Todays Quranic verse God has revealed (from time

Todays Quranic verse God has revealed (from time

Todays Quranic verse God has revealed (from time to time) the most beautiful Message in the form of a Book, consistent with itself, (yet) repeating (its teaching in various aspects): the skins of those who fear their Lord tremble thereat; then their skins and their hearts do soften to the celebration of God's praises. Such is the guidance of God: He guides therewith whom He pleases, but such as God leaves to stray,

can have none to guide. [039:023] 1 Every job is a self portrait of the person who does it Autograph your work with excellence! 2 CHRONIC INFLAMMATION

February 25, 2020 3 CHRONIC INFLAMMATION Specific Objectives: 1. 2.

3. 4. 5. 6. 7. 8. 9. Describe the pathogenetic pathways leading to chronic inflammation. List the principal cells of acute and chronic inflammation.

List the general features of chronic inflammation. Outline the Classification of chronic inflammation. Describe a granuloma and explain how it is formed. Discuss the varying patterns of granulomatous reactions. Discuss the Mononuclear Phagocyte System Explain the functions of macrophages Define the following macroscopic patterns of inflammation: serous inflammation, fibrinous inflammation, purulent inflammation, hemorrhagic inflammation, catarrhal inflammation, membranous & pseudomembranous inflammation, abscess, ulcer, wound, scar, and keloid.

10. Describe the typical local and systemic signs and symptoms of inflammation. 11. Explain the pathogenesis of fever. 4 CHRONIC INFLAMMATION It is defined as prolonged process in which destruction and inflammation are proceeding at the same time as attempt at healing. Conditions favouring chronic inflammation

Persistent infection by certain microorganisms Prolonged exposure to potentially toxic agent (exogenous / endogenous) Local or general conditions impairing the body defence Autoimmune diseases 5 Chronic inflammation may develop in the following ways: As a progression from acute inflammation if the original stimulus

persists, After repeated episodes of acute inflammation, De novo if the causative agent produces only a mild acute response. 6 GENERAL FEATURES OF CHRONIC INFLAMMATION

Acute inflammation Demolition phase

Healing-repair & regeneration Immune response The hallmark of chronic inflammation Presence of mononuclear inflammatory cells ("mononuclear cells", "round cells", i.e., monocytes, lymphocytes, and/or plasma cells). Some evidence of healing (scarring, fibroblast proliferation, angioblast

proliferation). 7 Acute inflammation Exudation & pus formation in chronic suppurative conditions like chronic brain abscess, osteomyelitis, empyema, pyosalpinx and pyonephrosis Fibrin presence in chronic empyema thoracis

Fluid exudation in chronic inflammations of serous sacs like tuberculous peritonitis & spider web clot in CSF of tuberculous meningitis Usually however overt acute inflammation is not an outstanding feature of chronic inflammation. 8 Demolition phase Presence of macrophages commonly derived from emigrating

monocytes of bone marrow origin. Healing Repair Presence of granulation tissue leads to repeated hemorrhage in peptic ulcer and bronchiectasis resulting in hematemesis & hemoptysis respectively. 9 Healing ( Repair)

Fibrosis seen in fibroproliferative tuberculosis, chronic peptic ulcer, chronic cholecystitis and in the walls of chronic abscesses. Cicatrisation leads to valvular stenosis and regurgitation in chronic rheumatic valvulitis, pyloric stenosis in chronic gastric ulcers & fibrous ankylosis in rheumatoid arthritis Endarteritis obliterance in bed of chronic peptic ulcer, following radiation damage & around gumma

10 Regeneration In gall bladder cholecystitis glandularis proliferans Regeneration of epithelium in ulcerative colitis leads to polypoidal overgrowth & malignancy Tumorlets in the lung in bronchiectasis

11 Immune response B & T lymphocytes & plasma cells in granulation tissue Extensive lymphoid infiltrate in Hoshimotos thyroiditis and occasionally skin reaction to arthropod bite Heavy plasma infiltrate in chronic inflammatory lesions of

juxtacutaneous mucous membrane 12 Note that the activated macrophage releases products that are similar to those released

by PMNs 13 CHRONIC NON-SPECIFIC INFLAMMATION (NON-GRANULOMATOUS)

It is the continuation of a partially successful acute inflammation & mostly reaction to persistent extracellular bacteria Histologically characterized by structureless unorganized diffuse infiltration of tissues by PMNs and Round cells Dominated by B cell immune response, with local amplification by B cell-derived plasma cells secreting specific antibodies to enhance bacterial phagocytosis and killing by WBC

Local tissue damage is caused directly by persistence of toxin producing bacteria and indirectly by release of lysosomal enzymes 14 from host phagocytes, especially dead PMNs 15 16 17

18 19 20 21 22

23 24 CHRONIC GRANULOMATOUS INFLAMMATION It is a special form of chronic inflammatory reaction which is histologically characterized by presence of structured response with recognizable single or coalescent units called granulomas .

It is dominated by cell mediated immune response (Type IV) when microorganisms are present and generally show presence of T cells and macrophages which transform locally into epithelioid cells and giant cells. It bypasses acute inflammation and is chronic from start . Mostly it is reaction to facultative intracellular pathogens (TB bacilli, fungi) or to inert indigestible foreign material (sutures, prostheses, etc.) that do not cause direct cell injury and do not release25

substances initiating acute inflammation. GRANULOMA An imprecise term applied to any small nodular delimited aggregation of mononuclear inflammatory cells, or such a collection of modified macrophages resembling epithelial cells (epitheloid cells) usually surrounded by a rim of lymphocytes, often with multinucleated giant cells. Some granulomas contain eosinophils and plasma cells, and fibrosis is commonly seen around the lesion.

While mostly granulomas are discrete & nodular, it does not usually have to be. The process can be more diffuse, without the formation of actual granulomas. This diffuse form of granulomatous inflammation is most often seen when an individual's immune system is either innately hyporesponsive to a pathogen (lepromatous leprosy) or compromised to the extent that it is difficult for the inflammatory process to form discrete granulomas (tuberculosis seen in persons with AIDS). 26

In its most classical form, a granuloma consists of concentric layers of cells that, together, form the distinctive lesion. This central focus is surrounded by a layer of specialized macrophages, called epithelioid cells, and multinucleated giant cells. The latter form as the result of cytoplasmic fusion of macrophages, due to stimulation by a cytokine. The next layer is predominantly lymphocytes, and the outer layer is most often fibroblasts, which are attempting to wall off the inciting

stimulus with fibrous connective tissue. Granulocytes, plasma cells, and other cells types may also be present. 27 *Macrophages are almost all recruited directly from the bloodstream monocytes. *Epithelioid cells have abundant pink cytoplasm, indistinct borders, and elongated, euchromatin-rich, reticulated nuclei oriented helterskelter

*The giant cells of granulomas occasionally contain altered cytoskeletal components in the shapes of stars, or asteroid bodies or they may show presence of laminated calcified nuggets, called Schaumann bodies ( "conchoid bodies"). *Plasma cells produce antibodies against the persistent antigen or the altered tissue components. *Lymphocytes are likely to be present even where there is no

involvement of the immune system. 28 If the agent is an inert foreign body, the granuloma will be of the non immune type. However, if the inciting agent is antigenic, the lesion will be an immune type of granuloma, in which the antigen-stimulated lymphocytes are producing cytokines, such as interferon-gamma, to activate the macrophages and their specialized forms (epithelioid and

multinucleated giant cells to heightened levels of microbicidal activity. Classic granulomatous disease Tuberculosis, leprosy, foreign body reactions (sutures, schistosome eggs), the deep fungal infections, berylliosis, and "sarcoidosis". In syphilis (the granuloms, if any, are small and loose) and silicosis (the granulomas, if any, are very fibrous). 29

30 31 32 33 34

TYPES OF GRANULOMATOUS REACTION Granulomas with suppuration (i.e., with pus in their centers; "stellate microabscesses") are typical of those bacterial diseases with a propensity to involve lymph nodes. These are lymphogranuloma venereum, cat scratch fever, brucellosis, plague, tularemia, glanders-melioidosis, listeria, and yersinia infection and blastomycosis. Granulomas with caseation are typical of certain fungal infections (histoplasmosis, blastomycosis,

and coccidioidomycosis ) and of mycobacterial (fungus-like bacteria) infections (basically TB; also BCG bacillus and atypical mycobacteria) 35 Granulomas with foreign bodies aspirated food, schistosome eggs, toxocara, silicone injections, splinters, sutures, windshield fragments, chalazion, ruptured epidermoid cysts, sea urchin spines, amyloidomas, dead aspergillus fungi, dead filaria, ingrown hairs, talc in the lungs, metastatic

calcification bits, uric acid crystals (in longstanding gout,"tophi"), sclerosing lipogranuloma of the penis, insect bites, * "actinic elastolytic granuloma of Mieschler" (a foreign body reaction to your own elastic fibers), etc. 36 Other solid granulomas are classified as immunologic diseases:

Straightforward immune problems: The organic pneumoconioses, berylliosis, zirconium disease (the infamous "armpit sarcoidosis", from zirconium-based deodorants), positive skin tests More arcane immune problems: Wegener's granulomatosis(and its variants Churg-Strauss and lethal midline granuloma) Immunologic reactions to tumors:

Lennert's lymphoma, seminoma (both are often rich in granulomas); 37 lymph nodes draining other cancers Idiopathic (? immune) problems: Sarcoidosis, Crohn's disease, primary biliary cirrhosis, bronchocentric granulomatosis Neutrophil deficiency syndromes: Chronic granulomatous disease

Miscelleneous Toxoplasmosis and Q-fever (curious little granulomas) and cutaneous leishmaniasis ("foamy granulomas", present if immune response is good). HIV encephalitis presents groups of giant cells, the result of macrophages recognizing HIV protein on each others' surfaces 38

39 40 41 42 43

44 45 46 47 48

MONONUCLEAR PHAGOCYTE SYSTEM (Reticuloendothelial system-RES) Consists of closely related cells of bone marrow origin including blood monocytes and tissue macrophages, the latter are diffusely scattered in connective tissue or clustered in organs (Kupffer cells in liver, sinus histiocytes in lymph nodes, alveolar macrophages in lung & Langerhans cells in skin) Monocytes from blood migrate into various tissues and transform into

macrophages Macrophage is a central figure in chronic inflammation. It can produce wide range of biological substances active against both unwanted invaders and the tissue Macrophages can release Enzymes (neutral proteases & acid hydrolases), Plasma proteins (complement components & coagulating factors), Reactive metabolites of oxygen, Eicosanoids, Cytokines, 49 Growth factors and Nitric oxide.

Mononuclear Phagocyte System Circulating blood monocytes Tissue macrophages Kupfer cells (liver) Sinus Histiocytes (spleen) Microglia (CNS) Alveolar Macrophages (lung) 50

51 Differences between Acute & Chronic inflammation ACUTE Vascular Changes Cellular Infiltrates CHRONIC

Vasodilation Minimal Increased permeability Minimal Primarily neutrophils

Mononuclear leukocytes, macrophages Stromal Changes Minimal Fibrosis, cellular

Edema and proliferation separation of layers scarring. 52

Comparison of Acute and Chronic Inflammation Process Acute Inflammation Chronic Inflammation Initiators

Microbial surfaces & fragments Injured tissue & tissue fragments Mediators Mast cell products (histamine) Bradykinin Lysosomal components Complement, lipid mediators

Non-digestable organisms Non-degradable foreign matter Auto-immune reactions T-lymophocytes& macrophage products- cytokines and GFs Proteases and reactive oxygen Complement, lipid mediators Vascular changes Vasodilatation & inc, permeability

Minimal Cell Populations Neutrophils Tissue macrophages Monocytes/Macrophages Plasma cells, Fibroblasts

Time course Acute onset, minutes days Insidious onset, weeks years Outcome Resolution, Abscess formation

Chronic inflammation Resolution, Tissue destruction, fibrosis 53 54

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