Inflammation PDF

Inflammation  Objectives Definition of inflammation Types Causes Inflammatory exudate Type of inflammatory cell  Inflammation Inflame – to set fire. Definition: A protective response involving host cells, blood vessels and proteins & other...

Inflammation  Objectives Definition of inflammation Types Causes Inflammatory exudate Type of inflammatory cell  Inflammation Inflame – to set fire. Definition: A protective response involving host cells, blood vessels and proteins & other mediators, that is intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from original insult and to initiate the process of repair. Serves to Dilute, isolate, destroy or neutralize harmful agent (microbes, toxins) Component of innate immunity Cells and molecules of defense have to be brought to site of damage A strong, prolonged or inappropriate reaction can also injure normal tissues  Inflammation Acute Chronic onset Rapid Insidious onset duration Short - Long duration days- mins/days years Edema Vascular proliferation exudation of Fibrosis and Tissue fluids & proteins necrosis Leukocyte neutrophils Lymphocytes mainly migration mainly & macrophages Local and prominent Less prominent systemic signs Practically the two patterns can coexist and are modified by many variables  Cardinal signs of inflammation Pain Redness Heat (calor) (dolor) (rubor) Hyperaemia. Nerve, Chemical med Hyperaemia.. Swelling Loss of function (tumor) (functio laesa) Exudation A manifestation of disease Controlled and self limited Types: Acute and Chronic  Red, Warm & Swollen (Flare, Flush & Weal – Lewis) Triple response  Definitions Exudation: Escape of Fluid rich in proteins and cells (exudate) from vascular system to interstitial tissues or body cavities – Secondary to increased vascular permeability – Specific gravity 1.020 or more Pus: Exudate rich in leukocytes and parenchymal cell debris in tissues Transudation: Ultra filtration of blood plasma due to increased hydrostatic pressure in vessels – no increase in permeability – Fluid have very little protein (mostly albumin) – Specific gravity 1.012 or less  Exudate vs transudate Exudate Transudate permeability increased normal protein 1.5-6g/dl 0-1.5g/dl Protein type all albumin Specific gravity 1.015-1.027 1.010-1.015 cells inflammatory none Components of inflammatory response  Components of inflammation Circulating cells: neutrophils. eosinophils., basophils, lymphocytes, monocytes and platelets Plasma proteins: clotting, complement, kinninogens Vascular wall cells: endothelial, smooth muscle Surrounding connective tissue – Cells: mast, lymphocytes, macrophages, fibroblast. – Extracellular matrix- collagen, elastin, proteoglycans, glycoproteins  Acute inflammation Immediate and early response of tissue to injurious stimuli, designed to deliver leukocytes and plasma proteins to the site of injury. Non specific Main roles 1. Formation of exudate (protein, fluid cells) 2. Elimination of cause. Protect against microorganisms 3. Dead tissue can be broken down and removed from the site of damage. 4. Allow the immune system access to damaged area  Stimuli / Causes Trauma: – Physical agents (blunt and penetrating) thermal (burn, frost bite), Irradiation and – Environmental Chemicals: acids, bases Infections : – bacteria, viruses, fungi, parasites Immunological: – hypersensitivity reactions Tissue necrosis: – Ischemia, physical and chemical injury Foreign bodies: – sutures, splinters, dirt, crystals Steps of inflammatory response (5 Rs) Recognition of the injurious agent by resident 1 cells Release of mediators 2 Recruitment of leukocytes 3 Removal of the agent 4 Regulation (control) of the response 5 Resolution (repair) Recognition of microbes, necrotic cells and foreign substances Phagocytes, dendritic cells, epithelial cells etc express receptors which sense the pathogens and substances from necrotic tissue. Two important receptors: Toll like receptors: present in plasma membrane and endosomes Inflammasomes: multi-protein cytoplasmic complex recognize products of necrosis. – activate caspase 1 – IL-1-1β – IL-1- leucocyte recruitment  Acute inflammation 2 components Vascular changes Cellular events Vascular changes – In caliber, structure – Endothelial cell activation – adhesion of leukocytes Changes in vascular caliber and flow: – Initial transient vasoconstriction. – Arteriolar vasodilatation - ↑ blood flow – engorgement of capillary bed Fig 3.3 Robin’s  Vascular events Increased vascular permeability: – Increased permeability and leakage from arterioles, capillaries, venules, protein rich fluid and cells –exudation – Increased osmotic pressure in tissues and more out flow of fluid - edema Mechanisms: 1. Endothelial cell contraction 2. Endothelial injury 3. Increased Transcytosis 4. leakage from new blood vessels Mechanism of vascular leakage in acute inflammation Fig 3.4 Robin’s  Vascular events: Mechanisms of Increased vascular permeability 1 Endothelial cell contraction Gaps in post capillary venules Immediate, transient response (15 -30 mins) caused by chemical mediators histamine, Bradykinin, Leukotrienes binding to receptors. delayed, prolonged retraction, open up intercellular junctions after 4-6hrs, caused by cytokines like TNF, IL 1 for 24 hrs.  Vascular events: Mechanisms of Increased vascular permeability 2 Endothelial injury At all levels of microcirculation moderate to severe injury by injurious agents or leukocytes. necrosis and detachment of cells immediate response 2-12 hrs and sustained for hrs or days 3 Increased transcytosis Increased transport of proteins via intracellular vesicular pathway across the cell cytoplasm, through small, inter-connected vesicles increasing permeability of venules. cause:- mediators e.g. Vascular endothelial growth factor VEGF  Vascular events: Mechanisms of Increased vascular permeability 4-leakage from new blood vessels During the process of healing, new blood vessels are formed (angiogenesis) these are leaky due to poorly developed I/c junctions, have more receptors for mediators and VEGF Mechanism of Inflammation: Fig 3.2 Robin’s  Responses of lymphatic vessels Increased lymph flow – drain edema fluid, leukocytes and debri Also transport offending agent and help in dissemination Reactive or inflammatory Lymphangitis and lymphadenitis, red streaks at wound site, enlarged painful lymph nodes  Cellular events Leukocyte recruitment. emigration from circulation to focus of injury usually extravascular space. Leukocyte activation to eliminate offending agent Role of WBCs in inflammation – Ingest, kill, degrade, tissue damage (prolonged inflammation) Neutrophils predominate in Acute inflammation in 6-24 hrs, replaced by monocytes in24-48 hrs  Cellular events Leukocyte Recruitment Lumen 1) Margination and Rolling 2) Adhesion to endothelium 3)Transmigration through Wall (Diapedesis) 4) Migration in Interstitium chemotaxis Fig 3.7 Robin’s  Cellular events- Margination and rolling usual axial flow system, leucocytes pushed out of central column esp. when disrupted by slowing of blood flow, accumulate at periphery of vessels - margination endothelial cells activation due to cytokine and other mediators – expression of adhesion molecules, loose attachment of neutrophils to endothelial cells, bind – detach- tumble on endothelial surface – Rolling. interaction between specific molecules – Selectins (E, P, L) on both leucocytes and endothelium. Selectins bind sialyl-Lewis X on leucocytes that are attached to glycoprotein s on various cells.  Cellular events- Adhesion Is mediated by integrins on leucocytes interacting with ligands on endothelial cells 1. complementary adhesion molecules on Endothelium - White cells a. Selectins(E, P, L) - sialyl-lewis X attached to Glycoproteins b. ICAM/VCAM - Integrins 2. Modulation by chemical mediators: 1. Redistribution on surface 2. Induction of production 3. Increased affinity Cellular events- Cellular events- Fid 3.9 Robin’s  Cellular events- Transmigration Leukocytes migrate through vessel wall by squeezing between cells at intercellular junctions. Extravasation called diapedesis occur at venules. Chemokines in extravascular tissues – drive the movement of leucocytes towards their chemical gradient PECAM-1 on endothelium and leucocytes mediates the binding to traverse endothelium Leukocytes produce collagenases to pass through basement membrane  Cellular events- Chemotaxis Unidirectional movement of leucocytes towards site of injury along a chemical gradient. Chemotactic agents: 1. exogenous: bacterial peptides and lipids 2. endogenous: Cytokines, Complement, Leukotriene LTB4 3. Products of the lipoxygenase pathway of arachidonic acid -leukotriene B4 These bind to cell surface receptors, trigger assembly of cytoskeleton. Leukocytes move by pseudopods, anchoring on ECM and pull in direction of extension Fig 3.5 Robin’s  Cellular events- leucocyte activation stimuli for activation dead cells and foreign substances, microbes and mediators are sensed by surface Receptors, induction of responses in leucocytes – activation – result in enhancement of following: Phagocytosis Destruction of phagocytosed material Liberation of substances to destry extracellular microbes Production of mediators  1. Recognition & Attachment Phagocytosis 2.Engulfment 3. Killing Step 1 Step 2 Step 3 Oxidative WBC bind burst ROS Pseudopods microbes via NADPH- extension - receptors Fc, Oxidse- phagosome CR1,3, C1q Ȱ,H2O2, HOCl, NO Opsonization Lysosomal * IgG Formation of enzymes acid phago- *C1 and C3 hydrolases lysosome (Elastase) *Collectins  Other Killing mechanisms Bactericidal permeability increasing protein Lysozyme Major basic protein Defensins  Extracellular excretion of lysosomal contents – Transiently open before complete closure – Frustrated phgocytosis of difficult substances- strong activation – release of contents to surrounding tissue – Damage to phagolysosomal membrane by injurious substances like Silica Neutrophil Extracellular Traps NETs – Extracellular fibrin networks composed of nuclear chromatin with granule proteins – in response to pathogens and mediators – Trap microorganisms -High concentration of antimicrobial peptides – Loss of nuclei and death of neutrophils  Leukocytes induced tissue injury – As part of normal defense in difficult infections – Clear dead or damaged tissue – Autoimmunity – Hypersensitivity  Neutrophils predominate in Acute inflammation in 6-24 hrs, replaced by monocytes in24-48 hrs