INFLAMMATION healing and repair and questions.pptx

INFLAMMATION healing and repair and questions.pptx

1. INFLAMMATION R. ADAMS

2. Definition The reaction of living, vascularised tissue to injury Unique feature - is the reaction of blood vessels, resulting in the accumulation of fluid and leukocytes in tissues. Requirement for the process - the presence of a vascular system Involves vascular, humoral and cellular responses. Serves to: Destroy dilute, contain the injurious agent, and/or minimize the extent of injury, and prepare the grounds for healing

3. Usually described by the suffix "-itis" , preceded by the name of the organ or tissue involved. E.g. appendicitis, meningitis, colitis, myocarditis, osteomyelitis, tonsilitis Divided into acute and chronic patterns Causes of inflammation. Infective agents like bacteria, viruses and their toxins, fungi, parasites. Immunological agents like cell-mediated and antigen antibody reactions. Physical agents like heat, cold, radiation, mechanical trauma. Chemical agents like organic and inorganic poisons. Inert materials such as foreign bodies

4. ACUTE INFLAMMATION

5. The immediate and early defensive response of the tissue to an injury. Consists of a well-defined series of events Of relatively short duration Serves to deliver mediators of host defence to the site of the injury Main features: the exudation of a protein-rich fluid (exudate) emigration of predominantly neutrophils from intravascular compartment Similar whatever the causative agent Causes – same as for cellular injury

6. 4 cardinal signs ( Celsus ) rubor (redness); tumor (swelling); calor (heat); dolor (pain) 5 th sign function laesa (loss of function) - Virchow Cardinal Signs of Inflammation

7. Redness

8. Redness

9. Redness and Swelling

10. Redness and Swelling

11. MECHANISM Three main events involved: CHANGES IN VASCULAR CALIBER Sequential changes are as follow: An inconstant, immediate and transient vasoconstriction – lasts a few seconds. Believed to neural-mediated Vasodilatation first at the precapillary arteriolar level, then opening up of capillary beds in the area of injury. Induced by action of chemical mediators and leads to increased blood flow (hyperaemia, the cause of the redness and heat). ALTERATION IN VASCULAR PERMEABILITY Quickly follows on vasodilatation

12. VASCULAR CONGESTION

13. Structural changes occur in the microvasculature resulting in increased vascular permeability allowing protein-rich fluid (exudate) to escape from blood into the tissues, increasing the viscosity of the blood as concentration of red cells in the small vessels increases and causing slowing of blood flow Increased vascular permeability is a hallmark of acute inflammation . Loss of protein from bloodstream reduces intra-vascular oncotic pressure and increases tissue oncotic pressure. Together with the increased hydrostatic pressure from increased blood flow, cause marked outflow and net increase of fluid into interstitial tissue resulting in swelling (tumour).

14. 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 . Altered Vascular Permeability

15. MECHANISMS OF INCREASED VASCULAR PERMEABILITY

16. Increased permeability may be due to several mechanisms all of which may play a role in response to one stimulus: Formation of endothelial gaps: Two mechanisms Endothelial cell contraction with widening of intercellular junctions or gaps; by far the commonest mechanism. Caused by chemical mediators- histamine, bradykinin, leukotrienes, neuropeptide substance P, C5a and C3a. Occurs rapidly after exposure to mediator, usually reversible and short-lived. Involves venules 20 to 60 µm in diameter, without involvement of capillaries and arterioles. Binding of mediators to their receptors on endothelial cells activates intracellular signalling pathways causing phosphorylation of contractile and cytoskeletal proteins resulting in endothelial cell contraction, separation of intercellular junctions and gap formation

17. Endothelial retraction induced by cytokine mediators, such as IL-1, TNF and IFN-  (released by activated macrophages and lymphocytes). Occurs through structural reorganisation of the cytoskeleton causing endothelial cells to retract from each other. This response is delayed (onset 4 to 6 hours) and long-lived (lasts 24 hours or more). Involves venules and capillaries. Also occurs following mild to moderate thermal injury, x-radiation, ultraviolet radiation, and certain bacterial toxins. The mechanism in these situations is unclear

18. Direct endothelial injury: causing endothelial cell necrosis and detachment In most cases leakage of fluid starts immediately after injury and continues at a high level for several hours until the damage vessels are repaired. All levels of the microvasculature are affected. Leucocyte-mediated endothelial injury May occur as neutrophils adhering to the endothelium may become activated (and release lysosomal enzymes or cause free radical-mediated injury). Restricted to venules and pulmonary and glomerular capillaries where neutrophils adherence is prolonged. Increased transcytosis across endothelial cytoplasm: Occurs across channels consisting of clusters of interconnected, uncoated vesicles and vacuoles called vesiculovacuolar organelle

19. Has been suggested that histamine and other chemical mediators induces increased permeability by this mechanism also Leakage from regenerating capillaries occurs during repair when new blood vessels form, until endothelial cells differentiate and form intercellular junctions Three patterns of increased permeability depending on the severity of the injury occur: Immediate transient response : occurs in response to mild injury . Confined to venules and small veins Due to endothelial cell contraction Occurs rapidly and is short-lived

20. Delayed prolonged response : occurs in response to moderate injury Follows some hours after the immediate transient response; lasts for several hours or even days . May be due largely to direct injury to endothelial cells with delayed damage by the initial injury. Fluid leakage involves venules as well as capillaries Immediate sustained response : occurs in response to severe injury Due to direct damage to the endothelium resulting in endothelial cell death All levels of the microcirculation affected (venules, capillaries and arterioles) Starts immediately after injury and is sustained for several hours to days until the damaged vessels are thrombosed or repaired

21. CELLULAR EVENTS Involves two processes: Leucocyte emigration and Phagocytosis Central to inflammation – leucocytes must be delivered to the site of injury and activated so that they can perform their function of host defence. Sequence of events occurs in the following steps: Margination Due to slowing of blood flow (following exudation) the leucocytes assume a peripheral position along the endothelial surface - margination.

22. Congestion & Margination CONGESTION MARGINATION OEDEMA

23. Following margination, leucocytes tumble slowly along ( rolling ) adhering transiently and finally adhere firmly to the endothelium Pavementing Endothelium becomes lined with adherent leucocytes - an appearance called pavementing Emigration Process by which motile leucocytes escape from blood vessels into the perivascular tissues. Leucocytes insert pseudopods into junctions between endothelial cells, squeeze through them and lie between endothelium and basement membrane and eventually cross the membrane into the extravascula space. Occurs predominantly in the venules except in the lungs, where it also occurs in capillaries

24. Pavementing PAVEMENTING OEDEMA

25. Pavementing

26. Cellular Events

27. Leukocyte Emigration

28. The type of emigrating leucocyte varies according to the type of stimulus: In most forms of acute inflammation, neutrophils predominate early and are later replaced by monocytes. In acute viral infections, lymphocytes may be the first cells to emigrate. In type I hypersensitivity reactions, eosinophils may the main cell type present Leucocyte adhesion and transmigration across venules is determined by binding of complementary adhesion molecules on leucocyte and endothelial cell surfaces, induced or their avidity increased by chemical mediators.

29. Chemotaxis and Leucocyte Activation After escape from blood vessels, leucocytes migrate toward the site of injury by the process of chemotaxis, the unidirectional movement along a chemical gradient Neutrophils have surface receptors for various chemotactic agents including: Bacterial products Complement components, especially C5a Arachidonic acid metabolites, especially LTB4 Chemokines Many chemotactic factors also induce responses in leucocytes referred to as leucocyte activation.

30. Leucocyte activation involves: Synthesis of arachidonic acid metabolites Degranulation and secretion of lysosomal enzymes Activation of the oxidative burst (process that occurs during intracellular killing of microorganisms and cells after engulfment), Increased stickiness of neutrophils to endothelium (that is vessel surface) during pavementing Phagocytosis Involves three stages : Recognition and Attachment - Leucocytes may recognise and engulf foreign material but most microorganisms are not recognised until they are coated by opsonins , which bind to specific leucocyte receptors. The two major opsonins are IgG (antibody) and C3b and C3bi (complement fractions).

31. Engulfment - Binding of the opsonised particle to receptors is enough to trigger engulfment; occurs by pseudopodial extensions of cytoplasm, which completely surrounds the particle to form a phagosome. Fusion of the phagosome with lysosomes forms a phagolysosome into which lysosomal contents are discharged. Killing/Degradation - Killing is accomplished largely by oxygen-dependent mechanisms resulting in the generation of oxygen-derived free radicals; also occurs by substances in leucocyte granules, which include bactericidal permeability increasing protein, lysozyme, lactoferrin, defensins and major basic protein. Following killing, acid hydrolases from granules in the neutrophils contribute to degradation of bacteria and other particles

32. Adhesion Molecules Four groups of adhesion molecules: Selectins : E-selectin (CD62E) - present on cytokine-activated endothelial cells and recognizes complex sialylated carbohydrate groups (Lewis X and A) covalently bound to mucin -like glycoproteins on surfaces of neutrophils, monocytes, and activated and memory T cells. Endothelial cell expression of E-selectin is a hallmark of acute cytokine-mediated inflammation P-selectin (CD62P) – found in secretory granules of endothelial cells ( Weibel -Palade bodies) and in secretory granules of platelets. Activation of endothelial cells and platelets results in translocation of P-selectin to the cell surface where it mediates binding of neutrophils, T lymphocytes and monocytes; recognizes same ligand as E selectin

33. L-selectin (CD62L) - present on neutrophils, lymphocytes and monocytes Serves to bind lymphocytes to high endothelial venules in lymph nodes allowing homing of lymphocytes to nodes; also binds neutrophils to cytokine-activated endothelial cells Involved in low-affinity binding with fast on and fast off rates and so leucocytes attach to endothelium but are easily detached by the flowing blood resulting in rolling. Expression is induced by chemical mediators and cytokines Mucin-like glycoproteins : Act as ligands for selectins GlyCAM-1 (glycosylation-dependent cell adhesion molecule 1found HEVs), mucosal addressin cell adhesion molecule-1 ( MadCAM-1 , on endothelial cells in gut-associated lymphoid tissue) and CD34 (a proteoglycan on endothelial cells) bind to L-selectin

34. PSGL-1 (P-selectin glycoprotein ligand 1) binds to P-selectin ESL-1 (E-selectin ligand 1) binds to both E- and P-selectins Immunoglobulin family : Includes ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) Normally present at low levels on endothelium, avidity increased by cytokines Both interact with integrins on leucocytes to induce adhesion ICAM-1 additionally is involved in transmigration of all leucocytes. PECAM-1 (platelet endothelial cell adhesion molecule) is present on the intercellular junction of endothelium and on leucocytes and is homophilic i.e. binds to each other, and is concerned with transmigration

35. Integrins Composed of two non-covalently linked polypeptide chains,  and  . Defined on the basis of the  subunit used to form the heterodimer  1-containing integrins are also called VLA (Very Late Activation) integrins. VLA-4 (  4  1) is expressed only on leucocytes and is one of the principal surface proteins that mediate homing of lymphocytes to endothelium at sites of inflammation The  2 integrins are also called CD11a-cCD18 , the CD11a-c referring to different  chains and CD18 to the common  2. They are also called the leucocyte function-associated antigen-1 ( LFA-1 ) family

36. Leucocytes normally express integrins in a state of low affinity so that they do not bind to their complementary molecules. When leucocytes are activated by cytokines and chemokines (released by histiocytes, mast cells and endothelial cells in response to injurious agents) integrins are converted into high-affinity binding toward their complementary molecules. CD11aCD18 ( LFA-1 ) and CD11bCD18 ( MAC-1 or CR3 ) bind to ICAM-1  4  1 ( VLA-4 ) and  4  7 ( LPAM-1 ) bind to VCAM-1. Differential migration of leucocytes depends on which adhesion molecules are induced or activated

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38. Chemical Mediators of Inflammation

39. 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 Chemical Mediators of Inflammation

40. Chemical Mediators of Inflammation

41. Sequestered in intracellular granules 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 Vasoactive amines Arachidonic acid metabolites Lysosomal component Platelet activating factors (PAF) Cytokines Reactive Oxygen Species (ROS) and nitrogen oxide (NO) Neuropeptides Cell-derived mediators

42. 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 physical injury immune reactions involving binding of IgE 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 Vasoactive Amines

43. arteriolar dilation & increased vascular permeability : endothelial contraction and interendothelial gaps itching and pain inactivated by histaminase Serotonin 5-hydroxytryptamine preformed vasoactive mediator - effects similar to those of histamine but less potent Released from platelet dense body granules during platelet aggregation Vasoactive Amines

44. Also known as eicosanoids . Variety of biologic processes, including inflammation and hemostasis - virtually every step of inflammation. short-range hormones that act locally at the site of generation and then decay spontaneously or are enzymatically destroyed Derived from : Leukocytes, mast cells, endothelial cells, and platelets Dietary linoleic acid Arachidonic Acid (AA) Metabolites

45. Component of cell membrane phospholipids. 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 Arachidonic Acid (AA) Metabolites

46. 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 Cyclooxygenase Pathway

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48. Lipo-oxygenase - predominant enzyme in neutrophils . Acts on activated AA to form hydroperoxy eicosatetraenoic acid (5-HPETE). Further peroxidation forms following metabolites 5-HETE ( hydroxy compound) - intermediate Leukotrienes (LT) Lipoxins (LX) Lipoxygenase Pathway

49. Lipoxygenase Pathway

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51. 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 Lysosomal Components

52. Phospholipid (membrane) -derived mediator with a broad spectrum of inflammatory effects. Membrane of neutrophils , monocytes , basophils , endothelial cells, and platelets (and other cells) by the action of phospholipase A 2. Functions of PAF Stimulating platelets, vasoconstriction and bronchoconstriction inducing vasodilation and increased vascular permeability – low conc. 100-1000 times potent than HISTAMINE enhanced leukocyte adhesion , chemotaxis , leukocyte degranulation , and the oxidative burst stimulates the synthesis of other mediators , particularly eicosanoids Platelet Activating Factor (PAF)

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

54. 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 - increased leukocyte binding and recruitment, enhance the production of additional cytokines (notably chemokines ) and eicosanoids Tumor Necrosis Factor and Interleukin-1

55. TNF – increases thrombogenicity of endothelium and causes aggregation and activation of neutrophils. IL-1 - fibroblasts, resulting in increased proliferation and production of extracellular matrix 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). Tumor Necrosis Factor and Interleukin-1

56. Act primarily as chemoattractants for different subsets of leukocytes Also activate leukocytes Chemokines are classified into four groups out of which 2 are the major group CXC chemokines : IL-8 CC chemokines : MCP-1 Chemokines

57. Synthesized via the NADPH oxidase – from neutrophils and macrophages by microbes, immune complexes, cytokines, and a variety of other inflammatory stimuli Within lysosomes - destroy phagocytosed microbes and necrotic cells low levels increase chemokine, cytokine, and adhesion molecule expression amplifying the cascade of inflammatory mediators Reactive Oxygen Species

58. High levels - tissue injury by several mechanisms endothelial damage, with thrombosis and increased permeability; protease activation and antiprotease inactivation, with a net increase in breakdown of the ECM; direct injury to other cell types Various antioxidant - protective mechanisms against this ROS catalase , superoxide dismutase, and glutathione Reactive Oxygen Species

59. 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 i /m Type II ( iNOS ) – induced by chemical mediators, macrophages and endothelial cells Type III ( eNOS ) - primarily (but not exclusively) within endothelium Nitric Oxide

60. 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. Nitric Oxide

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

62. Circulating proteins of three 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. Plasma-protein-derived mediators

63. 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. Hageman factor (factor XII)

64. 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 inflammation, Binding of thrombin to the receptors on endothelial cells - activation and enhanced leukocyte adhesion Clotting system

65. 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 Fibrinolytic System

66. Multifunctional protease that cleaves fibrin. Cleaves the C3 complement protein - production of C3a Activate Hageman factor - amplify the entire set of responses For more : Visit www.dentaltutor.in Fibrinolytic System : Plasmin

67. 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 For more : Visit www.dentaltutor.in Kinin System

68. Slow contraction of smooth muscle Bradykinin acts in the early stage of inflammation : vasodilatation; increased vascular permeability pain Kinin System : Bradykinin

69. Important role in host defense (immunity) and inflammation Consists of plasma proteins (C1 – C9) – activated at the sites of i /m Contribute to the inflammatory response by increasing vascular permeability and leukocyte chemotaxis. The activation of complement - tightly controlled by cell-associated and circulating regulatory proteins Inappropriate or excessive complement activation (e.g., in antibody-mediated diseases) - serious tissue injury in a variety of immunologic disorders Complement System

70. The critical step in the activation of biologically active complement products is the activation of the third component, C3 – C3a. This occurs in 3 steps : Classical Pathway : antigen-antibody complexes Alternative pathway : triggered by bacterial polysaccharides - microbial cell-wall components Lectin pathway : plasma lectin binds to mannose residues on microbes – activates early component of the classical pathway As C3 activated – further activation of other complement proteins takes place i.e. C1 – C9 Complement System

71. The actions of activated complement system in inflammation are as under: C3a, C5a, C4a ( anaphylatoxins ) - activate mast cells and basophils to release of histamine C3b - an opsonin . C5a - chemotactic for leucocytes. Membrane attack complex (MAC) (C5b-C9) - a lipid dissolving agent and causes holes in the phospholipid membrane of the cell Complement System

72. Complement System

73. Beneficial Effects Both fluid and cellular exudates may have useful effects. Fluid Exudate Dilution of Toxins - such as those produced by bacteria, and allows them to be carried away by lymphatics. Entry of Antibodies - increased vascular permeability allows antibodies to enter extra-vascular space where they enhance phagocytosis by acting as opsonins and participate in complement-mediated lysis of microorganisms or in toxin neutralisation

74. Fibrin formation activation of coagulation leads to fibrin formation. May serve to wall off microorganisms, limit their spread and facilitate phagocytosis Drug Transport fluid exudation carries with it therapeutic drugs to the site of inflammation Delivery of nutrients and oxygen essential for cell metabolism is aided by increased fluid flow through the area

75. Stimulation of Specific Immune Response drainage of fluid exudate into lymphatics allows particulate and soluble antigens to reach the local lymph nodes and stimulate the immune response Cellular Exudate Phagocytosis and intracellular killing of microorganisms is undertaken by neutrophils. Monocytes arrive late at the site and transform into macrophages and usually responsible for clearing away tissue debris (including dead and dying neutrophils) and damaged cells paving the way for healing and repair

76. Digestion of inflammatory exudate Both neutrophils and macrophages may discharge their lysosomal enzymes into the extracellular fluid and assist in digestion of inflammatory exudate

77. Harmful Effects Sometimes acute inflammation appears to serve no obvious purpose and may even be positively harmful The swelling that accompanies the process may be harmful causing mechanical effects or extensive cellular destruction to impair function Release of lysosomal enzymes by inflammatory cells may have harmful effects Neutrophils and monocytes contain lysosomal granules, which, when released may cause tissue destruction and contribute to the inflammatory response

78. Neutrophils contain 2 main types of granules: smaller specific or secondary granules and the large azurophil or primary granules Both can empty into phagosomes or into extracellular space(ECS) Azurophil granules, more destructive when released into ECS, release contents primarily within phagosomes; require high levels of agonists to be released into extracellular space Specific granules require low concentrations of agonists and are more readily secreted into extracellular space Enzymes such as collagenase and proteases may digest normal tissue, resulting in their destruction

79. Injury may also result from release of oxygen radicals (innocent bystander injury or damage) Injury to endothelial cells increase vascular permeability, fluid exudation and swelling ROI also inactivate antiproteases resulting in unopposed protease activity, with increased tissue destruction Thus, if the initial leucocyte infiltration is not checked, potentiation of increases in vascular permeability and tissue damage occur due to the destructive effects of leucocyte-derived factors Swelling - of acutely inflamed tissues may be harmful

80. eg. swelling of epiglottis in acute epiglottitis, raised intracranial pressure in cerebral abscess and meningitis, gastrointestinal obstruction Inappropriate inflammatory response - in hypersensitivity reactions may be life threatening

81. Outcomes of Acute Inflammation Depend on: the type and site of tissue affected the amount of tissue destruction the nature and intensity of the injurious agent and the responsiveness of the host Possible outcomes are: Resolution: complete restoration of affected tissues to normal after an episode of acute inflammation. Conditions favouring resolution include: minimal cell death and tissue destruction (limited injury)

82. short-lived injury of lower intensity occurence in an organ or tissue with regenerative capacity rapid destruction of injurious agent rapid neutralization of chemical mediators, return of normal vascular permeability, cessation of leucocytic infiltration and removal of oedema fluid and debris by lymphatics and good vascular drainage Suppuration: the formation of pus - a mixture of dead and dying neutrophils and bacteria, necrotic tissue debris and lipid

83. Causative stimulus, almost always an infective agent (usually pyogenic bacteria) is persistent, resisting complete removal and favouring continuing polymorph emigration The collection of pus is called an abscess Bacteria within an abscess are relatively inaccessible to antibodies and antibiotics An abscess usually 'points' onto a surface and ruptures followed by collapse of the cavity, which is obliterated by organisation (formation of granulation tissue) and healing by fibrosis leaving a small scar Surgical incision and drainage may be necessary to remove an abscess

84. Empyema : Used If an abscess forms within a hollow viscus or body cavity Healing by Organization (Repair): occurs under the following circumstances: after substantial tissue necrosis when dead tissue cannot be easily removed when injury occurs in tissues that do not have regenerative capacity

85. when there is abundant fibrin exudation which cannot be removed completely by fibrinolytic enzymes from plasma and neutrophils Granulation tissue grows and macrophages migrate into the area of injury, which is finally converted into fibrous tissue Progression to Chronic Inflammation: this transition occurs when the acute inflammation cannot be resolved, either because of persistence of the injurious agent or some interference with the normal process of healing (the presence of a foreign body such as indigestible suture, wood, metal etc.)

86. CHRONIC INFLAMMATION

87. Objectives At the end of the lecture, each student should be able to: Define and explain chronic inflammation List the cells involved in acute inflammation and describe how they function as chronic inflammatory cells State the factors that predispose to chronic inflammation and explain how they result in the development of chronic inflammation Describe the types of chronic inflammation and how they develop State the causes of primary chronic inflammation Describe chronic granulomatous inflammation and its pathognomonic lesion, the granuloma

88. Definition Inflammatory process in which macrophages, lymphocytes, and plasma cells predominate and tissue destruction and active inflammation are proceeding at the same time as attempts at healing (events which should occur sequentially) and which is usually accompanied by healing by repair It involves mainly following events Angiogenesis Mononuclear cell infiltrate - macrophages, lymphocytes, and plasma cells Fibrosis - Scar

89. Chronic Inflammatory cells Most important cell in chronic inflammation is the macrophage (histiocyte) is; it and forms part of the mononuclear phagocytic system Are derived from blood monocytes, which are attracted to sites of tissue damage by chemokines and other chemical mediators where they transform into larger phagocytic cells, macrophages Activated by cytokines, chemokines, other chemical mediators and extracellular matrix proteins

90. Activated macrophages secrete many products, several of which are injurious to cells and extracellular matrix (and cause tissue destruction), others attract other cell types while still others stimulate fibrosis and angiogenesis Other cells such as lymphocytes, plasma cells and eosinophils are important in chronic inflammation. Indeed, some chronic inflammatory lesions lymphocytes predominate, while in others such as chronic endometritis plasma cells are the diagnostic cells

91. Inflammation of prolonged duration (weeks to months to years) in which active inflammation, tissue injury, and healing proceed simultaneously. It involves mainly following events Angiogenesis Mononuclear cell infilterate - macrophages, lymphocytes, and plasma cells Fibrosis - Scar Chronic Inflammation

92. 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 Causes of Chronic Inflammation

93. Macrophages Lymphocytes, Plasma Cells, Eosinophils , Mast Cells Chronic Inflammatory Cells and Mediators

94. Dominant cells of chronic inflammation Derived from circulating blood monocytes Reticulo -endothelial system Also known as Mononuclear-phagocyte system. Macrophage present in liver - Kupffer cells spleen lymph nodes - sinus histiocytes central nervous system - microglial cells lungs - alveolar macrophages Macrophages

95. Inflammatory sites around parasitic infections or as part of immune reactions mediated by IgE Associated with allergies Induced by specific chemokines – eotaxin Granules contain major basic protein - highly charged cationic protein toxic to parasites also causes epithelial cell necrosis Eosinophils

96. Sentinel (watch) cells widely distributed in connective tissues throughout the body Play a role in both acute and chronic inflammatory responses. Elaborate cytokines such as TNF and chemokines atopic individuals - individuals prone to allergic reactions Mast cells Armed with IgE antibody As the environmental antigens enters It releases histamines and AA metabolites anaphylactic shock Mast cells

97. T and B lymphocytes migrate - inflammatory sites – chemokines. Lymphocytes and macrophages interact in a bidirectional way Important role in chronic inflammation Lymphocytes

98. Predisposing Factors Chronic inflammation may follow on acute inflammation but is usually primary, that is the response has all the features of chronic inflammation from the onset

99. PERSISTENCE OF ACUTE INFLAMMATION Common to all chronic inflammation caused by persistence of an injurious agent: Exudative inflammation, with polymorphs and fluid exudate, macrophages Organization as evidenced by new blood vessel formation, fibroblasts and collagen deposition (granulation tissue), and Regeneration in competent tissues Other cell types, such as lymphocytes, plasma cells, and eosinophils, are also present, depending on the particular immunological properties of the inciting agent

100. CHRONIC SUPPURATIVE INFLAMMATION Acute suppurative inflammation is characterised by the formation of pus and an abscess cavity This may become chronic with attempts at organization in the wall of the abscess cavity and formation of granulation tissue while suppurative exudation is still occurring This leads to the formation of a pyogenic membrane, which walls off the abscess from adjacent viable tissue, thus localizing the infection, but also has the disadvantage of making the abscess wall rigid

101. Thus if the pus eventually escapes to an external surface, either naturally or through surgical intervention (incision and drainage), the abscess will no longer collapse when tissue tension falls, and the inciting agent cannot be completely evacuated In addition, healing must then occur by second intention, a prolonged process that will produce much scarring

102. Factors predisposing to development of chronic from acute inflammation include: persistence of the injurious agent some interference with the normal process of healing (the presence of a foreign body such as indigestible suture, wood, metal etc.) Presence of necrotic or exogenous materials Tissue or exogenous material that resists liquefaction during suppuration acts as a refuge within which organisms survive and proliferate relatively protected from host defences

103. Organisms may persist in crevices too small for access by polymorphs, or deep within necrotic tissue or material through which polymorph migration is difficult and prolonged Endogenous material such as necrotic bone (in chronic osteomyelitis), and exogenous material, such as dirt, wood, cloth, glass, etc., in a wound, or surgical materials erroneously left behind after surgical procedures are examples Defective leucocyte function The accumulation of polymorph at site of tissue injury is dependent on number of circulating neutrophils, normal chemotaxis and adhesion

104. Removal of exogenous material depends on phagocytosis and killing and/or degradation of ingested material Impairment of any of these functions results in: prolonged injury of tissue by persistence of the inciting agent, tissue loss, and the accumulation of large numbers of functionally incompetent neutrophils occur Congenital deficiency of neutrophil specific granules . The granules are morphologically abnormal and

105. the cells are deficient in all the constituents of the specific granules. The neutrophils show reduced chemotaxis Disorders of neutrophil adherence . E.g. leucocyte adhesion molecule deficiency involving the CR3 receptor Lazy leucocyte syndrome . Reduced leucocyte mobility without any characteristic diagnostic feature. The molecular nature of the functional defects is unknown Defects in phagocytosis by neutrophils polymorphs . C3 deficiency

106. X-linked Bruton's agammaglobulinaemia in which there is deficiency of immunoglobulin. Absence of these opsonins results in inefficient ingestion of material in the presence of large numbers of polymorphs leading to chronic suppurative inflammation Abnormalities of killing and enzymatic degradation Defects in phagolysosome function Ch édiak -Higashi syndrome: an autosomal recessive disease with neutropaenia (low neutrophil count), defective degranulation, and delayed microbial killing. There is reduced transfer of lysosomal enzymes to phagocytic vacuoles.

107. Non-specific Chronic Inflammation Most examples of chronic inflammation are not associated with the formation of pus seen in chronic suppurative inflammation. Some injuries do not induce exuberant polymorph exudation but go on to chronicity due to persistence of injury. The histological pattern is typical There is fibrin exudate and polymorph accumulation without liquefaction in response to the injury Superimposed on these are the responses due to attempts at healing: chronic inflammatory cells including cells of demolition (macrophages), lymphocytes, plasma cells, granulation tissue and fibrosis

108. Seen as a response to chronic injury in a wide variety of setting and agents, and is frequently referred to as 'non-specific chronic inflammation' The injurious agent is usually of a low-grade nature and the severity of the tissue damage is largely dependent on the persistence of the injury accompanied by continuing inflammation and fibrosis Particular site involved is also of major importance in determining the consequences of the chronic inflammation e.g. basal meningitis and Chron’s disease

109. Primary Chronic Inflammation Chronic inflammation does not always follow persistence of agents that cause acute inflammation, but can also arise de novo An absence or only an insignificant phase of acute inflammation From the outset the cellular infiltrate is predominantly of chronic inflammatory cells, with few or no polymorphs Two main types: those conditions in which the immune system itself is responsible for most of the injury those in which mononuclear phagocytes dominate the histological picture

110. Causes of primary chronic inflammation Agents able to resist phagocytosis or intracellular killing (Persistent infections) Tuberculosis, leprosy, viral infections, Syphilis Agents able to resist digestion Endogenous material (Foreign body reactions) necrotic adipose tissue, bone, uric acid crystals (in gout), keratin, cholesterol crystals Exogenous materials e.g. talc, suture Allergens Contact dermatitis (e.g. hypersensitivity to certain metals) Some autoimmune diseases Rheumatoid arthritis

111. Primary granulomatous disease Sarcoidosis, Crohn's disease Specific disease of unknown cause eg. Ulcerative colitis

112. Special Forms of Chronic Inflammation Chronic granulomatous inflammation This is a specific type of chronic inflammation, which may occur in response to a variety of agents of relatively inert or low antigenicity The hallmark of chronic granulomatous inflammation is the epithelioid macrophage (a type of activated macrophage). Epithelioid macrophages may fuse to form multinucleate giant histiocytes (or giant cells) Types of giant cells: Foreign body, Langhans and Touton giant cells A granuloma is a focal area of granulomatous inflammation consisting of a collection of epithelioid macrophages (which may be surrounded by lymphocytes and plasma cells)

113. Granuloma

114. Granuloma

115. Granuloma

116. There are two types of granulomas: Foreign body granulomas - incited by relatively inert foreign bodies eg. talc, suture, inorganic dusts and metals. Foreign body giant cells are present Immune granulomas - due to presence of indigestible fragments organisms and T cell-mediated immunity to the inciting agent (delayed hypersensitivity reaction). Langhans giant cells may be present

117. SUMMARY In chronic inflammation, t issue destruction largely induced by the inflammatory cells and active inflammation occur at the same time as attempts at healing usually ends in healing by repair with relatively large amounts of scarring The predominant cell type is the macrophage, which may be accompanied by lymphocytes, plasma cells and/or eosinophils May follow on acute inflammation but is usually primary from the outset.

118. When it follows on acute inflammation, due to either persistence of the injurious agent or leucocyte dysfunction and presents as chronic suppurative or chronic non-specific inflammation Primary chronic inflammation arises when there is persistent infection by organisms of low toxicity, which evoke delayed hypersensitivity reaction, or the presence of agents able to resist digestion It also arises in the setting of autoimmune diseases in which autoantibodies induce a self-perpetuating immune reaction

119. Chronic granulomatous inflammation is a special type of chronic inflammatory response to a variety of agents of relatively inert or low antigenicity The predominant cell type in this reaction is a modified macrophage, the epithelioid cell

120. Robins basic pathology 8 ed Harsh Mohan - Textbook of Pathology 6th Ed. Color atlas of pathology References