Inflammation- Basic Concept

describes the vascular and cellular events of acute inflammation. The process involves diapedesis and phagocytosis. The various chemical mediators involved in the process have been discussed. Fate of acute inflammation and conversion into chronic inflammation is described.

1. INFLAMMATION- BASIC CONCEPT Dr. Anushri Gupta PG 1 st year Department of Periodontology Date: 27-04-20

2. Definition Inflammation is a response of vascularized tissues to infections and tissue damage that bring cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents. - Robbins, 10 th edition 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 tissue .

3. Agent causing inflammation Infective agent – like bacteria, viruses and toxins, fungi, parasites. Immunological agent- like cell-mediated and antigen antibody reaction. Physical agent- like heat, cold, radiation, mechanical trauma. Chemical agent- like organic and inorganic poison. Inert material- such as foreign bodies.

4. Signs of inflammation 4 cardinal signs of inflammation are- Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) - Celsus , Roman encyclopedist 5 th sign is functio laesa (loss of function) - Virchow, Father of Modern Pathology

5. Types of inflammation Depending upon the defense capacity of host and duration of response, inflammation can be classified as – Acute inflammation Chronic inflammation

6. Acute inflammation Short duration (lasting less than 2 weeks) Represent the early body reaction Resolves quickly and is usually followed by healing. The main feature of acute inflammation are- Accumulation of fluid and plasma at the affected site. Intravascular activation of platelets Polymorphonuclear neutrophils as inflammatory cells. Fulminant acute inflammation.

7. Chronic inflammation – longer duration – causative agent of acute inflammation persists for a long time • Another variant, Chronic active inflammation : stimulus is such that it induces chronic inflammation from the beginning.

8. A. Acute Inflammation The main features of acute inflammation are: – accumulation of fluid and plasma at the affected site; – intravascular activation of platelets; – polymorphonuclear neutrophils as inflammatory cells.

9. Divided into following two events – Vascular events – Cellular events This 2 events are followed intermittently by release of mediators of acute inflammation.

10. A. Vascular events Alteration in the microvasculature (arterioles, capillaries and venules ) is the earliest response to tissue injury. These alteration include – hemodynamic changes and changes in vascular permeability .

11. a . Haemodynamic changes The sequence of these changes is as under – Transient vasoconstriction: immediate vascular response irrespective of the type of injury, mainly arterioles – Mild injury - 3-5 seconds – Severe injury - 5 minutes

12. Persistent Progressive vasodilatation - involve mainly the arterioles venules and capillaries – obvious within half an hour of injury – increased blood volume in microvascular bed of the area – redness and warmth Local hydrostatic pressure- _ elevate the local hydrostatic pressure – transudation of fluid into the extracellular space – swelling

13. Slowing or stasis- of microcirculation causes increased concentration of red cells and thus raised blood viscosity. Leucocytic margination – peripheral orientation of leucocytes (mainly neutrophils ) along the vascular endothelium – stick to the vascular endothelium briefly – move and migrate through the gaps between the endothelial cells - extravascular space – This is known is emigration

14. Lewis experiment Features of hemodynamic changes was best demonstrated by Lewis. Lewis induced the changes in the skin of inner aspect of foramen by firm stroking with a blunt point. The reaction elected was triple response or red line response consisting of the following-

15. RED LINE- Appears within a few seconds following stroking and is due to local vasodilation of capillaries and venules . FLARE- Is the bright reddish appearance or flush surrounding the red line and result from vasodilatation of the adjacent arterioles. WHEAL – is the swelling or oedema of the surrounding skin occurring due to transudation of fluid into the extravascular space. A, ‘Triple response’ elicited by firm stroking of skin of forearm with a pencil. B, Diagrammatic view of microscopic features of triple response of the skin.

16. b . Altered Vascular Permeability Accumulation of oedema fluid – interstitial compartment which comes from blood plasma by its escape through the endothelial wall of peripheral vascular bed . • Escape of fluid is due to vasodilatation and consequent elevation in hydrostatic pressure - transudate . • Subsequently, the characteristic inflammatory oedema , appears by increased vascular permeability of microcirculation – exudate .

17. Difference between transudate and exudate - T ransudate Filtrate of blood plasma without changes in endothelial permeability It is a non- inflammatory edema Protein content is low mainly albumin, low firbrinogen hence no tendency to coagulate Exudate Edema of inflamed tissue associated with increased vascular permeability Inflammatory edema High protein content, coagulates due to high content of fibrinogen and the other coagulation factors.

18. T ransudate Glucose content is same as in plasma pH > 7.3 Cells- few cells, mainly mesothelial cells and cellular debris Example- edema in congestive cardiac failure Exudate Glucose content is low pH <7.3 Many cells, inflammatory as well as parenchymal . Purulent exudate such as pus.

19. Starling hypothesis- Apperance of inflammatory oedema due to increased vascular permeability of microvascular bed is explained by this hypothesis . The fluid balance is maintained by two opposing sets of forces – Forces that causes outward movement of fluid from microcirculation are intravascular hydrostatic pressure and colloid osmotic pressure of intestinal fluid. Forces that causes inward movement of interstial fluid into circulation are intravascular colloid osmotic pressure and hydrostatic pressure of interstitial fluid.

20. Fluid interchange between blood and extracellular fluid (ECF). ( HP = hydrostatic pressure, OP = osmotic pressure

21. Mechanism of increased vascular permeability- In acute inflammation non-permeable endothelial layer of microvasculature becomes leaky.

22. Contraction of endothelial cells • Affects venules exclusively. • Endothelial cells develop temporary gaps • Contraction resulting in vascular leakiness. • Mediated by the release of histamine , bradykinin and other chemical mediators. • Short duration (15-30 minutes) - immediately after injury.

23. Retraction of endothelial cells • Structural re- organisation of the cytoskeleton of endothelial cells - Reversible retraction at the intercellular junctions. • Mediated by cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF)-α.

24. Direct injury to endothelial cells • Causes cell necrosis and appearance of physical gaps. • Process of thrombosis is initiated at the site of damaged endothelial cells. • Affects all levels of microvasculature. • Either appear immediately after injury and last for several hours or days – severe bacterial infections • Or delay of 2-12 hours and last for hours or days - moderate thermal injury and radiation injury

25. Endothelial injury mediated by leucocytes • Adherence of leucocytes to the endothelium at the site of inflammation. • Activation of leucocytes - release proteolytic enzymes and toxic oxygen. • Cause endothelial injury and increased vascular leakiness. • Affects mostly venules and is a late response.

26. Leakiness and neovascularisation • Newly formed capillaries under the influence of vascular endothelial growth factor (VEGF). • Process of repair and in tumours are excessively leaky

27. B. Cellular events Consist of 2 process- Exudation of leucocytes Phagocytosis a. Exudation of leucocytes- The escape of leucocytes from the lumen of microvasculature to the interstitial tissue is the most important feature of inflammatory response. In acute inflammation, polymorphonuclear neutrophils (PMNs) comprise the first line of body defense. The changes leading to migration of leucocytes are-

28. Changes in the formed elements of blood- • Central stream of cells comprised by leucocytes and RBCs and peripheral cell free layer of plasma close to vessel wall. • Later, central stream of cells widens and peripheral plasma zone becomes narrower because of loss of plasma by exudation. • This phenomenon is known as margination . • Neutrophils of the central column come close to the vessel wall - pavementing

29. Rolling and adhesion – • Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cells lining the vessel wall ( rolling phase ). • Transient bond between the leucocytes and endothelial cells becoming firmer ( adhesion phase ). • The following molecules bring about rolling and adhesion phases – Selectins – Integrins – Immunoglobulin gene superfamily adhesion molecule

30. Events of Exudation of Leucocytes

31. EMIGRATION • 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 . • Cross the basement membrane by damaging it locally – collagenases and escape out into the extravascular space - emigration • Diapedesis - escape of red cells through gaps between the endothelial cells – passive phenomenon. – raised hydrostatic pressure – haemorrhagic appearance to the inflammatory exudate

32. 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.

33. Chemotaxis – After extravasating from the blood, Leukocytes migrate toward sites of infection or injury along a chemical gradient by a process called chemotaxis • They have to cross several barriers - endothelium, basement membrane, perivascular myofibroblasts and matrix . The following agents act as potent chemotactic substance or chemokines for neutrophils - Leukotrine b4 Components of complement system Cytokines (Interleukins, in particular IL-8) Soluble bacterial products (such as formylated peptides)

34. b. Phagocytosis - It is a process of engulfment of solid particulate material by the cells. (cell eating) Cells performing this function is phagocytic cells. 2 main types of phagocytic cells- PMNs –appears early in acute inflammatory response sometimes known as microphages. Macrophages-Circulating monocytes and fixed tissue This phagocytic cells releases proteolytic enzymes- lysozyme , protease, collagenase , elastase , lipase , proteinase , gelatinase and acid hydrolases

35. The microbe undergoes the process of phagocytosis and involve the following 3 steps- Recognition and attachment- the process of coating a particle such as microbe to target it for phagocytosis is called as OPSONISATION. substance are called OPSONINS. The main opsonin present in serum are – IgG , C3b and lectin .

36. Engulfment – • Formation of cytoplasmic pseudopods around the particle due to activation of actin filaments around cell wall . • Eventually plasma membrane gets lysed and fuses with nearby lysosomes – phagolysosome .

37. Killing and degradation- the micro-organism after being killed by organism after being killed by anti- bacterial substance are degraded by hydrolytic enzyme. • Sometimes this process fails to kill and degrade some bacteria like tubercle bacilli.

38. 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.

39. Disposal of microorganisms • Intracellular mechanisms – Oxidative bactericidal mechanism by oxygen free radicals – Oxidative bactericidal mechanism by lysosomal granules – Non-oxidative bactericidal mechanism • Extracellular mechanisms – Granules – Immune mechanisms

40. A. INTRACELLULAR MECHANISMS • Kill microbes by oxidative mechanism and less often non-oxidative pathways a). Oxidative bactericidal mechanism by oxygen free radicals . – production of reactive oxygen metabolites ( O’2, H2O2 , OH ’, HOCl , HOI, HOBr ) – activated phagocytic leucocytes requires the essential presence of NADPH oxidase present in the cell membrane of phagosome reduces oxygen to superoxide ion (O’2 ) Superoxide is subsequently converted into H2O2 which has bactericidal properties 2O2’ + 2H+ H2O2

41. b). Oxidative bactericidal mechanism by lysosomal granules – preformed granule-stored products of neutrophils and macrophages . – secreted into the phagosome and the extracellular environment. c). Non-oxidative bactericidal mechanism – Some agents released from the granules of phagocytic cells do not require oxygen for bactericidal activity • Granules : cause lysis of within phagosome , ex: lysosomal hydrolases , permeability increasing factors, cationic proteins ( defensins ), lipases, ptoteases , DNAases . • Nitric oxide : reactive free radicals similar to oxygen free radicals – potent mechanism of microbial killing – produced by endothelial cells as well as by activated macrophages

42. B. EXTRACELLULAR MECHANISMS • Granules – Degranulation of macrophages and neutrophils • Immune mechanisms – immune-mediated lysis of microbes – takes place outside the cells – by mechanisms of cytolysis, antibody-mediated lysis and by cell-mediated cytotoxicity

43. Chemical mediators of inflammation • Chemical mediators that are responsible for vascular and cellular events. • Knowledge of this mediators – basis of anti-inflammatory drugs. • It may either of two types, – Cell Derived - produced locally by cells at the site of inflammation – Plasma derived – mainly from liver • Some mediators are derived from Necrotic cells

44. Chemical mediators of inflammation

45. A. Cell derived mediators • Induce their effects by binding to specific receptors on target cells – it may be one or a very few targets, or multiple • Some may have direct enzymatic and/or toxic activities. Ex: lysosomal proteases • Some may stimulate target cells to release secondary effector molecules • Once activated and released from the cell, mediators either – quickly decay. Ex : arachidonic acid metabolites – inactivated by enzymes ex: kininase inactivates bradykinin – eliminated Ex: antioxidants scavenge toxic oxygen metabolites – Inhibited. Complement-inhibitory proteins

46. – Rapidly secreted upon cellular activation. Ex: histamine in mast cells – synthesized from beginning in response to a stimulus. Ex: Prostaglandins and cytokines • Tissue macrophages, mast cells, and endothelial cells – capable of producing different mediators. • Various cell derived mediators 1. Vasoactive amines 2. Arachidonic acid metabolites 3. Lysosomal component 4. Platelet activating factors (PAF) 5. Cytokines 6. Reactive Oxygen Species (ROS) and nitrogen oxide (NO) 7. Neuropeptides

47. 1. Vasoactive Amines • Stored as preformed molecules in mast cells or early inflammatory cells. • Histamine – many cell types, particularly mast cells adjacent to vessels, circulating basophils and platelets – variety of stimuli responsible for release of histamine: • physical injury like heat, cold, radiation, trauma etc. • immune reactions involving binding of IgG antibodies to Fc receptors on mast cells • C3a and C5a fragments of complement – anaphylatoxins • Leukocyte-derived histamine-releasing proteins • Neuropeptides e.g., substance P • Certain cytokines e.g., IL-1 and IL-8

48. Actions: - arteriolar dilation & increased vascular permeability : endothelial contraction and interendothelial gaps – itching and pain – Histamine inactivated by histaminase • Serotonin – 5-hydroxytryptamine – preformed vasoactive mediator - effects similar to those of histamine but less potent – Released from platelet, GIT, spleen, nervous system, mast cells

49. 2. ARACHIDONIC ACID (AA) METABOLITES • Also known as eicosanoids . • Most potent mediators of inflammation. • short-range hormones that act locally at the site of generation and then decay spontaneously or are enzymatically destroyed • Derived from cell membranes phospholipids of Leukocytes, mast cells, endothelial cells, and platelets by the action of phospholipases .

50. • AA is released from these phospholipids via cellular phospholipases – that have been activated by mechanical, chemical, or physical stimuli, or by inflammatory mediators such as C5a. • Metabolism proceeds along either of this two major enzymatic pathways • Cyclooxygenase : prostaglandins and thromboxanes - AUTOCOIDS • Lipoxygenase : leukotrienes and lipoxins

51. Cyclo-oxygenase Pathway • Cyclooxygenase - a fatty acid enzyme present as COX-1 and COX-2, • Metabolizes AA to following derivative – Prostaglandins (PGD2, PGE2 and PGF2-α) – Thromboxane A2 (TXA2) – Prostacyclin (PGI2) – Resolvins • Major anti-inflammatory drugs act by inhibiting activity of the enzyme COX – NSAIDs & COX-2 inhibitors

52. Arachidonic acid metabolites via cyclooxygenase pathway

53. Lipo-oxygenase Pathway

54. 3. LYSOSOMAL COMPONENTS • Inflammatory cells like neutrophils and monocytes – lysosomal granules. Its of 2 types : • Granules of neutrophils – Primary or azurophil : myeloperoxidase , acid hydrolases , acid phosphatase , lysozyme , defensin (cationic protein), phospholipase , cathepsin G, elastase , and protease – Secondary or specific : alkaline phosphatase , lactoferrin , gelatinase , collagenase , lysozyme , vitamin-B12 binding proteins, plasminogen activator – Tertiary : gelatinase and acid hydrolases • Granules of monocytes and tissue macrophages – acid proteases, collagenase , elastase and plasminogen activator – more active in chronic inflammation

55. 4. PLATELET ACTIVATING FACTOR (PAF) • released 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 .

56. 5. CYTOKINES • Polypeptide substances produced by activated lymphocytes ( lymphokines ) and activated monocytes ( monokines ). • Major cytokines in acute inflammation – TNF-alpha and IL-1, – Chemokines - a group of chemoattractant cytokines • Chronic inflammation : interferon-γ (IFN-γ) and IL-12

57. Tumor Necrosis Factor and Interleukin-1 • Produced by activated macrophages, as well as mast cells, endothelial cells, and some other cell types • Stimulated by microbial products, such as bacterial endotoxin , immune complexes, and products of T lymphocytes • Principal role in inflammation – endothelial activation – expression of adhesion molecules on endothelial cells results in increased leukocyte binding and recruitment, – enhance the production of additional cytokines (notably chemokines ) and eicosanoids • TNF – increases thrombogenicity of endothelium and causes aggregation and activation of neutrophils • IL-1 - results in increased proliferation and production of fibroblasts in extracellular matrix

58. • May enter the circulation - systemic acute-phase reaction – Fever & lethargy – hepatic synthesis of various acute-phase proteins, – metabolic wasting ( cachexia ), – neutrophil release into the circulation, – release of adrenocorticotropic hormone (inducing corticosteroid synthesis and release).

59. Chemokines Chemokines are a family of chemoattractants for inflammatory cells and include: IL-8 chemotactic for neutrophils ; platelet factor-4 chemotactic for neutrophils , monocytes and eosinophils ; MCP-1 chemotactic for monocytes ; and eotaxin chemotactic for eosinophils

60. 6. Nitric Oxide • short-lived, soluble, free-radical gas • formed by activated macrophages during the oxidation of arginine by the action of enzyme, NO synthase (NOS). • Three isoforms of NOS – Type I ( nNOS ) – neuronal, no role in inflammation – Type II ( iNOS ) – induced by chemical mediators, macrophages and endothelial cells – Type III ( eNOS ) - primarily (but not exclusively) within endothelium • NO plays many roles in inflammation including – relaxation of vascular smooth muscle ( vasodilation ), – antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation ) – reduction of leukocyte recruitment at inflammatory sites – action as a microbicidal ( cytotoxic ) agent (with or without superoxide radicals) in activated macrophages.

61. 7. Neuropeptides • initiate inflammatory responses • small proteins, such as substance P • transmit pain signals, regulate vessel tone, and modulate vascular permeability • prominent in the lungs and gastrointestinal tract

62. B. Plasma-protein-derived mediators • Circulating proteins of four interrelated systems - the complement, kinin , clotting and fibrinolytic systems • Inactive precursors that are activated at the site of inflammation – action of enzyme. • Each of these systems has its inhibitors and accelerators in plasma - negative and positive feedback mechanisms respectively. • Hageman factor (factor XII) of clotting system – a key role in interactions of the four systems

63. Hageman factor (factor XII) • protein synthesized by the liver. • initiates four systems involved in the inflammatory response – Kinin system - vasoactive kinins ; – Clotting system - inducing the activation of thrombin, fibrinopeptides , and factor X, – Fibrinolytic system - plasmin and inactivating thrombin; – Complement system - anaphylatoxins C3a and C5a • Gets activated - collagen, basement membrane, or activated platelets.

64. 1. Clotting system • factor XIIa -driven proteolytic cascade leads to activation of thrombin. • Functions of thrombin – cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot • Fibrinopeptides - increase vascular permeability & chemotactic for leukocytes. – In i /m, Binding of thrombin to the receptors on endothelial cells - activation and enhance leukocyte adhesion

65. 2. Fibrinolytic System • Hageman factor induces clotting system and fibrinolytic system concurrently – control over the 2 system • Limit clotting by cleaving fibrin - solubilizing the fibrin clot. • In absence of this – even minor injury could lead to coagulation of entire vasculature . • Plasminogen activator - released from endothelium, leukocytes, and other tissues) and kallikrein from kinin system – Cleave plasminogen , a plasma protein – further forms PLASMIN

66. • Multifunctional protease that cleaves fibrin. • Cleaves the C3 complement protein - production of C3a • Activate Hageman factor - amplify the entire set of responses

67. 3. Kinin System • Haegman Factor activates Prekallikrein activator - acts on plasma prekallikrein to give kallikrein . • Kallikrein acts on kininogen (HMW) to give Bradykinin . • Bradykinin are short-lived - rapidly degraded by kininases present in plasma and tissues

68. Bradykinin • Slow contraction of smooth muscle • Bradykinin acts in the early stage of i /m : – vasodilatation; – increased vascular permeability – pain

69. 4. Complement System • 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 include anaphylatoxins (C3a, C4a and C5a), and membrane attack complex (MAC) i.e. C5b,C6,7,8,9.

70. 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.

71. Outcomes of acute inflammation 1 . R esolution - restoration to normal, limited injury – chemical substances neutralization – normalization of vasc . permeability – apoptosis of inflammatory cells – lymphatic drainage 2. Healing by scar 3. Suppuration Neutrophilic infiltration pus formation Dense fibrous tissue formation leading to calcification 4 . Progression into chronic inflammation

72. B. Chronic inflammation Definition - Chronic inflammation is also referred to as slow, long-term inflammation lasting for prolonged periods of several months to years. Generally, the extent and effects of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage. Occur either after the causative agent of acute inflammation persists for a long time, or the stimulus is such that it induced chronic inflammation from the beginning.

73. Characteristic feature of chronic inflammation is presence of chronic inflammatory cells such as lymphocytes, plasma cells and macrophages, granulation tissue formation and in specific situation.

74. Chronic inflammation can be caused by one of the following 3 ways- • Following acute inflammation – persistence of the injurious agent or because of interference with the normal process of healing – e.g. in osteomyelitis , pneumonia terminating in lung abscess • Recurrent attacks of acute inflammation – repeated bouts of acute inflammation culminate in chronicity of the process – Ex: R ecurrent urinary tract infection - chronic pyelonephritis , Repeated acute infection of gall bladder – chronic cholecystitis • Chronic inflammation starting de novo – low pathogenicity is chronic from the beginning – Ex: infection with Mycobacterium tuberculosis, Treponema pallidum

75. Chronic Inflammatory Cells and Mediators • PMNs Macrophages • Lymphocytes, • Plasma Cells, • Eosinophils , • Mast Cells

76. Polymorphonuclear Neutrophils along with basophils and eosinophils are known as granulocytes due to the presence of granules in then cytoplasm. These granules contain many substances like proteases, myeloperoxidase , lysozyme , esterase, aryl sulfatase , acid and alkaline phosphatase , and cationic proteins. The functions of neutrophils in inflammation are as follows: i ) Initial phagocytosis of microorganisms as they form the first line of body defense in bacterial infection. ii) Engulfment of antigen-antibody complexes and nonmicrobial material. iii) Harmful effect of neutrophils in causing Basement membrane destruction of the glomeruli and small blood vessels.

77. Eosinophils share many structural and functional similarities with neutrophils like their production in the bone marrow, locomotion, phagocytosis , lobed nucleus and presence or granules in the cytoplasm containing a variety of enzymes, of which major basic protein and eosinophil cationic protein are the most important which have bactericidal and toxic action against helminthic parasites. The absolute number of eosinophils is increased in the following conditions: i ) allergic conditions; ii) parasitic infestations; iii) skin diseases; and iv) certain malignant lymphomas.

78. Basophils The basophils comprise about 1% of circulating leucocytes and are morphologically and pharmacologically similar to mast cells of tissue. granules are laden with heparin and histamine. The role of these cells in inflammation are: in immediate and delayed type of hypersensitivity reactions; and ii) release of histamine by IgE-sensitised basophils .

79. Lymphocytes Apart from blood, (20-45%), lymphocytes are present in large numbers in spleen, thymus, lymph nodes and mucosa-associated lymphoid tissue (MALT). They play role in antibody formation (B lymphocytes) and in cell-mediated immunity (T lymphocytes). These cells participate in the following types of inflammatory responses: In tissues, they are dominant cells in chronic inflammation and late stage of acute inflammation. ii) In blood, their number is increased ( lymphocytosis ) in chronic infections like tuberculosis.

80. Plasma Cells Plasma cells are normally not seen in peripheral blood. They develop from B lymphocytes and are rich in RNA and γ-globulin in their cytoplasm. These cells are most active in antibody synthesis. Their number is increased in the following conditions: i ) prolonged infection with immunological responses e.g. in syphilis, rheumatoid arthritis, tuberculosis; ii) hypersensitivity states; and iii) multiple myeloma.

81. Mononuclear-Phagocyte System ( Reticuloendothelial System) This cell system includes cells derived from 2 sources with common morphology, function and origin: Blood monocytes : These comprise 4-8% of circulating leucocytes. Tissue macrophages: These include the following cells in different tissues: i ) Macrophages in inflammation. ii) Histiocytes which are macrophages present in connective tissues. iii) Kupffer cells are macrophages of liver cells. iv) Alveolar macrophages (type II pneumocytes ) in lungs. v) Macrophages/ histiocytes of the bone marrow. vi) Osteoclasts in the bones. vii) Microglial cells of the brain. xiii) Langerhans ’ cells/ dendritic histiocytes of the skin. ix) Hoffbauer cells of the placenta. x) Mesangial cells of glomerulus .

82. Role of macrophages in inflammation: i ) Phagocytosis (cell eating) and pinocytosis (cell drinking). ii) Macrophages on activation by lymphokines released by T lymphocytes or by non-immunologic stimuli elaborate a variety of biologically active substances as under: a) Proteases like collagenase and elastase which degrade collagen and elastic tissue. b) Plasminogen activator which activates the fibrinolytic system. c) Products of complement. d) Some coagulation factors (factor V and thromboplastin ) which convert fibrinogen to fibrin. e) Chemotactic agents for other leucocytes. f) Metabolites of arachidonic acid. g) Growth promoting factors for fibroblasts, blood vessels and granulocytes. h) Cytokines like interleukin-1 and TNF-α. i ) Oxygen-derived free radicals.

83. General features of chronic inflammation Mononuclear cells infiltration- The macrophages comprise the most important cells in chronic inflammation Comprise blood monocytes and when it reach to extravascular space transform into tissue macrophages.

84. Tissue destruction or necrosis- It is central features of most forms of chronic inflammatory lesion. This is brought about by activated macrophages which release a variety of biologically active substance. Eg - protease, elastase , collagenase , lipase, reactive oxygen radicals, cytokines, nitric oxide etc.

85. Proliferative changes- As a result of necrosis, proliferation of small vessels and fibroblasts is stimulated resulting in formation of inflammatory granulation tissue. Healing by fibrosis and collagen laying takes place.

86. Systemic effects of chronic inflammation • Fever : infectious form of inflammation • Anaemia : accompanied by anaemia of varying degree • Leucocytosis : leucocytosis but generally there is relative lymphocytosis in these cases. • ESR : elevated • Amyloidosis : develop secondary systemic (AA) amyloidosis .

87. Types of chronic inflammation Non specific- when irritant substance produces a non- specific chronic inflammatory reaction with formation of granulation tissue and healing by fibrosis. Eg - chronic osteomylitis chronic ulcer Specific- when the injurious agent causes a characteristic histologic tissue response. Eg – tb syphilis leprosy

88. CONCLUSION The primary role of inflammation is protection of the host. The vascular and cellular events achieve the ideal outcome of inflammation, namely resolution, with return to pre-disease homeostasis. A clinician should have through knowledge of the basic concept of the disease inorder to achieve desired outcome and health of the patient.

89. REFERENCES • Robbinson's basic pathology 10 edition • Harsh Mohan - Textbook of Pathology 6th Edition Henry Trowbridge. Inflammation A review of the process; 4th ed. • Color atlas of pathology Marcelo O. Freire, Thomas E. Van Dyke :Natural resolution of inflammation; Periodontol 2000. 2013 Oct; 63(1): 149–164. Flannagan RS, Jaumouillé V, Grinstein S: The cell biology of phagocytosis , Ann Rev Pathol Mech Dis 7:61–98, 2012. Khanapure SP, Garvey DS, Janero DR, et al: Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers, Curr Top Med Chem 7:311, 2007. Roma Pahwa ;  Amandeep Goyal ;  Pankaj Bansal ;  Ishwarlal Jialal : Chronic Inflammation, Treasure Island (FL): StatPearls Publishing; 2020.