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Chronic inflammation By Dr. S Homathy Slide 2 Chronic inflammation Inflammation of prolonged duration(weeks to months to year) In which acute inflammation, tissue injury and healing proceed simultaneously Slide 3 Components of chronic inflammation 1.Acute inflammation 2.Demolition 3.Healing repair and regeneration 4.Immune response Slide 4 It is characterized by Infiltration with mononuclear (chronic inflammatory) cells, including Macrophage Lymphocytes Plasma cells Tissue destruction Largely directed by inflammatory cells Repair Involving new vessel proliferation( angiogenesis and fibrosis) Slide 5 1.Acute inflammation Evidence of acute inflammation is frequently seen in chronic inflammation Eg: pus rich in neutrophils in osteomyelitis, pyonephrosis, chronic brain abscess : exudates rich in Eosinophils in hypersensitivity reaction 2.Demolition Accomplished by macrophages derived from emigrating monocytes of bone marrow origin Slide 6 3.Healing Repair New vessel formation (angiogenesis) Fibrosis (dense fibrosis and loss of function) Regeneration Clearance of injurious stimuli Clearance of mediators and chronic inflammatory cells Regeneration and remodeling of damaged tissue Normal function Eg : surface epithelia Slide 7 4.Immune response Very common feature is the accumulation of lymphocytes of various types, plasma cells, and MP. Plasma immunoglobins levels may be elevated. Slide 8 Chronic inflammation can occur Following acute inflamation or Starting de novo Slide 9 Differ from AI Absence of cardinal signs New vessel formation No fluid exudation or oedema Time is prolonged Immune response Injurious agents most often cause insidious, progressive and often extensive tissue necrosis Accompanied by ongoing repair by fibrosis Specific ( immune response is activated) Systemic response low grade fever, weight loss, anaemia Slide 10 Causes of chronic inflammation Viral infections Intracellular infection of any kind require lymphocytes and macrophages To identify and eradicate infected cells. Persistent microbial infections By some specific organisms Eg: Mycobacteria, Treponema pallidum, certain fungi Organisms are low direct pathogenicity Typically evoke an immune response- delayed hypersensitivity Slide 11 Persistent injury Prolonged exposure to potentially toxic agents Eg : silica produce -silicosis of lung : chronically elevated plasma lipids- produce Atherosclerosis Autoimmune diseases Immune response to self- antigen and tissues Eg: Rheumatoid arthritis / multiple sclerosis. Slide 12 The Players (mononuclear phagocyte system ) Macrophages Scattered all over Microglia - CNS Kupffer cells - liver sinus histiocytes spleen, lymphnode alveolar macrophages - lungs. Circulate as monocytes reach site of injury within 24 48 hrs and transform into large macrophages Large MP now capable of phagocytosis Slide 13 Become activated by T cell-derived cytokines, endotoxins, and other products of inflammation Greater ability to kill ingested organisms LM appearance with H&E stain Large Flat Pink Similar to squamous cell ( called epithelioid macrophages) Slide 14 After activation, MP secretes a wide variety of biologically active products If unchecked leads to tissue injury and fibrosis Mediaters from MP Acid and neutral proteases Complement and coagulation factors C1 to c5 Propedin Coaguulation factor V and VIII Reactive oxygen speces and NO AA metabolites CK Slide 15 In CI MP accumulation persist and MP can proliferate lymphocytes derived factors recruit or immobilize the MP to the site of injury IL-4 or INF- Causes MP to fuse into large, multinucleated cells Called giant cells Slide 16 T and B lymphocytes Antigen-activated (via macrophages and dendritic cells) Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed) Plasma cells Terminally differentiated B cells Produce antibodies Slide 17 Eosinophils Found especially at sites of parasitic infection, or at allergic (IgE-mediated) sites Mast cells Participate in both acute and chronic inflammatory responses Armed with IgE to certain antigens Slide 18 Chronic endometritis withlymphocytes as well as plasma cells in the endometrial stroma. In general, the inflammatory infiltrate of chronic inflammation consists mainly of mononuclear cells ("round cells"): lymphocytes, plasma cells, and macrophages. Slide 19 Chronic cervicitis. Prolonged acute inflammation or repeated bouts of acute inflammation may lead to the appearance of more mononuclear cells, and chronic inflammation. In this case the inflammation is severe enough to produce mucosal damage with hemorrhage. Slide 20 Chronic inflammation can go on for a long time: weeks to months to years. Seen here in the synovium from the joint of a patient with rheumatoid arthritis are collections of dark blue lymphocytes. Slide 21 Types of chronic inflammation Granulomatous chronic inflmmation Non- granulomatous chronic inflammation Slide 22 Granulomatous inflammation Definition: Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction. It is a protective response to chronic infection or foreign material, preventing dissemination and restricting inflammation. Some autoimmune diseases such as Crohns disease is also associated with granulomas. Slide 23 Cellular constituents of Granulomas the predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance Lymphocytes. Occasional plasma cells Slide 24 What Is A Granuloma? A granuloma is a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. Older granulomas also develop a surrounding rim of fibroblast and connective tissue Due to CK elaborated by the activated MP Frequently, but not invariably multinucleated giant cells are also found Derived from fusion of 20 or more MP Slide 25 These are epithelioid cells around the center of a granuloma. They get their name from the fact that they have lots of pink cytoplasm similar to squamous epithelial cells. Their nuclei tend to be long and stringy Slide 26 Epithelioid cells fuse to form giant cells containing 20 or more nuclei. These giant cells can be found either at the periphery or the center of the granuloma Slide 27 Types of giant cells The nuclei arranged either Peripherally Langhans-type giant cell (Reaction to certain organism) haphazardly foreign body-type giant cell (reaction to insoluble materials) Slide 28 Nuclei enclose the central part of the homogeneous eosinophilic cytoplasm and the peripheral part of the cytoplasm is vacuolated due to its lipid content Touton giant cell (found in xanthomas) Slide 29 MP found in Rheumatic heart disease also called caterpillar cells, as they have a large amount of clear cytoplasm surrounding a rod- shaped nucleus that to some resembles a caterpillar. Larger Anitschkow cells may coalesce to form multinucleated Aschoff giant cells Slide 30 Slide 31 Nuclears appears as amirror image of one another Reed-sternberg giant cell found in Hodgkins lymphoma Slide 32 Fibrous connective tissue often surrounds granulomas (remodeling of tissue) Areas within the granuloma can undergo necrosis prototype: caseous necrosis in tuberculosis. Granular, cheesy Necrosis can lead to calcification or liquefaction and formation of a cavern if drained. Slide 33 Slide 34 Slide 35 CAUSES OF GRANULOMATOUS DISEASES Infectious causes: Bacteria Tuberculosis Leprosy(tuberculod type) Trepanema pallidum Brucella species Rickttsial organism Coxiella burnetii Parasites Schistosomiasis Slide 36 Fungi Histoplasmosis Blastomycosis coccidioidomycosis Metal/Dust Berylliosis Silicosis Slide 37 Foreign body Granulomas: endogenous ( keratin, necrotic bone or adipose tissue uric acid crystals) Exogenous (wood, silica, asbestos, silicone,suture) Specific chemicals: Beryllium unknown cause Sarcoidosis Crohns disease Slide 38 Type of granulomas 1.Foreign body granulomas form when material such as talc, sutures, or other fibers are large enough to preclude phagocytosis by a single macrophage. Slide 39 2. Epithelioid granuloma (Immune granulomas ) caused by insoluble particles that are capable of inducing a cell-mediated response. This type of immune response produces granulomas when the inciting agent is poorly soluble or particulate. Slide 40 Macrophages engulf the foreign material and process and present some of it to appropriate T lymphocytes, causing them to become activated, responding T cells produce cytokines, such as IL-2 which activates other T cells and IFN- which is important in transforming macrophages into epithelioid cells and multinucleate giant cells. Slide 41 Here is a foreign body type giant cell at the upper left of center adjacent to a segment of vegetable material aspirated into the lung. Such foreign body giant cells have nuclei scattered haphazardly about the cell Slide 42 Two foreign body giant cells are seen just to the right of center where there is a bluish strand of suture material from a previous operation Slide 43 Granulomatous disease can become quite extensive. Here are numerous confluent granulomas in upper lung fields in a case of active pulmonary tuberculosis. Slide 44 Grossly, a granuloma tends to be a focal lesion. Seen here in a hilar lymph node is a granuloma. Granulomas due to infectious agents such as mycobacteria are often described as "caseating" when they have prominent caseous necrosis. Slide 45 The focal nature of granulomatous inflammation of lung in which there are scattered granulomas in the parenchyma. This is why the chest radiograph with tuberculosis or other granulomatous diseases is often described as "reticulonodular". A biopsy could miss such lesions from sampling error, too. Slide 46 Slide 47 Slide 48 Giant cells are a "committee" of epithelioid macrophages. Seen here are two Langhans type giant cells in which the nuclei are lined up around the periphery of the cell. Additional pink epithelioid macrophages compose most of the rest of the granuloma Slide 49 This is a caseating granuloma. Epithelioid cells surround a central area of necrosis that appears irregular, amorphous, and pink. Grossly, areas of caseation appear cheese-like Slide 50 Granulomas caused by tuberculosis and pathogenic fungi such as Histoplasma capsulatum or Cryptococcus neoformans are often caseating. Here, the area of caseation is seen at the upper right. Slide 51 With a poor immune response to the agents producing granulomatous inflammation, there can be extensive spread of infection with the production of a "miliary" pattern of granulomas, as seen here in the lung of a patient with miliary tuberculosis. The 1 to 2 mm granulomas are scattered around like millet seeds (millet is a type of cereal grain). Slide 52 Types of chronic inflammation Granulomatous chronic inflmmation Non- granulomatous chronic inflammation Slide 53 Characterized by the accumulation of sensitized lymphocytes (activated by antigen) Plasma cells MP In the injured area These cells are scattered diffusely throughout the tissue. Do not form granuloma. Scattered tissue necrosis and fibrosis are common. Slide 54 Causes of non- granulomatous chronic inflammation 1.Characterized by lymphocytes and plasma cell infiltration of tissues with cell necrosis and fibrosis Chronic viral infection Chronic viral hepatitis Chronic viral infection of CNS Autoimmune diseases Chronic ulcerative colitis Hashimotos thyroiditis Chronic alcoholic liver disease and pancretitis Slide 55 2. Characterized by diffuse accumulation of MP with intracytoplasmic microorganisms, deficient T cell response Lepromatous leprosy Leishmaniasis 3.Characterized by presence of numerous eosinophils in conjuction with other inflammatory cells Type I hypersensitivity reactions BA Atopic dermatitis Slide 56 Certain etiologic agents such as viruses are more likely to lead to chronic inflammation, as seen here in the lung of a patient with influenza A. the inflammatory infiltrates of chronic inflammation are more likely to be interstitial (within tissues) rather than exudative (above surfaces or in spaces) like acute inflammation. Slide 57 Slide 58 You can find both acute and chronic inflammation here. This type of mixed inflammation is typical of repeated or recurrent inflammation. Examples "acute and chronic cholecystitis" or "acute and chronic cervicitis". Slide 59 The best possible outcome following an inflammatory process is complete resolution, leaving the tissues intact and undamaged. However, chronic inflammation may occur in conjunction with some degree of scarring. Here, chronic inflammation of the bronchi has led to dilation and scarringwith increased tan to white collagenous tissue. Slide 60 Chronic inflammation with destruction of the bronchial wall is seen here. An inflammatory infiltrate extends from the lumen to the left. Slide 61 An abscess may have elements of chronic inflammation if it persists for some time. Thus, it is possible to have a "chronic abscess" with elements of both acute and chronic inflammation. Seen here in the right middle lung lobe is just such a chronic abscess. Slide 62 Healing Repair By formation of granulation tissue Contain variety of cells Endothelial cells forming blood and lymphatic vessels Myofibroblast (fibroblast )forming collagen Astrocytes forming a glial scar in the CNS Small round cells- lymphocytes and plasma cells Slide 63 Healing of inflammation often involves in growth of capillaries and fibroblasts. This forms granulation tissue. Here, an acute myocardial infarction is seen healing. There are numerous capillaries, and collagen is being laid down to form a scar. Non-infarcted myocardium is present at the far left. Slide 64 These features are all seen in chronic inflammation In chronic suppuration the puss-filled cavity is lined by acutely inflamed granulation tissue. This is the pyogenic membrane Vascularity of the granulations predisposes to haemorrhage Eg: repeated haemorrhage is frequent in chronic peptic ulcer Slide 65 Microscopically, this abscess has a mixture of inflammatory cells, but the wall of the abscess is "organizing" with ingrowth of capillaries (filled with red blood cells) and fibroblasts. As organization continues there is resolution with decreasing size of the abscess, until only a scar remains. If the body's defensive systems cannot contain the agent causing the abscess, then the process may continue and even spread Slide 66 The wall of an abscess that is organizing has granulation tissue, at the left. The purulent exudate with some hemorrhage is seen at the right in the abscess center. Slide 67 At high magnification, granulation tissue has capillaries,fibroblasts, and a variable amount of inflammatory cells (mostly mononuclear, but with the possibility of some PMN's still being present). Slide 68 Fibrosis is a salient features of chronic inflamation The resulting cicatrisation leads to many of the importanat complications of CI Eg: MS and MR following chronic rheumatic valvulitis : Pyloric stenosis chronic gastric ulcer Slide 69 The end result of inflammation can be scarring. The alveolar walls are thickened and filled with pink collagen following an autoimmune disease lasting for decades. Slide 70 This is a healing biopsy site on the skin seen a week following the excision, The skin surface has re-epithelialized, and below this is granulation tissue with small capillaries and fibroblasts forming collagen. After a month, just a small collagenous scar will remain. Slide 71 Effects of chronic inflammation General effects Hyperplasia of mononuclear phagocytic system Eg : lymph nodehyperplasia : hepatomegaly :spleenomegaly in chronic malaria, SAIE :marrow hyperplasia Slide 72 Systemic immune response Antibody production is a feature of most chronic inflammatory disease Demonstration of specific immunogloulins is a useful diagnostic procedure Cell mediated immune response Delayed hypersensitivity reaction Eg : tuberculin, lepromin, Frei are based upon this. Slide 73 Cell- mediated hypersensitivity itself results in tissue damage. Long continued stress on the antibody producing mechanism may be associated amyloid disease. Slide 74 Changes in the blood Anaemia- normochromic, normocytic type. Reduction of plasma albumin Increase gamma globulin Increase ESR Slide 75 Mechanism Of granuloma formation The classic example for the immune granuloma is that caused by the bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis. Caseating necrosis is rare in other granulomatous diseases. Slide 76 There are many atypical presentations that it is always necessary to identify the specific etiologic agent by: special stains for organisms (acid-fast stains for tubercle bacilli) culture methods (tuberculosis, fungal disease), serologic studies (syphilis). In sarcoidosis, the etiologic agent is unknown Slide 77 Slide 78 Granuloma: bacilli are inhaled by droplets Bacteria are phagocytosed by alveolar macrophages After amassing substances that they cannot digest, macrophages lose their motility, accumulate at the site of injury and transform themselves into nodular collections; the Granuloma A localized inflammatory response recruits more mononuclear cells Slide 79 The granuloma consists of a kernel of infected macrophages surrounded by foamy macrophages and a ring of lymphocytes and a fibrous cuff (containment phase) Containment usually fails when the immune status of the patient changes; the granuloma caseates, ruptures and spills into the airway Slide 80 Pathology of Tuberculosis Slide 81 Etiology and incidence Characteristics of mycobacteria 2-10micrometer in length. Structurally gram positive but also contains large amount of lipids in the cell wall: making them acid fast. No toxins No spores Obligate Aerobic Elicit granulomatous inflammation. Slide 82 M. tuberculosis hominis & M. bovis M. avium, M.intracellulare in AIDS - Atypical TB Slide 83 Infects one third of world population..! 3 million deaths due to TB every year Under privileged population - Crowding, Poverty, malnutrition, economic burden. Since 1985 incidence is increasing in west AIDS, Diabetes, Immunosuppressed patients, Drug resistance. Slide 84 Tuberculosis is a chronic communicable disease in which the lungs are the prime target, although any organ may be infected. Slide 85 Primary TB SecondaryTB Progressive pulmonary TB Miliary TB Slide 86 PATHOGENESIS The course of tuberculosis depends on age and immune competence AND total burden of the organisms Tuberculous Infection: refers to growth of the organism in a person,whether there is symptomatic disease or not. Active Tuberculosis; refers to infection manifested by tissue destruction-----symptomatic disease. Slide 87 PRIMARY TUBERCULOSIS Primary tuberculosis is the form of disease that develops in a previously unexposed and unsensitized person. Tuberculosis is a type of delayed tissue hypersensitivity to the tuberculous bacillus which elicit a cell-mediated immune response which will resists the growth and spread of the mycobacterium. Slide 88 This hypersensitivity reaction produces the pathologic feature of tuberculosis in immunocompetent individuals, i.e. granulomas, caseation, cavity formation Slide 89 The sequence of events which occur after inhalation of infectious agent in a previously unexposed immunocompetent individual are: The mycobacterium will gain access to the alveolar macrophage through receptors. *Once the organisms are inside the cytoplasm ofthe macrophage it will inhibit the microbicidal response of the macrophage ineffective phagolysosome Slide 90 Multiplication of the organism inside the alveolar macrophage processing& presentation of the antigen on the surface A clone of sensitized T-cells proliferate, produce gamma INT. Activation of the macrophages(augmenting their capacity to kill mycobacteria) Slide 91 The lytic enzymes of the activated macrophages is released, also damaged host tissues. This activation of macrophages and destruction of mycobacteria comprises the cell mediated immunity. Slide 92 The earliest stage of primary tuberculosis (