Dr.ROOPA Premed 3 Pathophysiology Inflammation Dr.ROOPA Premed 3 Pathophysiology

Introduction: “Inflame” – to set fire. “Inflammation is a reaction of a tissue and its microcirculation to a pathogenic insult. It is characterized by the generation of inflammatory mediators and movement of fluid & leukocytes from the blood into extravascular tissues.” “dynamic response of vascularised tissue to injury.” Is a protective response. Serves to bring defense & healing mechanisms to the site of injury.

Naming of inflammatory diseases: [prefix] + ‘itis’ (exceptions exist) crohn’s disease

Types of Inflammation Acute Chronic

Acute Inflammation Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense—leukocytes and plasma proteins—to the site of injury. Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow; (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation; and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

Acute inflammatory reactions are triggered by a variety of stimuli: • Infections (bacterial, viral, parasitic) and microbial toxins • Trauma (blunt and penetrating) • Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) • Tissue necrosis (from any cause) • Foreign bodies (splinters, dirt, sutures) • Immune reactions (also called hypersensitivity reactions)

Acute Vs Chronic Flush, Flare & Wheal Acute inflammatory cells - Neutrophils Vascular damage More exudation Little or no fibrosis Little signs - Fibrosis, Chronic inflammatory cells – Lymphocytes Neo-vascularisation No/less exudation Prominent fibrosis

Table 5–1. Differences between Acute and Chronic Inflammation.   Acute Chronic Duration Short (days) Long (weeks to months) Onset Insidious Specificity Nonspecific Specific (where immune response is activated) Inflammatory cells Neutrophils, macrophages Lymphocytes, plasma cells, macrophages, fibroblasts Vascular changes Active vasodilation, increased permeability New vessel formation (granulation tissue) Fluid exudation and edema + – Cardinal clinical signs (redness, heat, swelling, pain) Tissue necrosis – (Usually) + (Suppurative and necrotizing inflammation) + (ongoing) Fibrosis (collagen deposition) Operative host responses Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosis Immune response, phagocytosis, repair Systemic manifestations Fever, often high Low–grade fever, weight loss, anemia Changes in peripheral blood Neutrophil leukocytosis; lymphocytosis (in viral infections) Frequently none; variable leukocyte changes, increased plasma immunoglobulin

Cardinal Signs of Inflammation Rubor : Redness – Hyperaemia. Calor : Warm – Hyperaemia. Dolor : Pain – Nerve, Chemical med. Tumor: Swelling – Exudation Loss of Function: Eg.

The 5 Cardinal Signs of Heat Redness Swelling Pain Loss Of Func.

Inflammation - Mechanism Vaso dilatation Exudation - Edema Emigration of cells Chemotaxis

Mechanism of Inflammation:

Leukocyte cellular events Leukocytes leave the vasculature routinely through the following sequence of events: Margination and rolling Adhesion and transmigration Chemotaxis and activation They are then free to participate in: Phagocytosis and degranulation Leukocyte-induced tissue injury

PRINCIPAL CELL EFFECTORS 1st 24 hours: NEUTROPHILS Bacterial infections, infarction Come from the bone marrow reserve pool Band neutrophils: less mature cells 16

Neutrophils -- the key cell type of the acute inflammatory response

2nd-3rd day: neutrophils are replaced by monocytes-macrophages Tuberculosis, salmonellosis

Eosinophils Allergic reactions Parasitic infections Hodgkin lymphoma

Mast cells and basophils Chronic myelogenous leukemia Myeloproliferative diseases histamine

Cellular response of leukocytes Emigration Margination Pavementing Rolling/Tumbling Adhesion Transmigration Chemotaxis Phagocytosis Opsonization Intracellular microbial killing Oxygen-dependent Oxygen-independent

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MARGINATION THE ENDOTHELIAL CELLS ARE ACTIVATED, ATTRACT THE SURFACE GLYCOPROTEINS ON NEUTROPHILS 25

INSINUATION OF THE NEUTROPHILS THRU THE ENDOTHELIAL CELLS DIAPEDESIS INSINUATION OF THE NEUTROPHILS THRU THE ENDOTHELIAL CELLS BASEMENT MEMBRANE EXTRAVASCULAR TISSUES 26

NEUTROPHIL DIRECT ITS MIGRATION TOWARDS THE CHEMOATTRACTANT CHEMOTAXIS NEUTROPHIL DIRECT ITS MIGRATION TOWARDS THE CHEMOATTRACTANT 27

FORMATION OF PHAGOSOME LYSOSOME PHAGOLYSOSOME PHAGOCYTOSIS FORMATION OF PHAGOSOME LYSOSOME PHAGOLYSOSOME 28

Intracellular microbial killing: Oxygen-dependent killing is the MOST important microbial process Phagocytosis activates HMP shunt oxidative burst suppplies electrons to NADPH oxidase superoxide anion Hydrogen peroxide

Hydrogen peroxide Oxides microbial proteins and disrupts cell walls Myeloperoxidase-halide system of bacterial killing

After killing and eliminating the microbes, the activated leukocytes play other functions 1.Macrophages produce GF(growth factor) that stimulate endothelial cell proliferation and fibroblasts. 2.Synthesis of collagen 3,Aids in the process of repair.

THE TOXIC SUBSTANCES MAY CAUSE LOSS OF FUNCTION (FUNCTIO LAESA) DEGRANULATION THE TOXIC SUBSTANCES MAY CAUSE LOSS OF FUNCTION (FUNCTIO LAESA) 34

INCREASED BLOOD FLOW DUE TO RELAXATION OF THE TERMINAL ARTERIOLES RUBOR AND CALOR 35

CONTRACTION OF CAPILLARY ENDOTHELIAL CELLS INCREASED VASCULAR PERMEABILITY SWELLING 36

TUMOR MILDEST: EXTRAVASATION OF WATER, LOW MOLECULAR WEIGHT PROTEINS MODERATE: + HMW(high molecular weight) PROTEINS SEVERE: + BLOOD CELLS 37

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MEDIATORS OF ACUTE INFLAMMATION Exogenous: microbial products Endogenous: 1. vasoactive amines histamine serotonin 2. Arachidonic acid metabolites cyclooxygenase pathway lipooxygenase pathway 3. Cytokines 4. Kinin system 5. Complement system

Histamine increase capillary permeability contracts postcapillary venules Source: basophils, mast cells,platelets Stimuli: binding of IgE binding of C3a and C5a:”anaphylotoxins” heat, cold Interleukin-1

Serotonin 5-hydroxytryptamine Action: similar to histamine Source: platelets

Arachidonic acid metabolites Cyclooxygenase pathway Enzymes:COX-1,COX-2 Products: Platelet TxA2 -vasoconstrictor,platelet aggregator 2. Endothelial prostacyclin -vasodilator,inhibits platelet aggregation Lipooxygenase pathway Products: hydroperoxyeicosatetraenoic acid (HPETE) 5-HPETE -leukotrienes

Important leukotrienes LTB4: chemotactic for neutrophils LTC4,LTD4,LTE4 “slow reacting substance of anaphylaxis” vasocontriction bronchospasm (bronchcontriction) increase capillary permeability

Cytokines Soluble proteins Secreted by numerous cells(monocytes-macrphages) Act as “effector molecules” IL-1 and TNF “acute phase response” Fever, increase WBC: systemic Synthesis of C-reactive proteins, complement components, fibrinogen, prothrombin Synthesis of adhesion molecules Neutrophil degranulation

Kinin system Formed during active secretion in sweat glands, salivary glands, pancreas, kidneys End product: bradykinin Actions: vascular permeability arteriolar dilation pain

Complement system 20 Plasma proteins HEPATOCYTES,MACROPHAGES, GIT CELLS Action: cell lysis

COMPLEMENT CASCADE classical pathway alternative pathway 49

ACTIVATE PMN, MACROPHAGES REGULATES AB RESPONSE OPSONIZE BACTERIA ACTIVATE PMN, MACROPHAGES REGULATES AB RESPONSE CLEARS AWAY IMMUNE COMPLEXES INFLAMMATION, TISSUE DAMAGE ANAPHYLAXIS 50

MAC

Classical pathway vs alternative pathway Starts with C1 + antigen-antibody Ends with the membrane attack complex Bacterial surface activates the pathway Works in the absence of antibodies Less efficient 52

C3b: opsonin C3a and C5a: anaphylotoxins C5b-C9: “MAC” membrane attack complex

Inflammation Outcome Acute Inflammation Resolution Chronic Inflammation Abscess Sinus Fistula Fibrosis/Scar Ulcer Injury

ABSCESS Cavity filled with pus Pus: neutrophils, monocytes and cellular debris Fibrous wall Inaccessible to circulation Bacterial infections, especially staphylococci

Ulcer Involves epithelial surfaces Loss of surface epithelium

Fistula Abnormal communication between 2 organs or between an organ and a surface

Scar Final result of tissue destruction Distortion of structure Altered function

Patterns of chronic inflammation Chronic nonspecific inflammation Granulomatous inflammation

Chronic nonspecific inflammation Proliferation of fibroblasts and new vessels Increased macrophages, lymphocytes, plasma cells Macrophage+antigen B lymphocyte activation antibody-producing plasma cells Scarring and distortion of tissue architecture

Most characteristic: CASEOUS NECROSIS Multinucleated giant cells TB, fungal infections, Syphyllis, cat-scratch fever, foreign bodies