INFLAMMATION: acute and chronic inflammation

Inflammation is a normal part of the body's healing process after an injury or infection. It occurs when the body releases chemicals to trigger an immune response to fight off infection or heal damaged tissue. The five cardinal signs of inflammation are heat, pain, redness, swelling, and loss of function

1. INFLAMMATION SRI SRUTHI PREMAN DEPARTMENT OF ORAL AND MAXILLOFACIAL PATHOLOGY

2. INTRODUCTION DEFINITION: Inflammation is defined as the local response of living tissues to injury due to any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent, followed by removal of the necrosed cells and tissues.

3. CAUSES The agents causing inflammation may be as under: 1. Infective agents like bacteria, viruses and their toxins, fungi, parasites. 2. Immunological agents like cell-mediated and antigen-antibody reactions. 3. Physical agents like heat, cold, radiation, mechanical trauma. 4. Chemical agents like organic and inorganic poisons. 5. Inert materials such as foreign bodies .

4. SIGNS OF INFLAMMATION The Roman writer Celsus in 1st century A.D. named the famous 4 cardinal signs of inflammation as: Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Fifth sign functio laesa (loss of function) was later added by Virchow. T

5. INFLAMMATORY CELLS

6. FACTORS DETERMINING VARIATION IN INFLAMMATORY RESPONSE 1. FACTORS INVOLVING THE ORGANISMS i ) Type of injury and infection ii) Virulence iii) Dose iv) Portal of entry v) Product of organisms 2. FACTORS INVOLVING THE HOST i ) Systemic diseases ii) Immune status of host iii) Congenital neutrophil defects iv) Leukopenia v) Site or type of tissue involved vi) Local host factors 3. TYPE OF EXUDATION i ) Serous, ii) Fibrinous, iii) Purulent or suppurative exudate iv) Haemorrhagic

7. SEQUENCE OF EVENTS

8. TYPES OF INFLAMMATION ACUTE & CHRONIC

9. 1.ACUTE INFLAMMATION : short duration 2. (lasting less than 2 weeks), early body reaction, resolves quickly and is usually followed by healing . Accumulation of fluid and plasma at the affected site Intravascular activation of platelets Polymorphonuclear neutrophils are the main inflammatory cells . CHRONIC INFLAMMATION : longer duration Presence of lymphocytes , plasma cells and macrophages, Granulation tissue formation. 3. SUBACUTE INFLAMMATION : inflammation between acute and chronic.

10. ACUTE INFLAMMATION Vascular events Cellular

11. Vascular events Alteration in the microvasculature (arterioles, capillaries and venules) is the earliest response to tissue injury. 1) Haemodynamic changes 2) Vascular permeability changes

12. 1.HAEMODYNAMIC CHANGES Immediate transient vasoconstriction - Mild injury, the blood flow may be re-established in 3-5 seconds - Severe injury, the vasoconstriction last for about 5 minutes. Vasodilatation -

13. Progressive vasodilatation - Elevates the local hydrostatic pressure - Transudation of fluid into the extracellular space - Swelling at the local site of acute inflammation . Slowing or stasis of microcirculation - Increased concentration of RBCs, thus raised blood viscosity

14. Lewis experiment i ) Stroking - Red line appears within a few seconds and is due to local vasodilatation of capillaries and venules. ii ) Flare or flush is the bright reddish appearance surrounding the red line and results from vasodilatation of the adjacent arterioles. iii) Wheal is the swelling or oedema of the surrounding skin occurring due to transudation of fluid into the extravascular space.

15. 2.ALTERED VASCULAR PERMEABILITY: Accumulation of oedema fluid in the interstitial compartment- from blood plasma by its escape through the endothelial wall Starling’s 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.

16. i )Contraction of endothelial cells. The endothelial cells develop temporary gap between them due to their contraction resulting in vascular leakiness. mediated by -histamine, bradykinin , short duration (15-30 minutes). ii)Retraction of endothelial cells. structural re- organisation of the cytoskeleton of endothelial cells Mediated by interleukin-1 (IL-1) and (TNF)-α, takes 4-6 hours iii) Direct injury to endothelial cells. Direct injury to the endothelium causes cell necrosis and appearance of physical gaps at the sites of detached endothelial cells. thrombosis is initiated at the site of damaged endothelial cells. iv) Endothelial injury mediated by leucocytes. Adherence of leucocytes - activation of leucocytes - release proteolytic enzymes- injury- leakiness, Late response.

17. FEATURES TRANSUDATE EXUDATE Definition Filtrate of blood plasma without changes in endothelial permeability Oedema of inflamed tissue associated with increased vascular permeability Character Non inflammatory edema Inflammatory edema Protein content Low (less than 1 gm/dl); mainly albumin, low fibrinogen; hence no tendency to coagulate. High ( 2.5-3.5 gm/dl), readily coagulates due to high content of fibrinogen and other coagulation factors Glucose content Same as in plasma Low (less than 60 mg/dl) pH > 7.3 < 7.3 Cells Few cells, mainly mesothelial cells and cellular debris Many cells, inflammatory as well as parenchymal cells Examples Oedema in congestive cardiac failure Purulent exudate such as pus

18. CELLULAR EVENTS 2 processes: 1. Exudation of leucocytes 2. Phagocytosis

19. 1. Changes in the formed elements of blood : Normal –centrally leucocytes and RBCs Peripherally cell free layer of plasma close to vessel wall. Due to slowing stasis, the central stream of cells widens and peripheral plasma zone becomes narrower because of loss of plasma by exudation - M argination . Neutrophils of the central column come close to the vessel wall- P avementing Exudation of Leucocytes

20. 2. ROLLING AND ADHESION Neutrophils slowly roll over vessel wall - Rolling Phase Bond between the leucocytes and endothelial cells - Adhesion Phase SELECTINS : expressed on the surface of activated endothelial cells which recognise specific carbohydrate groups found on the surface of neutrophils , P-selectin -rolling , (present on endothelial cells and platelets) E-selectin -rolling and adhesion (endothelial cell) L- selectin –(lymphocytes and neutrophils ) B. INTEGRINS : ( neutrophils and endothelial cells)-activated at the same time- A dhesion C. IMMUNOGLOBULIN GENE SUPERFAMILY ADHESION MOLECULE : Tighter adhesion & S tabilisation Intercellular adhesion molecule-1 (ICAM-1) & Vascular cell adhesion molecule-1 (VCAM-1)

21. 3. EMIGRATION Neutrophils move along the endothelial surface - throw out cytoplasmic pseudopods - lodged between the endothelial cells and basement membrane - cross basement membrane by secreting collagenases and escape out into the extravascular space - Emigration Escape of red cells through gaps between the endothelial cells- Diapedesis, gives hemorrhagic appearance to the inflammatory exudate

22. 4. CHEMOTAXIS The chemotactic factor-mediated transmigration of leucocytes after crossing several barriers (endothelium, basement membrane, perivascular myofibroblasts and matrix) to reach the interstitial tissues is called CHEMOTAXIS i ) Leukotriene B4 (LT-B4 ) ii) Components of complement system (C5a and C3a in particular) iii) Cytokines (Interleukins, in particular IL-8) iv) Soluble bacterial products (such as formylated peptides).

23. 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. 2 main types : Polymorph nuclear neutrophils ( MICROPHAGES) Circulating monocytes (MACROPHAGES)

24. STEPS IN A PHAGOCYTOSIS PROCESS Recognition and attachment Engulfment Killing and degradation

25. How do they recognize and attach? With the help of these NON -OPSONIC RECEPTORS: Toll like Receptor Mannose receptor Scavenger receptor OPSONINS: IgG opsonin C3b opsonin Lectin

26. Engulfment Opsonised particle binds to surface of phagocyte cytoplasmic pseudopods –activation of actin filaments beneath the cell wall-envelops the phagocytic vacuole-plasma membrane breaks – phagosome internilised -fuses with lysosome - phagolysosome

27. Phagosome free inside Phagosome + lysosome = Phagolysosome Phagolysosome is a bigger vacuole

28. KILLING AND DEGRADATION Once engulfed- phagosome- phagolysosome Phagolysosome – lysosomes produces digestive enzymes Pathogen destroyed into proteins taken up by phagocyte Enzymes = hydrolytic enzymes Can also kill by secreting highly toxic reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI)

29. CHEMICAL MEDIATORS OF INFLAMMATION Permeability factors /endogenous mediators of increased vascular permeability, these are a large and increasing number of endogenous compounds which can enhance vascular permeability

30. I. CELL-DERIVED MEDIATORS 1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides) 2. 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) 3 . Lysosomal components (from PMNs, macrophages) 4. Platelet activating factor 5. Cytokines (IL-1, TNF- α, TNF- β, IFN- γ, chemokines) 6 . Free radicals (Oxygen metabolites, nitric oxide)

31. II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES) Products of: 1. The kinin system 2. The clotting system 3. The fibrinolytic system 4. The complement system

32. VASOACTIVE AMINES 1) HISTAMINE It is stored in the granules of mast cells, basophils and platelets Actions - vasodilatation, increased vascular (venular) permeability, itching and pain Histamine is released from these cells by various agents as under: a) Stimuli / inducing substances - heat, cold, irradiation, trauma, irritant chemicals, immunologic reactions etc. b) Anaphylatoxins - fragments of complement C3a, and C5a c) Histamine releasing factors - from neutrophils, monocytes and platelets. d) Interleukins.

33. 2) 5-HYDROXYTRYPTAMINE (5-HT OR SEROTONIN) Present in tissues like chromaffin cells of GIT, spleen, nervous tissue, mast cells and platelets. The actions of 5-HT are similar to histamine It is a less potent mediator of increased vascular permeability and vasodilatation. 3) NEUROPEPTIDES Substance P, neurokinin A, vasoactive intestinal polypeptide (VIP) and somatostatin. Produced in the central and peripheral nervous systems. Actions are a) Increased vascular permeability. b) Transmission of pain stimuli. c) Mast cell degranulation

34. ARACHIDONIC ACID METABOLITES (EICOSANOIDS) Arachidonic acid is a fatty acid, eicosatetraenoic acid It is a constituent of the phospholipid cell membrane released by phospholipases. It is then activated to form arachidonic acid metabolites or eicosanoids by * Cyclooxygenase pathway * Lipo-oxygenase pathway

35. ARACHIDONIC ACID METABOLITES

36. LYSOSOMAL COMPONENTS GRANULES OF NEUTROPHIL Primary or azurophil granules - large azurophil granules which contain functionally active enzymes. - myeloperoxidase, acid hydrolases, acid phosphatase, lysozyme, defensin phospholipase, cathepsin G, elastase, and protease. Secondary or specific granules - alkaline phosphatase, lactoferrin, gelatinase, collagenase, lysozyme , Tertiary granules or C particles - gelatinase and acid hydrolases

37. GRANULES OF MONOCYTES AND TISSUE MACROPHAGES These cells on degranulation release mediators of inflammation Acid proteases, collagenase, elastase and plasminogen activator. they are more active in chronic inflammation

38. PLATELET ACTIVATING FACTOR (PAF) It is released from IgE-sensitised basophils, mast cells, leukocytes ,endothelium and platelets. It helps in platelet aggregation A ctions are : - increased vascular permeability - vasodilatation in low concentration and vasoconstriction otherwise - bronchoconstriction - adhesion of leucocytes to endothelium - chemotaxis

39. CYTOKINES P roduced by activated lymphocytes (lymphokines) and activated monocytes ( monokines ) The actions of various cytokines as mediator of inflammation are : 1) IL-1 and TNF ( alpha & beta ) - induce endothelial effects in the form of increased leucocyte adherence, thrombogenicity, elaboration of other cytokines, fibroblastic proliferation and acute phase reactions. 2) IFN gamma - causes activation of macrophages and neutrophils and is associated with synthesis of nitric acid synthase . 3) CHEMOKINES - Chemokines are a family of small proteins that act primarily as chemoattractants for specific types of leukocytes

40. FREE RADICALS OXYGEN-DERIVED METABOLITES They are released from activated neutrophils and macrophages Actions - Endothelial cell damage and thereby increased vascular permeability - Protease activation & antiprotease inactivation causing tissue matrix damage. - Damage to other cells.

41. NITRIC OXIDE (NO) formed by activated macrophages Actions in mediating inflammation are - Vasodilatation - Anti-platelet activating agent - Microbicidal action

42. 1. THE KININ SYSTEM Bradykinin acts in the early stage of inflammation and its effects include: smooth muscle contraction; vasodilatation; increased vascular permeability; and pain

43. 2. THE CLOTTING SYSTEM

44. 3. THE FIBRINOLYTIC SYSTEM

45. 4. THE COMPLEMENT SYSTEM . C3a , C5a, C4a (anaphylatoxins): activate mast cells and basophils to release of histamine, cause increased vascular permeability causing oedema in tissues, augments phagocytosis. Membrane attack complex (MAC) (C5b-C9) :is a lipid dissolving agent and causes holes in the phospholipid membrane of the cell.

46. SYSTEMIC EFFECTS OF ACUTE INFLAMMATION Fever Leucocytosis Lymphangitis-lymphadenitis Shock

47. FATE OF ACUTE INFLAMMATION

48. CHRONIC INFLAMMATION

49. DEFINITION AND CAUSES.: Chronic inflammation is defined as prolonged process in which tissue destruction and inflammation occur at the same time . CAUSED BY Chronic inflammation following acute inflammation. Recurrent attacks of acute inflammation Chronic inflammation starting de novo

50. TYPES OF CHRONIC INFLAMMATION Non-specific - when the irritant substance with formation of granulation tissue and healing by fibrosis e.g . chronic osteomyelitis, chronic ulcer. Specific -when the injurious agent causes a characteristic histologic tissue response e.g. tuberculosis, leprosy, syphilis.

51. ROLE OF MACROPHAGES The dominant cells in chronic inflammation They secrete cytokines & growth factors that destroys foreign invaders and tissues They activate T cells Products of activated macrophages eliminate injurious agents, initiate repair and also responsible for tissue injury in chronic inflammation

52. ROLE OF LYMPHOCYTES Microbes and other agents activate T & B lymphocytes which amplify and propagate chronic inflammation CD4+T cells secrete cytokines Activated B lymphocytes and plasma cells produce antibodies specific for persistent antigen.

53. EOSINOPHILS Abundant in immune reactions mediated by IgE and in parasitic infections They have granules that contain basic protein toxic and also injure host epithelial cells MAST CELLS They express on their surface the receptor that binds Fc portion if IgE antibody in immediate hypersensitivity reaction They secrete cytokines which promotes inflammation

54. NEUTROPHILS Though characteristic of acute inflammation, also present in many forms of chronic inflammation Induced by - persistent microbes - mediators produced by activated macrophages & T lymphocyte

55. GRANULOMATOUS INFLAMMATION Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in diameter, composed predominantly of collection of modified macrophages called epithelioid cells, and rimmed at the periphery by lymphoid cells.

56. COMPOSITION OF GRANULOMA

57. GENERAL FEATURES OF CHRONIC INFLAMMATION 1.MONONUCLEAR CELL INFILTRATION PHAGOCYTES & LYMPHOID CELLS Phagocytes : circulating monocytes, tissue macrophages, epithelioid cells and multinucleated giant cells. Macrophages -most important cells in chronic inflammation. I) chemotactic factors and adhesion molecules for continued infiltration of macrophages; Ii ) local proliferation of macrophages; Iii ) longer survival of macrophages at the site of inflammation.

58. 2.TISSUE DESTRUCTION OR NECROSIS This is brought about by activated macrophages which release a variety of biologically active substances e.g. protease, elastase, collagenase, lipase, reactive oxygen radicals, cytokines (IL-1, IL-8, TNF-α), nitric oxide, angiogenesis growth factor etc . 3.PROLIFERATIVE CHANGES As a result of necrosis, proliferation of small blood vessels and fibroblasts is stimulated resulting in formation of inflammatory granulation tissue. Eventually, healing by fibrosis and collagen laying takes place

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