Acute inflammation - V4US-33rd

Acute inflammation - V4US-33rd

Acute inflammation 5 By Dr. S. Homathy Basophils & Mast Cells Mast Cells & Allergy Specific mediators Serotonin: vasodilatory effects similar to those of histamine; platelet dense-body granules;

release triggered by platelet aggregation Specific mediators Plasma proteases Clotting system Complement Kinins Specific mediators Arachidonic acid metabolites (eicosanoids)

Prostaglandins and thromboxane: via cyclooxygenase pathway; cause vasodilation and prolong edema; but also protective (gastric mucosa); COX blocked by aspirin and NSAIDS Specific mediators Leukotrienes: via lipoxygenase pathway; are

chemotaxins, vasoconstrictors, cause increased vascular permeability, and bronchospasm Specific mediators PAF (platelet activating factor) Derived also from cell membrane phospholipid of Neutrophils, monocytes, basophils, endothelium and platelets.

causes Vasoconstriction and bronchoconstriction increased vascular permeability, increases leukocyte adhesion (integrin conformation) Leukocyte degranulation Platelet activation Release of histamine from platelets chemotaxis

Specific mediators Nitric Oxide short-acting soluble free-radical gas with many functions Produced by endothelial cells, macrophages, specific neurones in the brain causes:

Vascular smooth muscle relaxation and vasodilation Kills microbes in activated macrophages Counteracts platelet adhesion, aggregation, and degranulation Uncontroled NO production by activated MP in septic shock can lead to massive peripheral vasodilation and shock Oxygen derived free radicals Synthesized via the NADPH oxidase pathway

Released from N and MP after stimulation by chemotactic agents, immune cpx, phagocytic activity Production of microbicidal reactive oxygen intermediates within phagocytic vesicles. These include Superoxide

OH. H2O2 At low concentration amplifying the cascade of inflammatory mediators At high concentration causes variety of tissue injury mechanism include, Endothelial cell damage ,increased permeabiity and thrombosis Inactivation of antiproteases and activation of proteases

Direct injury to the other cell type Tumour cells, red cells,parenchymal cell Antioxidant protective mechanism found in tissues and serum to minimize the toxicity of the oxygen metabolites

Catalase Superoxide dismutase Glutathione Transferin Ceruloplasmin Specific mediators

Lysosomal components Leak from PMNs and macrophages after demise, attempts at phagocytosis, etc. 1. Acid proteases (only active within lysosomes). Degrade bacteria and debris within phagolysosomes 2. Neutral proteases such as

elastase and collagenase are destructive in ECM. Degade extracellular components Cleave C3 and C5 directly Counteracted by serum and ECM anti-proteases (alpha-1 antitripsin inhibits neutrophil elastase Deficiency of alpha-1 antitripsin lead to

3. Cationic proteins Increase vascular permeability Chemotaxis for monocytes Inhibition of movement of neutrophils and eosinophils More specific mediators

Cytokines They are polypeptide products of many cell types Products of activated lymphocytes and macrophages They modulate the function of other cell types

Many non lymphoid cells too produce these The secretion is transient and tightly regulated Their effects tend to be pleiotrophic Different cells are affected differently by the same cytokine Produced during immune and inflammatory responses Autocrine effect They can act on the same cell that produces them

Paracrine effect Act on other cells in the vicinity Endocrine effect Act systemically Types of Cytokines(CK) 1. CK that regulate lymphocyte function Activation, growth and differentiation Eg: IL-2 stimulate proliferation

TGF- inhibit lymphocyte growthinhibit lymphocyte growth 2. CK involved in innate immunity TNF and IL-1 3.CK that activate inflammatory cell(MP) during cell- mediated immune response Interferon- (IFN- ) and IL-12 4.Chemokines

Chemotactic for various leukocytes 5.CK that stimulate haematopoises Granulocyte inhibit lymphocyte growth monocyte colony stimulating factor(GM-CSF) and IL-3 IL-1 & Tumor Necrosis Factor (TNF) Both have additional effects that are important in inflammatory response

Both are produced by activated MP IL-1 also produced by other cell types. TNF also causes aggregation and activation of neutrophils Release of proteolytic enzymes from mesenchymal cells- contributing to tissue damage Major effects of interleukin-1 (IL-1) and tumor Complement system

Consist of cascade of plasma proteins (C1-C9) Play an important role in both immunity and inflammation Has 20 component proteins, together with their cleavage products Mediate biologic reactions All of which serve in the defense against microbial agents Their function in immunity primarily by

generating membrane attack complex(MAC) They effectively punches holes in the membranes of invading microbe In the process of producing MAC number of complement fragments are produced. Complement components are present in plasma as inactive form Most critical step in the elaboration of the

biological function of complement is the activation of the 3rd component, C3. Activation of complement by different pathways leads to cleavage of C3. C3 cleavage occurs via Classic pathway- triggered by fixation of C1 to Ag-Ab complex Alternative pathway- triggered by bacterial polysaccharide

Complement Activation Pathways The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC) Functions of complement Vascular effects

C3a and C5a ( anaphylatoxins) inhibit lymphocyte growthincrease vascular permeability and vasodilation by inducing mast cells to release histamine. C5a Potent chemotactic agent for N, M, E, B Activate leukocytes Increase their adhesion to the vascular endothelium Activate Arachidonic acid pathway Phagocytosis C3b and C3bi act as opsonins

C5-9(MAC) Membrane lysis of cells Production of oxygen metabolites C3 and C5 can be activated by several proteolytic enzymes present in the inflammatory infiltrate (plasmin, lysosomal enzymes)

Clotting fibrinolytic system Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on

platelets, endothelium, smooth muscle cells, other cells. 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 Counter regulate clotting by cleaving fibrin thereby solubilizing the the fibrin clot Fibrin inhibit lymphocyte growth insoluble clot

Fibrinopeptide inhibit lymphocyte growth increased vascular permeability, chemotaxis Thrombin inhibit lymphocyte growth leukocyte adhesion, fibroblast proliferation 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) Fibrinolytic system Plasminogen is converted into plasmin Plasmin lyses fibrin clots Increase vascular permeability

Activates factor XII- amplify the entire set of response Cleaves C3 to produceC3 fragments Degrades fibrin to fibrin split products Arachidonic Acid Metabolites PG,LT3, Lipoxins Also called eicosanoids Derived from the metabolism of AA Affect variety of biological processes including

Inflammation and haemostasis They are short range hormones Act locally at the site of generation Rapidly spontaneously decay / enzymatically destroyed AA is a 20-carbon polyunsaturated fatty acid Derived from dietary linoleic acid and cell membrane phospholipids.

AA released from phospholipids via cellular phospholipases Which is activated by mechanical, chemical, physical stimuli inflammatory mediaters- C5a Which is inhibited by steroids. AA metabolism proceed along one of the two pathway

Cyclooxygenase pathway- Synthesizing prostaglandins and thromboxanes Lipoxygenase pathway- Synthesizing Leukotrienes and lipoxins They can mediate virtually every step of inflammation Generation of arachidonic acid metabolites

and their roles in inflammation. The molecular targets of some antiinflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. Prostaglandins Major metabolite of the COX pathway in mast cell. Regarded as autocoid -Rapidly spontaneously

decay / enzymatically destroyed Act locally at the site of generation Also cause pain and fever Can pass from one cell to another Cyclooxygenase pathway There are two forms of cyclooxygenase COX-1 COX-2 COX-1 is found in the gastric mucosa

Mucosal PGs produced by COX -1 are protective against acid induced damage Inhibition of COX by Aspirin and NSAIDs predispose to gastric ulceration To prevent this, highly selective COX-2 inhibitors are now available(COX-2 not expressed in the gastric mucosa Role of Mediators in Different Reactions of inflamma

Vasodilatation Prostaglandins Nitric oxide Histamine Increased vascular permeability Vasoactive amines C3a and C5a (through liberating

amines) Bradykinin Leukotrienes C4, D4, E4 PAF Substance P Chemotaxis, leukocyte recruitment and activation C5a

Leukotriene B4 Chemokines IL-1, TNF Bacterial products Fever IL-1, TNF Prostaglandins

Pain Prostaglandins Bradykinin Tissue damage Neutrophil and macrophage lysosomal enzymes Oxygen metabolites

Nitric oxide Systemic effects of acute inflammation Fever Endogenous pyrogens produced: IL1 and TNFa IL-1 act on vascular receptors in the thermoregulatory center of the hypothalamus Leads to production of prostaglandins in

hypothalamus(hence aspirin etc. reduce fever) PGE act on the vasomotor center Resulting in sympathetic nerve stimulation Vasoconstriction of skin vessels Causes reduced heat dissipation and fever. Leukocytosis IL1 and TNFa produce an accelerated release of cells from bone marrow Rise in number of more immature Nin the

blood(shift to the left) Macrophages, T lymphocytes produce Colony-Stimulating Factors Causes proliferation of precursors in bone marrow Clinically useful Bacterial infections - neutrophilia viral - lymphocytosis Parasitic infestation- eosinophilia Typhoid and viral infections- leucopenia

Acute phase response Decreased appetite, altered sleep patterns

Hypotension Increased degradation of proteins changes in plasma concentrations of acute phase proteins Acute phase proteins:

C-reactive protein (CRP) (Clinically useful) 1 antitrypsin Haptoglobin Fibrinogen Serum amyloid A protein Complement Coagulation protein

Most of these are mediated by IL-1, IL-6 and TNF Problems caused by acute inflammation Local Swelling: Blockage of tubes, e.g. bile duct, intestine Exudate: Compression e.g. cardiac tamponade

Loss of fluid e.g. burns Pain & loss of function - especially if prolonged Bystander effect exacerbates damage, may initiate autoimmunity Systemic Acute phase response Spread of micro-organisms and toxins

SHOCK Laboratory manifestations Leukocytosis (granulocytosis vs. lymphocytosis) Elevated serum acute phase proteins (C-reactive protein, fibrinogen, etc) Increased ESR (erythrocyte sedimentation rate) Hypercoagulability

Diagnosis of acute inflammation Cardinal features of inflammation Fever Laboratory evidence ESR CRP, fibrinogen, haptoglobulin Increased WBC- neutrophils with toxic granules, left shift Examination of inflammatory exudate

Biopsy Test for specific aetiology Serum antibody, complement Culture, grame stained smear Outcome of acute inflammtion 1. Complete resolution Little tissue damage Capable of regeneration

2. Scarring (fibrosis) In tissues unable to regenerate Excessive fibrin deposition organized into fibrous tissue 3. Abscess formation occurs with some bacterial or fungal infections 4. Progression to chronic inflammation (next

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