Inflammation

Abisha.S.JFC&RITuticorin

Inflammation is an important protective process for the host.

Inflammation is a stereotyped response in a living animal to a variety of injuries that involves the Vasculature, various inflammatory cells, and potent chemical mediators.

Definition

Inflammation and Healing Defects in the inflammatory response can lead to chronic illness as well as death. In addition to its protective function, inflammation also sets the stage for healing and repair. The purpose of the inflammatory response is to dilute, isolate, and destroy the injurious agent, and to facilitate healing.

The body only has a limited number of ways to respond to an injury, hence the pathogenesis of an inflammatory lesion and the histological appearance of that lesion can be similar whether the injury was caused by a bacterial cell, a foreign body, ionizing radiation, a toxin, or trauma.

Agents causing inflammationInfective agents

Immunological agents

Physical agents

Chemical agents

Inert materials

Bacteria

Viruses and their toxins,

fungi, parasites

Cell mediated

Antigen antibody reactions

Heat

Cold

Radiation

Mechanical trauma

Organic

Inorganic poisons

Foreign bodies

Inflammatory Cells

The circulating cells includes-Neutrophils MonocytesEosinophilsLymphocytesBasophils Platelets

The connective tissue cells are-Mast cells FibroblastMacrophages Lymphocytes

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INFLAMMATORY CELLS

Cardinal signs of inflammation

Signs of InflammationCardinal signs are• Heat (calor)• Redness (rubor)• Swelling (tumor)

additional signs seen in acute inflammation• Pain (dolor)• Loss of function (function laesa)

Types of inflammationInflammation can be divided into acute and chronic forms which differ histologically as well as in duration.

Acute inflammatory episodes, characterized by vascular events and exudation, usually progress over a period of 3 to 10 days, then resolve as the injurious agent is eliminated.

Chronic inflammation, characterized by cellular proliferation, can extend from weeks to months to the lifetime of the host, continuing as long as the injurious agent persists.

Acute Inflammation

It is a rapid response to injury or microbes and other foreign substances that is designed to deliver leukocytes and plasma proteins to sites of injury

Acute inflammation has two major components• Vascular changes• Cellular events

Vascular• Changes in Vascular Caliber and Flow• Increased Vascular Permeability

Vasodilationwhich allow the largest serum protein molecules such as fibrinogen and immunoglobulins, normally confined within the circulation, to exude into the tissue.

Vasodilatation- increase blood flow Increased intravascular hydrostatic pressure

Red line appears within seconds resulting from vasodilatation of capillaries and venules

Flare is a bright reddish appearance or flush surrounding the red line results from vasodilatationof the adjacent arterioles

Wheal is the swelling or edema of the skin occurring from transudation of fluid in extra vascular space

Changes in Vascular Caliber and Flow• Changes in blood vessels begin rapidly after infection or injury but may develop at variable rates, depending on the nature and severity of the original inflammatory stimulus.

1. Leakage of exudate

Cellular Events• an important function of the inflammatoryresponse is to deliver leukocytes to the site of injury and to activate them

Leukocyte recruitmentSequence consists of:1. margination, adhesion to endothelium & rolling along the vessel wall

2. firm adhesion to endothelium

3.transmigration between endothelial cells;4. migration in interstitial tissues toward a chemotactic stimulus

5.Phagocytosis (recognition, attachment, engulfment, killing)6.Termination7.100% resolution, scar or chronic inflammation three

possible outcomes

Patterns of acute inflammationvascular and cellular reactions that characterize acute inflammation are reflected in the morphologic appearanceof the reaction

Grossly• According to principle

constituent of exudates:- SEROUS

FIBRINOUS

NEUTROPHILIC

SUPPURATIVE

ACUTE INFLAMMATION

serouscharacterized by:• the outpouring of a watery• relatively protein-poor fluid that, depending on the site of injury

Neutrophilic exudate: neutrophils are the prominent cellular component; common with bacterial infections in most animal species, but this type of exudate is not as prominent in fish as in other species; e.g. abscess

fibrinous• occurs as a consequence of more severe injuries,• resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier

suppurative• manifested by the presence of largeamounts of purulent exudate (pus)consisting of neutrophils, necrotic cells, and edema fluid

Histologcially, these exudates consist of eosinophilic staining in the intercellular space; fibrin will have the appearance of eosinophilic strands.

More severe injuries, particularly bacterial infections, will elicit a cellular component to the exudate.

Histologcially

Chronic Inflammation• is inflammation of prolonged duration (weeks to months to years) in which active inflammation, tissue injury, andhealing proceed simultaneously.

Characterized by:• infiltration with mononuclear cells• plasma cells tissue destruction• repair• angiogenesis• fibrosis

Chronic Inflammatory Cells • fundamental feature of chronic inflammation is its persistence• results from complex interactions between the cells that are recruited to the site of inflammation and are activatedat this site

NeutrophilsNeutrophils are the classic hallmarks of acute inflammation, many forms of chronic inflammation may nevertheless continue to show extensive neutrophilic infiltrates

Polymorphonuclear leucocytes

Mediates tissue injuryPhagocytosis of microorganisms and tissue debris

Polymorphonuclear leucocytes

Macrophages

dominant cell of chronic inflammation derived from circulating blood monocytes act as filters for particulate matter, microbes, and senescent cells, as well asacting as sentinelsscattered in most connective tissues, also found in organs such as the liver spleen and lymph nodes

Lymphocytes mobilized to the setting of any specificimmune stimulus as well as non-immune-mediatedinflammation

Eosinophils• characteristically found in inflammatory sites around parasitic infections• or as part of immune reactions mediated by IgE, typically associated with allergies modulates mast cell-mediated reactions

Mast cells• sentinel cells widely distributed in connective tissues throughout the body,• participate in both acute and chronic inflammatory responses• "armed" with IgE antibody specific for certain environmental antigens

Chronic inflammatory response;Chronic inflammatory lesions can be composed purely of macrophages, lymphocytes, or plasma cells.

Macrophages provide phagocytic and killing activity, whereas the other cell types provide antibody and cell-mediated immune activity.

Chronic inflammatory cell

Granulomatous inflammation is the more commonly observed form of chronic inflammation in fish as well as other animals.

It consists of a mixture of macrophages, lymphocytes, plasma cells, fibroblasts, and sometimes neutrophils, all oriented in and around the site of injury.

The lesions of BKD and mycobacteria are examples of this type of inflammatory response.

Multinucleated giant cells or epithelioid macrophages are often found in these sites as well.

Other classifications of inflammation

According to duration According to fate of inflammation

Per-acute inflammation Hyperplastic inflammationAcute inflammation Hypertrophic inflammationSub-acute inflammation Atrophic inflammation Chronic inflammation Fibrous inflammation Adhessive inflammation

HealingThe inflammatory response sets the stage for healing.

Healing can occur by regeneration of the damaged tissue or scar formation.

The form of healing that occurs is determined by the nature of the injured tissue and its ability to regenerate as well as the severity and duration of injury.

Tissues composed of cells that can readily divide (e.g. epithelium) can easily regenerate, replacing cells lost to inflammation and necrosis.

However, for this to occur the infrastructure of the tissue, i.e. reticular fibers, basement membranes, etc., must remain intact and provide a scaffold for cell replacement.

If that infrastructure is lost, fibrosis (scar formation) will likely occur.

Fibrosis also occurs in tissues composed of cells that cannot regenerate, such as myocardial cells.

Fibrosis is typical of the healing process of gaping wounds as well, particularly in the skin.

In some cases of extensive tissue loss, a cavity may simply remain at the site of injury (cavitation). This is most often seen in the brain

DefinitionDiffusible molecules that act locally at the site of tissue damage and infection, and at more distant sites. They can be divided into exogenous and endogenous mediators.

Mediators

Inflammatory mediators Inflammatory mediators can be classified into seven groups

according to their biochemical properties• Vasoactive amines• Vasoactive peptides• Fragments of complement components• Lipid mediators• Cytokine• Chemokines and proteolytic enzymes.

Chemical mediators are released from cells ,plasma, or damaged tissue

Chemical mediators

Cell derived Plasma derived1. Vasoactive amine2. Eicosanoids3. Lysosomal contents4. PAF5. Cytokines6. Free radicals

1. Kinins2. Clotting system3. Fibrinolytics4. Complement

system

• Cell derived & Plasma derived

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VASOACTIVE AMINES¡) Histamine Stored in the granules of

mast cells, basophils and platelets.

Main actionsVasodialation, incresed vascular

permeability, itching, pain

Cell derived mediators

ARACHIDONIC ACID METABOLITES (EICOSANOIDS)

Arachidonic acid (fatty acid) is released from the cell membrane by phospholipases.

It is then activated to form arachidonic acid metabolites or eicosanoids by one of the following two pathways: cyclo - oxygenase and lipo – oxygenase pathway

LYSOSOMAL COMPONENTS

The inflammatory cells neutrophils and monocytes contain lysosomal granules which on release elaborate a variety of mediators.

. PLATELET ACTIVATING FACTOR (PAF)

Released from IgE sensitised basophils or mast cells, leucocytes, endothelium and platelets.

ACTIONSIncreased vascular permeabilityVasodialation and vasoconstictionBronchoconstrictionAdhesion of leucocytes to endotheliumChemotaxis

CYTOKINES These are polypeptide substances produced by activated lymphocytes (lymphokines) and activated monocytes (monokines) Major cytokines- interleukin-1(IL-1), tumour necrosis factor (TNF)α and β, Chemokines.

ACTIONS IL-1 and TNF-α, TNF-βInduce endothelial effectsIncreased leucocyte adhereceThrombogenicityFibroblastic proliferation

(1)derived from metabolism of phospholipids and arachidonic acid (e.g., prostaglandins, thromboxanes, leukotrienes, lipoxins, platelet-activating factor [PAF])

(2) preformed and stored in cytoplasmic granules (e.g.,histamine, serotonin, lysosomal hydrolases),

(3) derived from altered production of normal regulators of vascular function (e.g., nitric oxide and neurokinins).

IMPORTANT FUNCTIONS

(1) Cycloxigenases (COX1, 2) acts on Arachidonic acid through cyclooxygenation, production of prostaglandins and thromboxanes

(2) lipoxygenation, to form leukotrienes and lipoxins.

Mediators of inflammationMediators Principal sources Actions

CELL DERIVED

Histamine Mast cell, basophil, platelet

Vasodilation , increased vascular permeability, pain, endothelial activation

Serotonin Chromaffin cells of GIT, spleen & platelet

Vasodilation , increased permeability

Prostaglandin Mast cell, leukocyte Vasodilation, pain, fever

Leukotrienes Mast cell, leukocyte Increase permeability, Chemotaxis, leukocyte adhesion & activation

Platelet- activating factor Leukocyte, mast cell Increase permeability, bronchoconstriction, chemotaxis

Reactive Oxygen Species Leukocyte Microbicidal, Tissue damage

Nitric Oxide Endothelium, Macrophages

Vascular smooth muscle relaxation

Cytokine ( TNF, IL-1)Chemokines

Macrophage, mast cellleukocyte

Local endothelial activationChemotaxis, leukocyte activation

These include the various products derived from activation and interaction of 4 interlinked systems: kinin,clotting, fibinolytic and complement

Plasma derived mediators

Hageman factor(factor xii) of clotting system plays a key role in interactions of the 4 systems

oActivation of factor xii in vivo by contact with basement membrane and bacterial endotoxins, and in vitro with glass or kaolin leads to activation of clotting, fibrinolytic, and kinin systems.oThe end products of the activated clotting, fibrinolytic and kinin system activate the complement system

Hageman factor (clotting factor XII), generated within the plasma

Conversion of plasminogen to plasmin.Conversion of prekallikrein to kallikrein.

Activation of the alternative complement pathway.

Activation of the coagulation system.

Kinins are potent inflammatory agents formed in plasma and tissue by the action of serine protease kallikreins on specific plasma glycoproteins termed kininogens

THE COMPLEMENT SYSTEM

I. The activation of complement system can occur by:

i. Classic pathway via non immunological agents

ii. Alternate pathway via non immunological agents

Complement system on activation yields activated products – anaphylotoxins (C3a, C4a, C5a) and membrane attack complex (MAC) – C5b, C6, C7….

Mediator Principal source Functions

PLASMA PROTEIN DERIVED

Complement Products(C5a, C3a, C4a)

Plasma (produced in liver)Leukocyte chemotaxis and activation, vasodialation

Increased permeability, smooth muscle contractionVasodilation, pain.

Endothelial activation, leukocyte recruitment

Kinins Plasma (produced in liver)

Protease activated during coagulation

Plasma (produced in liver)

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