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PATHOLOGY NOTES

CELLULAR PATHOLOGY Important causes of monocytosis (i.e., increased number of monocytes in the peripheral blood) include tuberculosis, brucellosis, typhus, and salmonella infection. lymphocytosis (i.e., an increased number of lymphocytes in the peripheral blood) is most often caused by viral infections such as influenza, mumps, rubella, and infectious mononucleosis and certain bacterial infections such as whooping cough and tuberculosis. In older individuals, chronic lymphocytic leukemia is a common cause of lymphocytosis. PDA (close with indomethacin); PGE keeps PDA open. Neutrophil, eosinophil, and antibody mediated are seen in acute inflammation. p53 genes trigger the cells to undergo apoptosis. When p53 is inactivated, this pathway of cell death can be blocked. The BAX gene product promotes apoptosis. The FAS gene encodes for a cellular receptor for FAS ligand, which signals apoptosis. Granzyme B can trigger apoptosis, but it is found in cytotoxic T cells and not in tumor cells. BCL-2 and NF-B activity favor cell survival (inhibit apoptosis). BCL-2 is an antiapoptotic protein that prevents cytochrome c release from mitochondria and prevents caspase activation. The release of cytochrome c from the mitochondria is a key step in many forms of apoptosis, and it leads to the activation of caspases. Mitochondrial permeability is increased to release cytochrome c, which activates caspases leading to apoptosis. Caspase activation is a universal feature of apoptosis. The calcium activates ATPases, phospholipases, proteases, and endonucleases, which injure cell components. Glutathione in the cytosol helps to reduce cellular injury from many toxic metabolites and free radicals. Glutathione promotes free radical breakdown, though chronic excessive alcohol consumption depletes hepatocyte glutathione. NADPH oxidase generates superoxide, which is used by neutrophils in killing bacteria. Nitric oxide synthase in macrophages produces nitric oxide, which aids in destroying organisms undergoing phagocytosis. Superoxide dismutase helps break down superoxide anion to hydrogen peroxide, thus clean up free radicals.

PATHOLOGY NOTES
Lipofuscin is a wear-and-tear pigment that increases with aging, particularly in liver and myocardium. The pigment has minimal effect on cellular function in most cases. Rarely, there is marked lipofuscin deposition in a small heart, a so-called brown atrophy. Hemosiderin is the breakdown product of hemoglobin that contains the iron. Hearts with excessive iron deposition tend to be large. Hemosiderin is a storage form of iron from excess local or systemic accumulation of ferritin, and by itself does not cause cell injury until large amounts are present, as with hemochromatosis. The increase in uterine size is primarily the result of an increase in myometrial smooth muscle cell size. Telomerases aid in promoting continued cell division. The one sure way to increase life span is calorie restriction. The histone deacetylase activity of sirtuins may promote transcription of genes encoding for proteins that increase metabolic activity and inhibit effects of free radicals. Ascorbic acid (vitamin C), A, and vitamin E act as antioxidants to protect against free radical injury. Autophagy is a form of cellular down-sizing in response to stress, as the cell consumes itself, by up-regulating Atgs genes. There is slow autophagy with aging, but autophagy is accelerated with stressors such as malnutrition and chronic disease. Cancer cells acquire the ability to avoid autophagy, perhaps by down-regulating PTEN gene expression, and maintain a survival advantage even as the patient is dying. Hyaline is a generic term for intracellular or extracellular protein accumulations appearing pink and homogenous with H&E staining. ACUTE & CHRONIC INFLAMMATON The COX-2 enzyme is inducible with acute inflammatory reactions, particularly in neutrophils, in synovium, and in the central nervous system. The cyclooxygenase pathway of arachidonic acid metabolism generates prostaglandins, which mediate pain, fever, and vasodilation. Asthma results from bronchoconstriction mediated by leukotrienes that are generated by the lipoxygenase pathway of arachidonic acid metabolism. Easy bruisability results from prolonged glucocorticoid administration, which also causes leukopenia. Chemokines include many molecules that are chemotactic for neutrophils, eosinophils, lymphocytes, monocytes, and basophils.

PATHOLOGY NOTES
Bradykinin causes pain and increased vascular permeability. Complement C3a causes increased vascular permeability by releasing histamine from mast cells. complement C3b may promote phagocytosis. Bacteria are opsonized by complement C3b and IgG, allowing the bacteria to be more readily phagocytosed. Interferon- is secreted by activated T cells and is an important mediator of granulomatous inflammation. It causes activation of macrophages and their transformation into epithelioid cells and then giant cellsLanghans giant cells are seen with granulomatous inflammatory responses. Interferon- secreted from lymphocytes stimulates monocytes and macrophages, which secrete their own cytokines that further activate lymphocytes. Interferon- also is important in transforming macrophages into epithelioid cells in a granulomatous inflammatory response Activated macrophages can secrete various cytokines that promote angiogenesis and fibrosis, including platelet-derived growth factor, fibroblast growth factor, interleukin-1, and tumor necrosis factor. Plasma cells can secrete immunoglobulins. Eosinophils are most prominent in allergic inflammations and in parasitic infections. Epithelioid cells, which are aggregations of activated macrophages, are typically seen with granulomatous inflammation. Thromboxane A2, platelet-activating factor, and leukotriene E4 have vasoconstrictive properties. Aspirin (acetylsalicylic acid) blocks the cyclooxygenase pathway of arachidonic acid metabolism, which leads to reduced prostaglandin generation. Prostaglandins promote vasodilation at sites of inflammation. Leukocyte release from the marrow can be driven by the cytokines. Fever is produced by various inflammatory mediators, but the major cytokines that produce fever are interleukin-1 (IL-1) and tumor necrosis factor (TNF), which are produced by macrophages and other cell types. IL-1 and TNF can have autocrine, paracrine, and endocrine effects. They mediate the acute phase responses, such as fever, nausea, and neutrophil release from marrow. Histamine is found in abundance in mast cells, which are normally present in connective tissues next to blood vessels beneath mucosal surfaces in airways. Binding of an antigen (allergen) to IgE antibodies that have previously attached to the mast cells by the Fc receptor triggers mast cell degranulation, with release of histamine. This response causes increased vascular permeability and mucous secretions.

PATHOLOGY NOTES
Bradykinin, generated from the kinin system on surface contact of Hageman factor with collagen and basement membrane from vascular injury, promotes vascular permeability, smooth muscle contraction, and pain. So, bradykinin mainly increases vascular permeability and produces pain. Hageman factor (factor XII) Leukotriene B4, generated in the lipoxygenase pathway of arachidonic acid metabolism, is a potent neutrophil chemotactic factor. Platelet-activating factor (PAF) can be released by neutrophils, mast cells, monocytes, macrophages, endothelial cells, and platelets. PAF promotes vascular permeability, neutrophil aggregation, and platelet activation. acute inflammatory process leads to production of acute-phase reactants, such as C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. These proteins, particularly fibrinogen, and immunoglobulins increase red blood cell rouleaux formation to increase sedimentation, which is a nonspecific indicator of inflammation. CRP production is up-regulated by interleukin-6, whereas fibrinogen and SAA are up-regulated mainly by tumor necrosis factor and interleukin-1. If the patient has a defect in leukocyte rolling, the first step in transmigration of neutrophils from the vasculature to the tissues. Rolling depends on interaction between selectins (P-selectin and Eselectin on endothelial cells, and L-selectin on neutrophils) and their sialylated ligand molecules (e.g., sialylated Lewis X). Integrins are involved in the next step of transmigration, during which there is firm adhesion between neutrophils and endothelial cells. The polarizable material is the suture, and a multinucleated giant cell reaction, typically with foreign body giant cells, is characteristic of a granulomatous reaction to foreign material. Chronic granulomatous disease is characterized by reduced killing of ingested microbes because of inherited defects in the NADPH oxidase system. Two thirds of cases are X-linked, and one third are autosomal recessive. This system generates superoxide anions (O2), essential for the subsequent production of microbicidal products such as H2O2, OH, and HOCl. The respiratory, or oxidative, burst generates reactive oxygen species (i.e., superoxide anion) that are important in destruction of engulfed bacteria Lysozyme contained in neutrophil granules is responsible for oxygen-independent killing of bacteria. Macrophage activation by interferon- is a key feature of granulomatous inflammation, which is typical of mycobacterial infections. During acute inflammation, neutrophils extravasate from the blood vessels. This process depends on adhesion molecules expressed on the neutrophils and endothelial cells. In the first stage of

PATHOLOGY NOTES
extravasation, the neutrophils roll over the endothelium. At this stage, the adhesion between the neutrophils and endothelial cells is weak. Rolling is mediated by binding of selectins to sialylated oligosaccharides. The next step, firm adhesion, is mediated by binding of integrins on the leukocytes to their receptors, intracellular adhesion molecule-1 or vascular cell adhesion molecule-1 (VCAM-1), on endothelial cells. Integrins have two chains, and . A genetic lack of chains prevents firm adhesion of leukocytes to endothelial cells. Protein C antagonizes coagulation factor V, which catalyzes activation of prothrombin to thrombin, thereby breaking the cycle of thrombin generation.

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