic infections and IgE mediated allergic reactions.

4) MAST CELLS: Mast cells are tissue cells which are like basophils in shape. They are present in bone marrow and around blood vessels and do

not enter the blood. They release histamines and amino acid metabolites. They cause

initial vascular changes in acute inflammation and also cause anaphylactic reactions.

Types of chronic inflammation

1) Agranulomatous: Granuloma is not formed, Inflammation is characterized by all features of chronic inflammation.Examples:• Chronic viral infections e.g., Hepatitis• Chronic autoimmune diseases e.g., Rheumatoid arthritis and Ulcerative

colitis• Chronic chemical intoxication e.g., Chronic alcoholic liver disease• Allergic reactions e.g., Bronchial asthma

2) Granulomatous inflammation Characterized by aggregates of activated macrophages that assume

a squamous cell like epitheloid appearance. GRANULOMA is defined as aggregates of macrophages formed due

persistant response of T-lymphocytes to particular antigens. This has a granular cheesy appearance called as caseous necrosis.

Bacterial:Tuberculosis,Leprosy,Syphilis,gumma etcParasitic:Schistosomiasis Fungal:Histoplasma capsulatum,Blastomycosis.

Inorganic metals / Dust:SilicosisForeign bodies:Suture, Vascular graft.Unknown:Sarcodiosis..

Leukocyte Emigration AdhesionTransmigrationChemotaxis

Phagocytosis

Injurious agent


Endothelial contractionRetraction

TranscytosisDirect endothelial injury

Vasodilation

Summary



when an injurious agent enters body it triggers inflammatory response.

conclusion

Inflammation is fundamentally a protective response, designed to eliminate the cause of injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues).

Inappropriately triggered or poorly controlled inflammation is the cause of tissue injury in many disorders.

REFERENCES

Robbins and Cotran Pathologic Basis of Disease eighth edition Essential pathology for dental students-Harsh Mohan 3rd

edition

THANK YOU

inflammation and repair rince

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