Dr. Hiba Wazeer Al Zou’bi Chronic Inflammation Dr. Hiba Wazeer Al Zou’bi

Chronic Inflammation Inflammation of prolonged duration (weeks to years). Characterized by: Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells Tissue destruction, by the products of the inflammatory cells Repair

Chronic Inflammation Under what circumstances, does it develop? Progression from acute inflammation. Persistent microbial infections that are difficult to eradicate Mycobacterium Tuberculosis, Treponema Pallidum, certain viruses and fungi. Immune mediated inflammatory disease (Hypersensitivity disease) Rheumatoid arthritis, Inflammatory bowel disease, Psoriasis Prolonged exposure to potentially toxic agent Silica, Cholesterol crystals.

Macrophages and mononuclear phagocyte system Macrophages (Dominant cells of chronic inflammation): Derived from circulating blood monocytes Scattered in tissues: Kupffer cells (liver), sinus histiocytes (spleen & Lymph node), alveolar macrophages (lung) microglia (CNS)

How do Macrophages Accumulate at Sites of Chronic Inflammation? Recruitment of monocytes from circulation by chemotactic factors to the site of injury within 24-48 hours. When reach to extravascular tissue transform into macrophages. Macrophages are larger, have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes.

Lymphocytes B and T lymphocytes (CD4 and CD8) Mobilized in the setting of: Any specific immune stimulus (i.e., infections) Non–immune-mediated inflammation (e.g., due to ischemic necrosis or trauma) In the tissues: B lymphocytes may develop into plasma cells, which secrete antibodies CD4+ T lymphocytes are activated to secrete cytokines.

Three subsets of CD4+ helper T cells : TH1 cells: produce the cytokine IFN-γ, which activates macrophages in the classical pathway. TH2 cells: secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation. TH17 cells: secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and monocytes .

Macrophage-lymphocyte interaction

Eosinophils: Characteristic in: A. Inflammatory sites around Parasitic infections Allergic diseases such as asthma - Eosinophil granules contain major basic protein, a highly charged cationic protein that is toxic to parasites but also causes epithelial cell necrosis. Mast cells: - Source of histamine early in allergic reactions

An important point: Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates, as a result of either persistent microbes or necrotic cells, or mediators elaborated by macrophages. Such inflammatory lesions are sometimes called “acute on chronic”.

Complete Resolution of Inflammation

Granuolmatous Inflammation A distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages with scattered lymphocytes Tuberculosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified.

Formation of a granuloma effectively “walls off” the offending agent and is therefore a useful defense mechanism. However, granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing or degradation Granulomatous inflammation with subsequent fibrosis may be the major cause of organ dysfunction in some diseases, such as tuberculosis.

Examples of Granulomatous Inflammation Bacterial Mycobacterium tuberculosis Mycobacterium Leprae (Leprosy) Trepnema pallidum (Syphilis) Parasitic Shcistosomiasis Fungal Histoplasmosis Foreign body Suture material Immune mediated crohn disease Unknown Sarcoidosis

Histopathology of Granuloma Epithelioid cells (activated macrophages) The aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes. Multinucleate giant cells 40 to 50 μm in diameter (from the fusion of multiple activated macrophages) Older granulomas may have a rim of fibroblasts and connective tissue

In granulomas associated with certain infectious organisms (most classically the tubercle bacillus), a combination of hypoxia and free radical injury leads to a central zone of necrosis. - Gross examination: Granular, cheesy appearance ( caseous necrosis). - Microscopic examination: Eosinophilic amorphous, structureless, granular debris, with complete loss of cellular details.

The granulomas associated with Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be “noncaseating.” Healing of granulomas is accompanied by fibrosis that may be quite extensive.

Histopathology of Granuloma

Histopathology of Granuloma

Caseating Granuloma

AFB Stain in Caseating Granuloma

Systemic Effects of Inflammation (Acute phase reactions)

Systemic Acute-phase Reactions

The acute-phase response of inflammation A. Fever,: - Elevation of body temperature Produced by substances called pyrogens that act by stimulating prostaglandin synthesis in vascular and perivascular cells in hypothalamus Bacterial products, such as lipopolysaccharide (LPS) (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens), which increase the levels of cyclooxygenases that convert AA into prostaglandins

B- Elevated plasma levels of acute-phase proteins. - These proteins are synthesized in the liver, stimulated by IL6: 1. C-reactive protein (CRP) - Binds to microbial cell walls, and they may act as opsonins and fix complement, thus promoting the elimination of the microbes. 2. Fibrinogen, - Binds to erythrocytes and causes them to form stacks (Rouleaux) that sediment more rapidly than individual erythrocytes and this is the basis for measuring the erythrocyte sedimentation rate (ESR) - ESR is a simple test for the systemic inflammatory response, 3. Serum Amyloid A (SAA)

C. Leukocytosis: - Common feature of inflammatory reactions, especially those induced by bacterial infection The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some cases it may reach 40,000 to 100,000 cells/mL. called leukomoid reaction The leukocytosis occurs initially because of accelerated release of cells (under the influence of cytokines, including TNF and IL-1) from the bone marrow Prolonged infection also stimulates production of colony-stimulating factors (CSFs), which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells in the inflammatory reaction

- Most bacterial infections induce an increase in the blood neutrophil count (neutrophilia) - Viral infections, such as infectious mononucleosis, and mumps, german measles associated with increase numbers of lymphocytes (lymphocytosis). Bronchial asthma and parasite infection cause increase in the number of eosinophils Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are paradoxically associated with a decreased number of circulating white cells (leukopenia), because of cytokine-induced sequestration of lymphocytes in lymph nodes.

Other: Increase heart rate and blood pressure Anorexia Malaise Rigor (shivering) Chills (perception of being cold )