INFLAMMATION-G PATHOLOGY {S1}

INFLAMMATION-G PATHOLOGY {S1} BY RANJEET RAMAN

What can happen after inflammation? • Resolution: injury and inflammation subside leaving normal tissue. • Reconstitution: differentiated cells are replaced by new cells of the same cell type with overall preservation of architecture • Regeneration: differentiated cells are replaced by new cells of the same cell type, but the resultant tissue architecture is abnormal.

Scarring • Keloids: abnormally heavy scars characterized by broad bands of collagen that replace normal dermal structures such as skin appendages. • Abscess formation • Chronic inflammation • The outcome of inflammation depends on differential gene expression

Chronic Inflammation • What is it and what causes it? • Features: slower onset, more protracted course, lymphocytes, macrophages, plasma cells, fibroblasts, vessels • Causes: acute inflammation (or repeated bouts of it), persistent inflammatory stimulus, intracellular microorganisms, non-degradable foreign matter, autoimmune disease

What cells and mediators are involved? • Cells involved • Lymphocytes • Macrophages (distributed through the reticuloendothelial system) • Giant cells (Syncytial macrophages) • Mediators • Macrophages can activated by antigen-specific or by non-specific means.

Activation is an operational term indicating an enhanced capacity to do inflammatory battle. • Activated macrophages are secretory cells. (This is a very important point and a key distinction form neutrophils. Macrophages can secrete cytokines and many other key molecules directly at the inflammatory site.

Lymphocytes, in contrast, are smaller and less directly equipped to serve as effector cells, except as cytotoxic cells. The major role that they play is the initiation of an immune response, its regulation, and, later, the maintenance or down-regulation of that response.)

What is granulomatous inflammation? • Granulomatous inflammation is a specialized variant that is characterized by the presence of large macrophages with abundant slightly pink cytoplasm. Such macrophages are referred to as epithelioid cells. Giant cells and caseation may be present as well.

Possible causes: mycobacteria, fungi, parasites, foreign body, idiopathic • Granulomatous inflammation is regulated by a special class of T cell receptors known as gamma-delta cells after the isotype of the T cell receptor utilized. • Granulomas are so-called because they feel like small, hard granules in a tissue.

These granulomas consist of epithelioid cells surrounded by a rim of lymphocytes. Some granulomatous, particularly those caused by tuberculosis, have central necrosis termed caseation after its resemblance to cottage cheese. Other granulomas, like those shown here, have no necrosis, and are termed non-caseating.

What morphologic patterns occur? • Serous inflammation • Fibrinous inflammation: characterized by the almost exclusive presence of the soluble mediator, fibrin. • Suppurative / Purulent inflammation: severe acute inflammation that effectively destroys, or suppurates the tissue in which it occurs. • Ulcers: areas where the epithelial covering has been effaced. Necrotic vessels may be present

Pseudomembranous inflammation: Pseudomembranous colitis is iatrogenic. Some patients receiving antibiotics develop antibiotic associated colitis. Here, Clostridium difficile has taken over opportunistically and has caused the characteristic Pseudomembranous lesions. Note its failure to involve the mucosa directly.

What is granulation tissue? • Granulation tissue is characterized by the lush influx of capillaries and fibroblasts. When wounds become pink-red to the naked eye, it is a good sign reflective of the underlying granulation tissue.

Other features include • Capillary proliferation • Fibroblast proliferation • Myofibroblast proliferation (wound contraction) Collagen deposition • Debris removal by macrophages • Don’t confuse granulation tissue versus granuloma

Leprosy: comes in two man forms. Tuberculoid leprosy has relatively few, well-circumscribed lesions with a brisk inflammatory reaction, few mycobacteria, and a favorable prognosis. Lepromatous leprosy has many lesions containing abundant organisms, a modest inflammatory reaction, and a poor progonsis. • Psoriasis: manifests as a type of epithelial hyperplasia. Its pathogenesis lies in a complex cytokine network that produces growth factors. The etiology is uncertain.

Inflammation II • Inflammation can lead to resolution, scarring, abscess, or chronic inflammation. The outcome is highly dependent on gene expression. • Resolution is when injury/inflammation subside, leaving normal tissue. • Reconstitution is when differentiated cells are replaced by new cells of the same cell type with normal architecture (like new factory parts).

Regeneration is when differentiated cells are replaced by new cells of the same cell type but with abnormal architecture. • Inflammation can resolve and regenerate, or if chronic can create a granuloma and scarring. Granulomas are epithelioid macrophages surrounded by lymphocytes.

Often they show central necrosis called “caseation.” • Keloids are heavy scars packed with broad bands of collagen that replace normal skin tissue. • Granulation tissue is characterized by capillary, fibroblast, myofibroblast, and collagen proliferation. It is the reparative process that makes healing wounds look pink.

Chronic inflammation has lymphocyte, plasma cell, and macrophage infiltration, as well as fibroblasts laying down collagen, and the formation of new capillaries. It is less stereotypic than acute inflam.

Causes of chronic inflammation include acute or persistent inflammation, non-degradable foreign matter, and autoimmune disease. • Signs of inflammation include edema, accumulation of neutrophils, macrophages, and lymphocytes, and evidence of repair such as fibroblasts laying collagen. But you could also look molecularly for signs of Ig induction, cytokines, macrophage secretions, etc.

Granulomatous inflammation is like chronic but there are also giant cells (fused “epithelioid” macrophages forming a syncytia). Sometimes it appears caseous (synonymous with tuberculosis). Caused by parasites, fungi, foreign bodies. Mediated by special gamma-delta T cell

Suppurative inflammation: tissue is destroyed and just falling apart. Also, fluid accumulation. • Fibrinous inflammation: few cells present, but tons of fibrin (a clotting factor). “Bread and butter” appearance. • Pseudomembranous inflammation: inflam cells overly normal mucosal layer, but doesn’t directly involve the mucosa.

Looks like a layer of inflammation sitting on top of tissue. • Ulcers: erosion of surface epithelium. • Mononuclear Phagocytes (Macrophages) • Perform phagocytosis. Secrete proteases, chemotactic factors, reactive oxygen species, clotting factors, cytokines, prostaglandins, leukotrienes. Possess receptors for inflam mediators such as Ig, complement, and cytokines.

Macrophages can be activated humorally (innate) or by toxins or by Ig (specific). Activation just ramps up everything from the list above. Activated = very secretory. • Macrophages differ from neutrophils in that they can present antigen, differentiate into other cells, and secrete cytokines and other inflammatory signals.

Lymphocytes • Include helper T, killer T, NK, and B cells. Mostly they initiate and regulate immune response. • Leprosy (mycobacterium) • Two forms: • tuberculoid, which is well-circumscribed, brisk inflam reaction, good prognosis. Lots more Toll-like receptor in tuberculoid leprosy. • lepromatous, which has many organisms, many lesions, low inflam rxn, bad prognosis

Psoriasis • Epithelial hyperplasia (keratinocyte proliferation). Too many normal cells. • Dermis becomes inflamed, and subsequent TNF causes keratinocytes to produce TGF (cytokine) that stimulates keratinocyte proliferation.

INFLAMMATION-G PATHOLOGY {S1}