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Inflammation DR SINDHURA.pptx
- 1. inflammation -Dr SINDHURA DEPARTMENT OF PERIODONTICS
- 2. CONTENT ď DEFINITION AND CAUSES OF INFLAMMATION ď AGENTS CAUSING INFLAMMATION ď SIGNS OF INFLAMMATION ď TYPES OF INFLAMMATION ďą ACUTE INFLAMMATION ďą CHRONIC INFLAMMATION ď REGULATION OF INFLAMMATION ď THE INFLAMMATORY CELLS ď PERIODONTAL INFLAMMATION ď REFERENCES
- 3. DEFINITIONS HARSH MOHAN: Inflammation is the local response of living mammalian tissues to injury due to any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent. KIETH L KIRKWOOD (CARRANZA) Inflammation is an observable alteration in tissues associated with changes in vascular permeability and dilation, often with infiltration of leukocytes into affected tissues . N.C.DEY & T.K.DEY: Inflammation is a series of pathological changes associated with Local vascular reaction and cellular response of the living tissue to an injury, insufficient to kill the tissue.
- 4. AGENTS CAUSING INFLAMMATION INFECTIVE AGENTS: Bacteria , viruses & toxins PHYSICAL AGENTS : Heat, cold ,radiation & mechanical trauma CHEMICAL AGENTS : Organic and inorganic poisons IMMUNOLOGICAL AGENTS : Cell mediated antigen antibody reaction INERT MATERIAL: Foreign bodies
- 5. 5 CARDINAL SIGNS OF INFLAMMATION
- 6. Depending upon the defence capacity of the host & duration of response ACUTE CHRONIC ď§ Short duration > 2 weeks ď§ Early body reaction ď§ Resloves quickly ⢠Longer duration ⢠Occurs after causative agent of acute inflammation persist for long time/chronic inflammation from begining
- 9. Acute Inflammation Vascular events Cellular events Haemodynamic changes Altered Vascular permeability Exudation of leucocytes phygocytosis
- 10. The main features of acute inflammation are: 1. accumulation of fluid and plasma at the affected site 2. intravascular activation of platelets and 3. polymorphonuclear neutrophils as inflammatory cells. ACUTE INFLAMMATION
- 11. I.Vascular events A. Haemodynamic changes B. Altered vascular permeability
- 12. A. HAEMODYNAMIC CHANGES Immediate transient vasoconstriction (3-5 sec to 5 min) Persistent progressive vasodilation- mainly arterioles involved ď within 1/2 hr of injury ď redness and warmth Local hydrostatic pressure ď transudation of fluid into extracellular spaceď swelling Slowing or stasis of microcirculationď permeabilityď exudation ď conc. of RBCs ď blood viscosity Leucocytic margination /Peripheral orientation of leucocytes(mainly neutrophils)ď Emigration
- 13. Lewis Experiment Also known as TRIPLE RESPONSE or RED LINE RESPONSE
- 14. B. Altered vascular permeability In initial stages the escape of fluid is due to vasodilatation consequent increase in hydrostatic pressure This is transudate in nature Subsequently Increased vascular permeability, which results in characterstic inflammatory oedema, exudate appears
- 15. Inflammed tissue - accumulation of oedema fluid in interstitial compartment Starlingâs hypothesis
- 16. MECHANISMS OF INCREASED VASCULAR PERMEABILITY
- 17. II. CELLULAR EVENTS The cellular phase of inflammation consists of 2 processes: A. exudation of leucocytes; and B. phagocytosis
- 18. EXUDATION OF LEUCOCYTES PMNs Monocytes & Macrophages
- 19. The changes leading to migration of leucocytes are as follows : 1.CHANGES IN THE FORMED ELEMENTS OF BLOOD 2. ROLLING AND ADHESION. 3. EMIGRATION 4. CHEMOTAXIS
- 21. SELECTINS L-selectin P-selectin E-selectin Selectins are expressed on the surface of activated endothelial cells which recognise specific carbohydrate groups found on the surface of neutrophils, the most important of which is s-Lewis X molecule.
- 22. INTEGRINS
- 23. Immunoglobulin gene superfamily adhesion molecule Tighter adhesion & stabilise the interaction between leucocyte & endothelial cells. ďIntercellular adhesion molecule-1(ICAM-1) ďVascular cell adhesion molecule-1 (VCAM-1) ďPlatelet-endothelial cell adhesion molecule-1(PECAM-1) ďCD31 activated by TNF& IL-1 Involved in margination
- 24. Emigration After sticking â PMNs move along surface till suitable site found between endothelial cells Throw cytoplasmic pseudopodsď cross membrane by damaging it locally ď by collagenases Escape into extracellular space- EMIGRATION
- 25. Diapedesis simultaneous to emigration of leukocytes-diapedesis of red cells between endothelial cells takes place ď Passive phenomenon ď Forced out â increased hydrostatic pressure or escape after emigration ď gives haemorrhagic appearance to exudate
- 26. Chemotaxis The chemotactic factor-mediated transmigration of leucocytes after crossing several barriers to reach the interstitial tissues is called chemotaxis.
- 27. 1.Leukotriens B4 2.Components of complement system C3a C5a 3.Cytokines ( lnterleukins IL-8 ) 4.Soluble bacterial products (formulated peptids) Chemotactic factors:
- 28. Phagocytosis ⢠Phagocytosis is defined as the process of engulfment of solid particulate material by the cells (cell-eating). ⢠The cells performing this function are called phagocytes
- 29. There are 2 main types of phagocytic cells: i) Polymorphonuclear neutrophils (PMNs) ii) Circulating monocytes and fixed tissue mononuclear phagocytes, commonly called as macrophages
- 31. 1.Recognition & Attachment stage (Opsonisation ) ďą receptors on macrophages-(mannose receptor & scavenger receptor) ďąOpsonins coat target(IgG & C3b)
- 32. 2.Engulfment stage:- Binding of opsonised particle -engulfment with cytoplasmic pseudopods-Phagocytic vacuole-phagolysosome formation.
- 33. ďąPreformed granules-stored products of PMNs are discharged or secreted into phagosome/ECM ďą Synthesis of certain enzymes (IL2 , IL6, TNF)AA metabolites and Oxygen metabolites. 3.Killing & degradation :
- 34. killing of microorganism Intracellular mechanisms: ďOxidative bactericidal mechanism by oxygen free radical. ďąMPO-dependent ďąMPO-independent ďOxidative bactericidal mechanism by lysosomal granules. ďNon-oxidative bactericidal mechanism ďąGranules ďąNitric oxide dependent
- 36. Chemical mediators of inflammation They are broadly classified into 2 groups: i) mediators released by cells; and ii) mediators originating from plasma
- 39. Histamine physical injury- trauma or heat Anaphylatoxins ; C3a and C5a Neutrophils, monocytes &platelets cytokines (e.g., IL-1 and IL-8) Derived from- Mast cells, basophils and platelets
- 40. 5-HT or Serotonin- Derived from- cromaffin cells of GIT , spleen, nervous tiss52ue, mast cells and platelets. ⢠Actions of 5-HT are similar to histamine but it is a less potent mediator of increased vascular permeability and vasodilatation than histamine. ⢠It may be mentioned here that carcinoid tumour is a serotonin-secreting tumour .
- 41. 2)Arachidonic acid metabolites (Eicosanoids) i. Metabolites via cyclo-oxygenase pathway ii. Metabolites via lipo-oxygenase pathway
- 42. Metabolites via cyclo-oxygenase pathway
- 43. Metabolites via lipo-oxygenase pathway
- 44. 3. Lysosomal components Neutrophils and monocytes, contain lysosomal granules which on release elaborate a variety of mediators of inflammation. I. Granules of neutrophils II. Granules of monocytes and tissue macrophages
- 45. 4) Platelet Activating Factor(PAF) It is released from: ⢠IgE-sensitised basophils or mast cells, ⢠other leucocytes, endothelium and platelets.
- 46. Actions of PAF vascular permeability; bronchoconstriction; Vasodilatatio n (low conc.) Vasoconstrictio n(high conc) Leukocyte adhesion
- 47. 5. CYTOKINES Cytokines are polypeptide products of activated lymphocytes (lymphokines) and monocytes (monokines) that modulate the function of other cell types. ďśMany cell types produce multiple cytokines ďśpleiotropic-different cells are affected differently by the same cytokines ďśredundant in that the same activity may be induced by many different cytokines
- 48. Cytokines may be roughly grouped into five classes based on their actions or target cells. ⢠Regulate lymphocyte function e.g., IL-2, and TGFď˘. ⢠Involved in innate immunity, like TNF and IL-1. ⢠Activate inflammatory cells like IFN- ď§ and IL-2. ⢠Chemotactic activity for various leukocytes. ⢠Stimulate hematopoiesis, like granulocyte-monocyte colony-stimulating factor (GM-CSF) and IL-3.
- 49. 6) Free Radical :Oxygen Metabolites and Nitric Oxide
- 51. Many of the effects of inflammation are mediated by 4 interrelated plasma-derived factors: ⢠The Kinin system ⢠The Clotting system ⢠The Fibrinolytic system ⢠The Complement system â all 4 systems are linked by the initial activation of Hageman factor II. Plasma-derived Mediators (Plasma Proteases)
- 52. The Kinin System
- 59. Activation of Complement System alternate pathway classic pathway
- 60. Inter-relationship among clotting, fibrinolytic, kinin and complement systems.
- 62. RESOLUTION ABSCESS FORMATION HEALING BY FIBROSIS CHRONIC INFLAMMAT- ION Outcomes of Inflammation
- 64. Spontaneous decay of chemical mediaters Return of normal vascular per meability Cessation of new leucocyte formation Apoptosis of neutrophils Removal of oedema fluid & protein leukocyte foreign agents & necrotic debris Complete resolution
- 66. Chronic Inflammation Chronic inflammation is of prolonged duration in which active inflammation, tissue injury, and healing proceed simultaneously. Characterized by : ⢠Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells. ⢠Tissue destruction, largely directed by the inflammatory cells. ⢠Repair, involving angiogenesis and fibrosis.
- 67. 1.Follows acute inflammation 2.Chronic inflammation starting de novo 3.Recurrent attacks of acute inflammation Causes of chronic inflammation
- 69. Outcome of chronic inflammation fistulas Combinatio n of above Granuloma tous diseases Fibrosis, (scarring)
- 70. Periodontal inflammation Inflammatory response of periodontium can be divided into 2 main groups 1. Subgingival microflora (i.e. microbial virulence factor) 2. Host immune-inflammatory response
- 72. Histopathology of Gingivitis & Periodontitis Infiltration of connective tissue Disruption of normal anatomy of connective tissue Collagen depletion & proliferation of Junctional epithelium Vasodilation & increased vascular permeability Leakage of fliuid oout of vessel Facilitate the passage of defence cells from vasculature into tissue Enlagement of tissue Clinical appearance of gingivitis
- 73. ⢠MMPs ⢠Prostaglandins ⢠Cytokines- IL-1,TNF Inflammatory Mediators
- 84. Direct Damage To PMNs & Macrophages ⢠leukotoxin PMN chemotaxis ⢠AA, PG, capnocytophaga species Ig degradation ⢠Gm âve black- pigmented anaerobes Capnocytophaga sp âproteases â degrade IgG & IgA Modulation of cytokine function ⢠Argenine specific trypsin like proteinase (RgpA) of PG â cleave, activate â pro & anti-inflammatory cytokines ⢠The balance â influences inflammatory status of local cytokine network in periodontium (Tsai et al 1979) (Slots & Genco 1984) (Jansen et al 1995) (Aduse-Opoku et al 1995)
- 85. ⢠Inflammation is a major & first event which takes place during any alteration in the body tissue, indicating a need of the treatment for the altered condition. ⢠Indeed the survival of the individual depends upon the ability of his or her normal cells to respond to altered condition. ⢠Without it none of us would be alive. Conclusion
- 86. References 1.Harshmohan Textbook of Pathology 6th Ed 2.Robins: Basic pathology 10th edition. 3. CARRANZAâs Clinical periodontology 11th edition 4. Adriana d.b. ,Isabella G. ,Silvia C. , Maria g.Periodontal disease :linking the primary inflammation to bone loss. Clin Dev Immunol 2013. 5. Thomas E. Van Dike Inflammation and periodontal diseases : a reappraisal. J Periodntol 2008 6.Thomas E. Van Dike The management of inflammation in periodontal disease .J Periodntol 2008
Editor's Notes
- SIGNS OF INFLAMMATIONRoman writer CELSUS in 1st century A.D. named 4 cardinal signs of inflammation as :Rubor (redness) 2. Tumor (swelling)3. Calor (heat)4. Dolor (pain)Rudolf Virchow (1902) added FUNCTIO LAESA (loss of function) as the fifth cardinal sign of inflammation
- The features of haemodynamic changes in inflammation are best demonstrated by the Lewis experiment. Lewis induced the changes in the skin of inner aspect of forearm by firm stroking with a blunt point. The reaction so elicited is known as triple response or red line response consisting ofthe following i) Red line appears within a few seconds following stroking and is due to local vasodilatation of capillaries andvenules. ii) Flare is the bright reddish appearance or flush surrounding the red line and results from vasodilatation of theadjacent arterioles. iii) Wheal is the swelling or oedema of the surrounding skin occurring due to transudation of fluid into the extravascularspace These features, thus, elicit the classical signs of inflammationâredness, heat, swelling and pain.
- The appearance of inflammatory oedema due to increased vascular permeability of microvascular bed is explained on the basis of Starlingâs hypothesis. In normal circumstances,the fluid balance is maintained by two opposing sets of forces: i) Forces that cause outward movement of fluid from microcirculation are intravascular hydrostatic pressure and colloid osmotic pressure of interstitial fluid. ii) Forces that cause inward movement of interstitial fluid into circulation are intravascular colloid osmotic pressure and hydrostatic pressure of interstitial fluid. Whatever little fluid is left in the interstitial compartment is drained away by lymphatics and, thus, no oedema results normally However, in inflamed tissues, the endothelial lining of microvasculature becomes more leaky. Consequently, intravascular colloid osmotic pressure decreases and osmotic pressure of the interstitial fluid increases resulting in excessive outward flow of fluid into the interstitial compartment which is exudative inflammatory oedema (Fig. 6.2,B).
- Mechanism Microvasculature Response type Pathogenesis Examples Endothelial cellContraction Venules Immediate transient(15-30 min) Histamine ,bradykinin Mild thermal injury Endothelial cell Retraction Venules Delayed(4-6hrs)Prolonged(24 hrs or more) IL-1, TNF-Îą In vitro only Direct endothelial cell injuryArteriolesvenules,capi (2-12 hrs)(hrs to days) Cell necrosis & detachment Moderate to severe burns, bacterial infection , radiation injury Leucocytes mediated endo injury Venules capillaries Delayed , prolonged Leucocyte activation Pulmonary venules & capillaries Neovascularisation All levels All levels Angiogenesis, VEGFHealing, tumors
- first line of body defense, followed later by monocytes and macrophages A critical function of inflammation is to deliver leucocytes to the site of injury and to activate the leucocytes to perform their normal functions in host defense
- Sequence of changes in the exudation of leucocytes. A, Normal axial flow of blood with central column of cells and peripheral zone of cell-free plasma. B, Margination and pavementing of neutrophils with narrow plasmatic zone. C, Adhesion of neutrophils to endothelial cells with pseudopods in the intercellular junctions. D, Emigration of neutrophils and diapedesis with damaged basement membrane. 1. CHANGES IN THE FORMED ELEMENTS OF BLOOD. In the early stage of inflammation, the rate of flow of blood is increased due to vasodilatation. But subsequently, there is slowing or stasis of bloodstream. With stasis,changes in the normal axial flow of blood in the microcirculation take place. The normal axial flow consists of central stream ofcells comprised by leucocytes and RBCs and peripheral cellfreelayer of plasma close to vessel wall. Due to slowing and 2. ROLLING AND ADHESION. Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cells lining the vessel wall (rolling phase). This is followed by the transient bond between the leucocytes and endothelial cells becoming firmer (adhesion phase
- Selectins are expressed on the surface of activated endothelial cells which recognise specific carbohydrate groups found on the surface of neutrophils, the mostimportant of which is s-Lewis X molecule. While P-selectin (preformed and stored in endothelial cells and platelets) is involved in rolling, E-selectin (synthesised by cytokineactivated endothelial cells) is associated with both rolling and adhesion; L-selectin (expressed on the surface of lymphocytesand neutrophils) is responsible for homing of circulating lymphocytes to the endothelial cells in lymph nodes.
- ii) Integrins on the endothelial cell surface are activated during the process of loose and transient adhesions between endothelial cells and leucocytes. At the same time the receptors for integrins on the neutrophils are also stimulated. This process brings about firm adhesion between leucocyte and endothelium.
- After sticking of neutrophils to endothelium,the former move along the endothelial surface till a suitable site between the endothelial cells is found where the neutrophils throw out cytoplasmic pseudopods. Subsequently, the neutrophils lodged between the endothelial cells and basement membrane cross the basement membrane by damaging it locally with secreted collagenases and escape out into the extravascular space; this is known as emigration. The damaged basement membrane is repaired almost immediately. As already mentioned, neutrophils are the dominant cells in acute inflammatory exudate in the first 24 hours, and monocyte-macrophages appear in the next 24-48 hours. However, neutrophils are short-lived (24-48hours) while monocyte-macrophages survive much longer.
- Simultaneous to emigration of leucocytes, escape of red cells through gaps between the endothelial cells, diapedesis,takes place. It is a passive phenomenonâRBCs being forcedout either by raised hydrostatic pressure or may escape through the endothelial defects left after emigration of leucocytes. Diapedesis gives haemorrhagic appearance to inflammatory exudate
- barriers(endothelium, basement membrane, perivascular myofibroblasts and matrix)
- which appear early in acute inflammatory response, sometimes called asmicrophages. Circulating monocytes and fixed tissue mononuclear phagocytes, commonly called as
- Stages in phagocytosis of a foreign particle. A, Opsonisation of the particle. B, Pseudopod engulfing the opsonised particle. C, Incorporation within the cell (phagocytic vacuole) and degranulation. D, Phagolysosome formation after fusion of lysosome of the cell.
- Phagocytosis is initiated by the expression of surface receptors on macrophages which recognise microorganisms: mannose receptor and scavenger receptor. The process ofphagocytosis is further enhanced when the microorganisms are coated with specific proteins, opsonins, from the serum or they get opsonised. Opsonins establish a bond between bacteria and the cell membrane of phagocytic cell. The main opsonins present in the serum and their corresponding receptors on the surface of phagocytic cells (PMNs or macrophages) are as under: i) IgG opsonin is the Fc fragment of immunoglobulin G; it is the naturally occurring antibody in the serum that coats thebacteria while the PMNs possess receptors for the same.ii) C3b opsonin is the fragment generated by activation ofcomplement pathway. It is strongly chemotactic for attracting PMNs to bacteria. iii) Lectins are carbohydrate-binding proteins in the plasmawhich bind to bacterial cell wall. The opsonised particle bound to the surface of phagocyteready to be engulfed. This is accomplished by formation of cytoplasmic pseudopods around the particle due to activation of actin filaments beneath cell wall, enveloping it in a phagocytic vacuole. Eventually, the plasma membrane enclosing the particle breaks from the cell surface so that membrane lined phagocytic vacuole or phagosome lies internalised and free in the cell cytoplasm. The phagosome fuses with one or more lysosomes of the cell and form bigger vacuole called phagolysosome.
- 2. ENGULFMENT The opsonised particle bound to the surface of phagocyteready to be engulfed. This is accomplished by formation of cytoplasmic pseudopods around the particle due to activation of actin filaments beneath cell wall, enveloping it in a phagocytic vacuole. Eventually, the plasma membrane enclosing the particle breaks from the cell surface so that membrane lined phagocytic vacuole or phagosome lies internalised and free in the cell cytoplasm. The phagosome fuses with one or more lysosomes of the cell and form bigger vacuole called phagolysosome.
- Next comes the stage of killing and degradation of microorganism to dispose it off justifying the function of phagocytes as scavanger cells. The microorganisms after being killed by antibacterial substances are degraded by hydrolytic enzymes. However, this mechanism fails to kill and degrade some bacteria like tubercle bacilli.
- Oxidative bactericidal mech by oxygen free radiclas A phase of increases o2 consumption (respratory burst) by activated phagocytic leucocytes requires the essential prepresence of NADPH oxidase In phagosome cell memb NADPH oxidase reduces oxygen to superoxide ion,this is cnvrtd 2 H2O2 wic hs bctricdl prop O2 ď Oâ2 ď H2O2ď Bactericidal prop ď MPO dependent/Ind MPO Dep H2O2 Halide system : MPOď (halides)ď H2O2ď Hypocholus acid(HOCL,HOI,HOBr) MPO Indepn (mature macrophages lack MPO enzyme) they kill by producing OH- ion H2O2 ď OH-(Haber Weiss Reaction in presence of oxide ion) = OH- Fe+2 (Fenton Reaction) = OH- ROSď imp in eliminating those org wic grow inside phagocytes e.g M. tuberculosis, Histoplasmosis capsulatum Oxidative Bact Mech by LYSOSOMAL GRANULES Preformed granules stored products of neutrophils & macrophages are discharged/secreted into phagosome & extracellular environment----- Mpo, tyrosinase & alk phosphotase Prog degradation of neutrophils & macrophages along with ORS ď proteolysis(protein degradation)
- Also called as permeability factors or endogenous mediators of increased vascular permeability The substances acting as chemical mediators of inflammation may be released from the cells, the plasma, or damaged tissue itself.
- 5 HYDROXY TRAPTAMINE
- i) Histamine. It is stored in the granules of mast cells, basophils and platelets. Histamine is released from these cells by various agents as under: a) Stimuli or substances inducing acute inflammation e.g. heat, cold, irradiation, trauma, irritant chemicals, immunologic reactions etc. b) Anaphylatoxins like fragments of complement C3a, and C5a, which increase vascular permeability and cause oedema in tissues. c) Histamine-releasing factors from neutrophils, monocytes and platelets. d) Interleukins. Oâ2 OHâ H2O2 OHâ (Hydroxyl radical) Haber-Weiss reactionFe ++ Fenton reactionThe main actions of histamine are: vasodilatation, increased vascular (venular) permeability, itching and pain. Stimulation of mast cells and basophils also releases products of arachidonic acid metabolism including the release of slowreacting substances of anaphylaxis (SRS-As). The SRS-As consist of various leukotrienes (LTC4, LTD4 and LTE4). i
- Arachidonic acid metabolites (Eicosanoids) i. Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane A2, prostacyclin, resolvins) ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes, lipoxins)
- Cyclo-oxygenase (COX), a fatty acid enzyme present as COX-1 and COX-2, acts on activated arachidonic acid to formprostaglandin endoperoxide (PGG2). PGG2 is enzymatically transformed into PGH2 with generation of free radical ofoxygen. PGH2 is further acted upon by enzymes and results in formation of the following 3 metabolites a) Prostaglandins (PGD2, PGE2 and PGF2-Îą). PGD2 and PGE2 act on blood vessels to cause increased venular permeability, vasodilatation and bronchodilatation and inhibit inflammatory cell function. PGF2-Îą induces vasodilatation and bronchoconstriction.b) Thromboxane A2 (TXA2). Platelets contain the enzyme thromboxane synthetase and hence the metabolite,thromboxane A2, formed is active in platelet aggregation, besides its role as a vasoconstrictor and broncho-constrictor. c) Prostacyclin (PGI2). PGI2 induces vasodilatation, bronchodilatation and inhibits platelet aggregation. d) Resolvins are a newly described derivative of COXpathway. These mediators act by inhibiting production of pro-inflammatory cytokines. Thus, resolvins are actually helpfulâdrugs such as aspirin act by inhibiting COX activityand stimulating production of resolvins.It may be mentioned here that some of the major antiinflammatorydrugs act by inhibiting activity of the enzyme COX; e.g. non-steroidal anti-inflammatory drugs (NSAIDs),COX-2 inhibitors.
- ii) Metabolites via lipo-oxygenase pathway: 5-HETE, leukotrienes, lipoxins. The enzyme, lipo-oxygenase, apredominant enzyme in neutrophils, acts on activated arachidonic acid to form hydroperoxy eicosatetraenoic acid (5-HPETE) which on further peroxidation forms following 2 metabolites (Fig. 6.9):a) 5-HETE (hydroxy compound), an intermediate product,is a potent chemotactic agent for neutrophils.b) Leukotrienes (LT) are so named as they were first isolated from leucocytes. Firstly, unstable leukotriene A4 (LTA4) is formed which is acted upon by enzymes to form LTB4 (chemotactic for phagocytic cells and stimulates phagocytic cell adherence) while LTC4, LTD4 and LTE4 have common actions by causing smooth muscle contraction and therebyinduce vasoconstriction, bronchoconstriction and increased vascular permeability; hence they are also called as slowreactingsubstances of anaphylaxis (SRS-As). c) Lipoxins (LX) are a recently described product of lipooxygenase pathway. Lipooxygenase-12 present in platelets acts on LTA4 derived from neutrophils and forms LXA4 and LXB4. Lipoxins act to regulate and counterbalanceactions of leukotrienes.
- i) Granules of neutrophils. Neutrophils have 3 types of granules: primary or azurophil, secondary or specific, andtertiary.a) Primary or azurophil granules are large azurophil granules which contain functionally active enzymes. These are myeloperoxidase, acid hydrolases, acid phosphatase, lysozyme, defensin (cationic protein), phospholipase, cathepsin G, elastase, and protease. b) Secondary or specific granules contain alkaline phosphatase, lactoferrin, gelatinase, collagenase, lysozyme, vitamin-B12 bindingproteins, plasminogen activator.c) Tertiary granules or C particles contain gelatinase and acid hydrolases.ii)Granules of monocytes and tissue macrophages. These cells on degranulation also release mediators of inflammation like acid proteases, collagenase, elastase and plasminogen activator. However, they are more active in chronic inflammation than acting as mediators of acute inflammation
- 4. PLATELET ACTIVATING FACTOR (PAF). It isreleased from IgE-sensitised basophils or mast cells, other leucocytes, endothelium and platelets. Apart from its action on platelet aggregation and release reaction, the actions of PAF as mediator of inflammation are: increased vascular permeability;vasodilatation in low concentration and vasoconstriction otherwise;bronchoconstriction; adhesion of leucocytes to endothelium; and chemotaxis.
- Free radicals act as potent mediator of inflammation:i) Oxygen-derived metabolites are released from activated neutrophils and macrophages and include superoxide oxygen (Oâ2), H2O2, OHâ and toxic NO products. Theseoxygen-derived free radicals have the following action in inflammation: Endothelial cell damage and thereby increased vascular permeability. Activation of protease and inactivation of antiprotease causing tissue matrix damage. Damage to other cells.The actions of free radicals are counteracted by antioxidants present in tissues and serum which play aprotective role ii) Nitric oxide (NO) was originally described as vascular relaxation factor produced by endothelial cells. Now it is known that NO is formed by activated macrophages duringthe oxidation of arginine by the action of enzyme, NO synthase. NO plays the following role in mediating inflammation:VasodilatationAnti-platelet activating agent
- This system on activation by factor Xlla generates bradykinin, so named because of the slow contraction of smooth muscle induced by it. First, kallikrein is formed from plasma prekallikrein by the action of prekallikrein activator which is a fragment of factor Xlla. Kallikrein then acts on high molecular weight kininogen to form bradykinin . Bradykinin acts in the early stage of inflammation and its effects include: smooth muscle contraction;vasodilatation; increased vascular permeability; andpain.
- THE CLOTTING SYSTEM. Factor Xlla initiates the cascade of the clotting system resulting in formation of fibrinogen which is acted upon by thrombin to form fibrin and fibrinopeptides The actions of fibrinopeptides in inflammation are: increased vascular permeability; chemotaxis for leucocyte; and anticoagulant activity.
- This system is activated by plasminogen activator, the sources of which include kallikrein of the kinin system, endothelial cells and leucocytes. Plasminogen activator acts on plasminogen present as component of plasma proteins to form plasmin. Further breakdown of fibrin by plasmin forms fibrinopeptides or fibrin split products (Fig. 6.13). The actions of plasmin in inflammation are as follows: activation of factor XII to form prekallikrein activator thatstimulates the kinin system to generate bradykinin; splits off complement C3 to form C3a which is a permeability factor; and degrades fibrin to form fibrin split products which increase vascular permeability and are chemotactic to leucocytes.
- The activation of complement system can occur either: i) by classic pathway through antigen-antibody complexes; Or ii) by alternate pathway via non-immunologic agents such as bacterial toxins, cobra venoms and IgA. Complement system on activation by either of these two pathways yields activated products which includeanaphylatoxins (C3a, C4a and C5a), and membrane attack complex (MAC) i.e. C5b,C6,7,8,9. The actions of activated complement system in inflammation are as under: C3a, C5a, C4a (anaphylatoxins) activate mast cells and basophils to release of histamine, cause increased vascular permeability causing oedema in tissues, augments phagocytosis. C3b is an opsonin. C5a is chemotactic for leucocytes. Membrane attack complex (MAC) (C5b-C9) is a lipid dissolving agent and causes holes in the phospholipid membrane of the cell.
- Hageman factor (factor XII) of clotting system plays a key role in interactions of the four systems. Activation 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. In inflammation, activation of factor XII is brought about by contact of the factor leaking through the endothelial gaps. The end-products of the activated clotting, fibrinolytic and kinin systems activate the complement system that generate permeability factors. These permeability factors, in turn, further activate clotting system
- Although, as might be expected, many variables may modify the basic process of inflammation, including the nature and intensity of the injury, the site and tissue affected, and the responsiveness of the host, acute inflammatory reactions typically have one of three outcomes ⢠Complete resolution. In a perfect world, all inflammatory reactions, after they have succeeded in eliminating the offending agent, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics. ⢠Healing by connective tissue replacement (scarring, or fibrosis). This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue. ⢠Progression of the response to chronic inflammation. Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing.
- FATE OF ACUTE INFLAMMATIONThe acute inflammatory process can culminate in one of the following outcomes (Fig. 6.17):1. Resolution. It means complete return to normal tissuefollowing acute inflammation. This occurs when tissuechanges are slight and the cellular changes are reversible e.g.resolution in lobar pneumonia.2. Healing. Healing by fibrosis takes place when the tissuedestruction in acute inflammation is extensive so that thereis no tissue regeneration. But when tissue loss is superficial,it is restored by regeneration.3. Suppuration. When the pyogenic bacteria causing acute inflammation result in severe tissue necrosis, the processprogresses to suppuration. Initially, there is intense neutrophilic infiltration. Subsequently, mixture of neutrophils, bacteria, fragments of necrotic tissue, cell debris and fibrincomprise pus which is contained in a cavity to form an abscess. The abscess, if not drained, may get organised by dense fibrous tissue, and in time, get calcified.4. Chronic inflammation. Persisting or recurrent acute inflammation may progress to chronic inflammation in which the processes of inflammation and healing proceed side by side.
- In terms of relative importance of each it is now clear that great majority of tissue breakdown results from h the host inflammatory immune response Bactera are important because they drive and perpetuate the inflammation
- Defense cells neutrophis macrophages plasma cells
- Mmp matrix metaloprotinases