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  1. Chronic Inflammation PATHOLOGY

  2. Chronic Inflammation Chronic inflammation may occur: either as a sequel to acute inflammation (acute inflammationchronic inflammation), or as a primary immune response to a foreign antigen (usually viral).

  3. Inflammation A dynamic contunium of change Resolution (no scar) Organization (exudatescar *) Chronic Inflammation Chronic-active Inflammation Inciting Stimulus Acute Inflammation Resolutionwith scarring* Abscess *The longer the stimulus persists, the greater the scarring will be.

  4. Chronic inflammation is considered to be inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at healing are proceeding simultaneously. • It may follow acute inflammation, as described earlier, chronic inflammation frequently begins insidiously, as a low-grade, flaming, often asymptomatic response.

  5. Etiology of Chronic Inflammation • Persistent infections by certain microorganisms • Mycobacterium • Treponema pallidum • certain fungi. • Prolonged exposure to potentially toxic agents, either exogenous or endogenous (silicosis) • Autoimmune diseases

  6. Chronic inflammation is characterized by: • (1) infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells, a reflection of a persistent reaction to injury, • (2) tissue destruction, largely induced by the inflammatory cells, • (3) attempts at repair by connective tissue replacement, namely proliferation of fibroblasts, in particular, fibrosis.

  7. FIBROSIS There are four components to this process: • Formation of new blood vessels (angiogenesis) • Migration and proliferation of fibroblasts • Deposition of extracellular matrix • Maturation and organization of the fibrous tissue

  8. Fibrosis after chronic bronchitis.

  9. Scarring after chronic inflammation-Lung

  10. InflammationChronic Inflammation – Syphilis Lymphocytic chronic inflammatory infiltrate in the wall of the aorta in syphilitic aortitis.

  11. InflammationChronic Inflammation • Histologic features • Mononuclear cells – macrophages, lymphocytes, and plasma cells • Tissue destruction by ongoing inflammation, • thought to be due to cytokines produced locally by the mononuclear cells • Attempts at healing, including fibroblasts and fibrosis.

  12. InflammationChronic Inflammation • Monocyte/Macrophages • They are components of the mononuclear phagocyte system (MPS), previously known as the reticuloendothelial system (RES). • Key cell in chronic and granulomatous inflammation • Reproduce locally, at the site of injury • Produce numerous cytokines, which continue to recruit additional cells, including more macrophages • May present antigen to T-cells, producing specific hypersensitivity reactions

  13. The MPS consists of closely related cells of bone marrow origin, including blood monocytes, and tissue macrophages. • The latter are diffusely scattered in the connective tissue or clustered in organs such as the liver (Kupffer’s cells), spleen and lymph nodes (sinus histiocytes), and lungs (alveolar macrophages).

  14. Blood monocytes begin to emigrate early in acute inflammation, and within 48 hours predominant cell type. • Extravasation of monocytes is governed by the same factors involved in neutrophil emigration, namely adhesion molecules and chemical mediators with chemotactic and activating properties. • When the monocyte reaches the extravascular tissue it undergoes transformation into a larger phagocytic cell, the macrophage. • In addition to performing phagocytosis, macrophages have the potential of being “activated,” a process that results in an increase in cell size, increased levels of lysosomal enzymes, more active metabolism, and greater ability to phagocytose and kill ingested microbes.

  15. Activation signals include cytokines (e.g., IFN-g) secreted by sensitized T lymphocytes, bacterial endotoxins, other chemical mediators, and ECM proteins like fibronectin. • Following activation, the macrophages secrete a wide variety of biologically active products that are important mediators of the tissue destruction, vascular proliferation, and fibrosis characteristic of chronic inflammation

  16. In chronic inflammation macrophage accumulation persists, mediated by different mechanisms, each predominating in different types of reactions: 1. Continued recruitment of monocytes from the circulation, which results from the steady expression of adhesion molecules and chemotactic factors. (most important source for macrophages) Chemotactic stimuli for monocytes C5a; cytokines of the IL-8 family (chemokines) produced by activated macrophages and lymphocytes (MCP-1 for monocytes); certain growth factors (PDGF and TGF-b); fragments from the break-down of collagen, fibronectin and fibrinopeptides. 2. Local proliferation of macrophages after their emigration from the bloodstream. 3. Immobilization of macrophages within the site of inflammation. Indeed, certain cytokines (macrophage inhibitory factor) and oxidized lipids can cause such immobilization

  17. Lymphocytes:Lymphocytes are mobilized in both antibody- and cell-mediated immune reactions and also, for reasons unknown, in non-immune mediated inflammation. • Lymphocytes of different types (T, B) or states (naive, activated or memory T cell) use various adhesion molecules (VLA-4/VCAM-1 and ICAM-1/LFA-1 predominantly) and chemical mediators (largely cytokines) to migrate into inflammatory sites. • Lymphocytes can be activated by contact with antigen. Activated lymphocytes produce cytokines (formerly called as: “lymphokines”), and one of these, IFN-g is a major stimulator of monocytes and macrophages.

  18. Plasma cells: They produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components. • Eosinophils: They are characteristic of immune reactions mediated by IgE and of parasitic infections. • Like neutrophils, they use adhesion molecules and chemotactic agents (derived from mast cells, lymphocytes, or macrophages) to exit the blood. • Eosinophils are phagocytic and undergo activation. • Their granules contain major basic protein (MBP), a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells. They may thus be of benefit in parasitic infections but contribute to tissue damage in immune reactions.

  19. Plasma cells

  20. Types of Chronic Inflammation 1. Non-granulomatous Chronic Inflammation a) Chronic viral infections b) Chronic autoimmune diseases c) Chronic chemical intoxications d) Chronic nonviral infections e) Allergic inflammation and metazoal infections, 2. Granulomatous Chronic Inflammation

  21. Non-granulomatous Chronic Inflammation • Characterized by the accumulation of sensitized lymphocytes (specifically activated by antigen), plasma cells, and macrophages in the injured area. • These cells are scattered diffusely throughout the tissue, however, and do not form granulomas. • Scattered tissue necrosis and fibrosis are common.

  22. Classification of non-granulomatous chronic inflammation: a) Chronic viral infections b) Chronic autoimmune diseases c) Chronic chemical intoxications d) Chronic nonviral infections e) Allergic inflammation and metazoal infections

  23. a) Chronic viral infections: • Persistent infection of parenchymal cells by viruses • main components are a B cell response and a T cell cytotoxic response. • The affected tissue shows accumulation of lymphocytes and plasma cells that produce cytotoxic effects on the cell containing the viral antigen, causing cell necrosis. • This cytotoxic effect is mediated either by killer T lymphocytes or by cytotoxic antibody acting with complement. • Ongoing parenchymal cell necrosis is associated with repair characterized by fibroblast proliferation and deposition of collagen.

  24. b) Chronic autoimmune diseases: • immune response mediated by cytotoxic antibody and killer T cells occurs in several autoimmune diseases. • The antigen involved is a host cell molecule that is perceived as foreign by the immune system. • The pathologic result is similar to the non-granulomatous chronic inflammation seen in chronic viral infections, with cell necrosis, fibrosis, and lymphocytic and plasma cell infiltration of the tissue.

  25. c) Chronic chemical intoxications: • Persistent toxic substances such as alcohol produce chronic inflammation, notably in the pancreas and liver. • The toxic substance is not antigenic, but by causing cell necrosis it may result in alteration of host molecules so that they become antigenic and evoke an immune response. • The features of cell necrosis and repair by fibrosis in such cases dominate the features of the immune response. • In many cases of alcoholic chronic pancreatitis, the lymphocytic and plasma cell infiltration is slight.

  26. d) Chronic nonviral infections: • specific type of non-granulomatous chronic inflammation is seen with certain microorganisms; • (i) survive and multiply in the cytoplasm of macrophages after direct phagocytosis • (ii) evoke a very ineffective T cell response. • accumulation of large numbers of foamy macrophages in the tissue. The macrophages are present diffusely in the tissue without aggregating into granulomas. • The ability of the macrophage to kill the organism is limited because of the poor T cell response, permitting the organisms to multiply in the cell. • large numbers of organisms are present in the cytoplasm of the macrophages. The main defense appears to be direct phagocytosis by the macrophages. Variable numbers of plasma cells and lymphocytes may be present. • Accumulation of infected macrophages in the tissue causes nodular thickening of the affected tissue, a clinical feature that is typical of this type of chronic inflammation.

  27. e) Allergic inflammation and metazoal infections: • Eosinophils are present in acute hypersensitivity reactions and accumulate in large numbers in tissues subject to chronic or repeated allergic reactions. • Eosinophils may have evolved as a defense against infection with various metazoal parasites. • Eosinophils respond chemotactically to complement C5a and factors released by mast cells and in turn release a variety of enzymes and basic proteins. • Eosinophils bear high-affinity Fc receptors for IgA and low-affinity receptors for IgE. • Eosinophils are derived from a bone marrow precursor in common with mast cells and basophils, • play a role in modulating histamine release or histamine catabolism. • Mast cells and basophils have high-affinity Fc receptors for IgE.

  28. Chronic Granulomatous Inflammation • This is a distinctive pattern of chronic inflammatory reaction in which the predominant cell type is an activated macrophage with a modified epithelial-like appearance(epithelioid cells) .

  29. Granuloma:aggregation of macrophages that are transformed into epitheloid cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells . • The cells in a granuloma are: • macrophages and/or histiocytes (principal), • lymphocytes(principal), • fibroblasts, • giant cells.

  30. A cellular mechanism for dealing with indigestible substances The principal cells involved in granulomatous inflammation are macrophages and lymphocytes Epithelioid histiocytes are the hallmark of granulomatous inflammation

  31. A granuloma is an abnormal structure built from at least two activated macrophages adhering to one another. • Such macrophages are called epithelioid cells. • Epithelioid cells have • abundant pink cytoplasm, • indistinct borders, • elongated, euchromatin-rich, reticulated nuclei.

  32. There are two types of granulomas: • Foreign body granulomas incited by relatively inert foreign bodies. • Immune granulomas Two factors determine the formation of immune granulomas: • The presence of indigestible particles of organisms (e.g., the tubercle bacillus) • T cell-mediated immunity to the inciting agent.

  33. Granulomas with suppuration • With pus in their centers, • stellate microabscesses. • Bacterial diseases with a propensity to involve lymph nodes: • lymphogranuloma venereum, • cat scratch fever, • brucellosis, • plague, • tularemia, • glanders-melioidosis, • listeria, • camphylobacter, • yersinia infection.

  34. Granulomas with caseation necrosis • Typical of certain fungal and mycobacterial infections: • histoplasmosis, • blastomycosis, • coccidioidomycosis, • tuberculosis, • leprosy, • atypical mycobacteria.

  35. Granulomas can contain syncytial giant cells (polykaryons): • Langhans giant cells(in the necrotizinggranulomas:tuberculosis) • nuclei arranged in a horseshoe around the edge • Foreign body giant cells(in the non-necrotizinggranulomas:foreign body granuloma) • with nuclei dispersed more or less evenly • Asteroid bodies(in the non-necrotizinggranulomas:foreign body granuloma, sarcoidosis) • altered cytoskeletal components in the shapes of stars • Schaumann bodies(in the non-necrotizing granulomas:sarcoidosis) • laminated calcified nuggets; "conchoid bodies“.

  36. Granulomatous Inflammation Immunity may be judged by its effect on the invading organism, but an adverse effect on the host is generally termed hypersensitivity. Destruction of tissue is primarily via the action of killer T cells (CD8+), directed by macrophages. Products of activated T lymphocytesare important in transforming macrophages into epitheloid cells and multinucleated giant cells.

  37. Mycobacterial infections: tuberculosis leprosy Fungal diseases Sarcoidosis Lymphogranulomainguinale Foreign body granuloma Chronic granulomatous disease Crohn’s disease Leishmaniasis cutis Berylliosis Brucellosis Syphilis Granulomatous diseases***

  38. InflammationGranulomatous Inflammation Fibroblasts Lymphocytes Macrophages, Epithelioid Cells, and Giant Cells Caseous Necrosis CaseatingGranuloma Non-caseating Granuloma

  39. Langhans giant cells

  40. Asteroid bodies

  41. Schaumann bodies