1. d. Cell injury can be caused by physical agents such as extremes of temperature, chemical agents such as drugs and toxins, infectious organisms, immunologic agents, and deficiency of nutrients and oxygen to the cells such as in monoxyhemoglobinemia. ATP is a natural substance that plays a role in energy, metabolism, and cell survival.

2. e. Cell death occurs by apoptosis or oncosis (cell swelling). Pyknotic, karyolytic, and karyorrhectic nuclei are examples of irreversible processes that occur with cell death. Other processes such as formation of membrane myelin figures, cytoplasmic vacuolization, swelling of endoplasmic reticulum, and mitochondrial densities can be found in reversible cell injury.

3. c. Apoptosis is an irreversible process that is triggered by increased TNF and a p53/bcl2 ratio and is not usually associated with inflammation. It can be blocked (but not reversed) by apoptosis inhibitor proteins such as survivin. It may occur as normal physiologic or pathologic processes as seen in hepatitis or graft-versus-host disease (immunologic injury).

4. c. Intracellular proteolysis is carried out by the caspases, which can be classified into procaspases such as caspase 8 or 9 and effector caspases such as caspase 3. Activation of caspase 3 is a late event in apoptosis.

5. c. Hyperplasia involves cell division, is part of the tissue response in wound healing, and may be accompanied by an increased MIB-1 proliferation index. On the other hand, hypertrophy occurs in nondividing cells and may show polyploidy. Both hyperplasia and hypertrophy are influenced by cytokines and growth factors.

6. c. Squamous metaplasia of the bronchial epithelium can be caused by intubation trauma, chronic bronchitis, vitamin A deficiency, and damage due to smoking.

7. a. Cells of certain carcinomas forming papillary structures tend to calcify, forming tiny gritty calcified bodies called psammoma bodies. Corpora amylacea is a glycogen-like material with attached phosphate and sulfate groups and occurs in aging brains and in the prostate. Hypercalcemia and metastatic calcifications can occur in sarcoidosis but sarcoid granulomas do not usually have central necrosis or calcifications. Gamna Gandy bodies are organized and fibrotic deposits of hemosiderin in the spleen caused by hemorrhage. Kimmelstiel-Wilson lesions contain basement membrane material deposited in the glomeruli of diabetic patients.

8. b. Telomerase enzyme adds nucleotides to the end of chromosomes and is important in cell aging. It is absent in most nondividing somatic cells but is up-regulated in cancer cells, stem cells, and dividing germ cells.

9. c. Mutations of the DNA helicase gene (WRN gene) occur in Werner syndrome, possibly accounting for the increased cell aging. Accelerated aging is also seen in Cockayne syndrome, Bloom syndrome, and progeria.

10. a. Vasodilatation leads to increased hydrostatic pressure and increased vascular permeability. Vasodilatation is induced by histamine, serotonin, and bradykinin, which can also cause increased vascular permeability.

11. a. Histamine and other mediators produce an immediate effect on venules, leading to vascular leakage. Vascular leakage can also occur by direct injury, in granulation tissue, and in diapedesis.

12. a. The image shows leukocyte adhesion and transmigration through a dilated vein in the wall of inflamed appendix. Selectins are involved in rolling and loose adhesion. Firm adhesion (or sticking) is brought about by linking of integrins (CD11a/CD18 forming a heterodimer called LFA-1) and ICAM-1 (member of the immunoglobulin family). PECAM 1 (platelet endothelial cell adhesion molecule 1) is essential for transmigration or diapedesis.

13. e. Chemotactic agents for leukocytes are diverse and include bacterial products such as endotoxin lipopolysaccharides and fMLP, complement components C3a, C4a, C5a, thrombin, fibrinolytic breakdown products, chemokines, and leukotrienes. Prostaglandin A1 as well as several serum factors such as chemotactic factor inactivator (CFI) are actually inhibitors of chemotaxis.

14. a. Phagocytosis and chemotactic stimuli (antigen-antibody complexes, complement 5a, TNF) activate leucocytes, leading to increased surface expression of LFA-1 integrin family and change in their configuration so that they can bind to endothelial ligand, ICAM-1.

15. a. This is histamine which, when injected, produces acute inflammation with pain and arteriolar dilatation and increased vascular permeability. Histamine is stored in mast cells and platelets.

16. a. Chronic granulomatous disease (resulting from X-lined mutation in the NADPH oxidase enzyme [gp91 phox deficiency]), myeloperoxidase deficiency, glutathione reductase deficiency, and Chediak-Higashi syndrome are all primarily defects of phagocytosis and intracellular killing. Leukocyte adhesion deficiency syndromes are autosomal recessive conditions characterized by recurrent infections, pneumonia, and sepsis in paradoxical association with neutrophilic leukocytosis. In type I of this disorder, neutrophils lack the cell surface glycoproteins CD11/CD18, resulting in decreased adhesion and motility.

17. b. NF-κB is a cytoplasmic molecule that locates to the nucleus to activate genes related to inflammation. PGE1 antagonizes the effect of histamine, serotonin, and other mediators and, unlike PGE2, is classified as an anti-inflammatory agent. Leukocidins produced by staphylococci and protease inhibitors such as alpha-1 antitrypsin also inhibit the effect of inflammation.

18. a. Serotonin, similar to histamine, is released by platelets and results in increased vascular permeability and arteriolar dilatation. Unlike histamine, serotonin stimulates fibroblasts and may result in fibrosis.

19. b. Collectins bind to carbohydrates on surfaces of bacteria and other organisms and activate the classic pathway. Complement components mediate many aspects of acute inflammation, including increased vascular permeability, leukocyte chemotaxis, phagocytosis by neutrophils, and degranulation of mast cells. C3a, C4a, and C5a are anaphylatoxins and can also cause vascular leakage. C3b is also involved in phagocytosis by opsonization.

20. e. Activated Hageman factor actives four enzyme cascades: the kinin system, clotting system, fibrinolytic system, and complement.

21. d. Toll-like receptors recognize microbial molecules, such as gram-negative bacterial lipopolysaccharides, peptidoglycans, and bacterial lipoproteins, and in turn activate innate immune response against microbial organisms.

22. e. Lipoxins are negative regulators of leukotrienes and inhibit neutrophils chemotaxis. On the other hand, leukotrienes can cause chemotaxis and vasoconstriction while prostaglandin E2 causes vasodilatation.

23. a. Chemokines are small, 8-10 KD proteins that include interleukin 8, C-X-C chemokines, and C-C chemokines. The group has chemotactic specificity for leukocytes and also serves as receptors for HIV virus.

24. d. Nitric oxide is produced by the enzyme nitric oxide synthase, which uses the substrate L-arginine. It is a free radical but also has important functions in inflammation. It reduces platelet aggregation and leukocyte adhesion and causes vasodilatation. Transferrin and ceruloplasmin are serum protein antioxidants that are also important in the O2-radicals scavenger system.

25. a. Superoxide dismutase, together with catalase, is part of the enzyme system that eliminates free radicals. Superoxide dismutase forms hydrogen peroxide, which is then eliminated by catalase. Superoxide dismutase is an intracellular enzyme found mainly in mitochondria and the cytosol.

26. c. Substance P is released by sensory nerve endings and degranulates mast cells. Mast cells secrete histamine, which causes local vasodilatation. In triple skin response, as shown in the picture, a red line appears first because of vasodilatation followed by a red flare spreading to several centimeters from the line. Skin swelling (a wheal) then forms after a few minutes and is caused by vascular leakage. Platelet-activating factor also has versatile function in acute inflammation with possible exception of vasodilatation. It is produced from neutrophils, eosinophils, platelets, vascular endothelial cells, vascular smooth muscle cells, monocytemacrophages, renal epithelial cells, and mesangial cells.

27. b. Myofibroblasts have distinctive features not found in fibroblasts. These include expression of alphasmooth muscle actin, cytoplasmic fibrils with dense bodies, and extensive gap junctions between cells. These features allow the myofibroblasts to have contractile properties, which are important in wound closure. Myo D1 is protein involved in myogenesis and is not found in myofibroblasts.

28. b. The list of cytokines that induce fibrosis is long and includes platelet-derived growth factor, insulin-like growth factor, fibroblast growth factors, and fibronectin. Fibronectin, although does not induce fibroblasts, plays a secondary role and forms, with fibrin filaments, scaffold, or footholds for epidermal cells and migrating fibroblasts.

29. c. Eosinophils are important in the defense against parasites. They differentiate in the bone marrow under the influence of interleukins 5 and 3. Eotaxins 1 and 2 are chemokines that act as chemotactic factors that cause eosinophils to migrate from blood vessels and accumulate in tissue. Eosinophils, similar to neutrophils, can phagocytize and kill bacteria and generate superoxide anions.

30. e. IL-12, produced by macrophages and dendritic cells, is crucial in T-helper lymphocyte response and induction of delayed hypersensitivity. γ-Interferon is also a key mediator of delayed-type hypersensitivity and is a powerful activator of macrophages. Platelet-derived growth factor stimulates fibroblast proliferation and collagen synthesis. Other cytokines that play a role in delayed hypersensitivity include IL-2, TNF, lymphotoxin, and chemokines such as IL-8.

31. d. Interleukin (IL) 1 and TNF are proinflammatory cytokines that produce fever, inflammation, and tissue destruction when administered to humans. IL-8 is a chemoattractant for neutrophils and causes degranulation. Interferon-γ is also considered a proinflammatory molecule because it augments TNF and induces nitric oxide. Major anti-inflammatory cytokines that control the proinflammatory response include IL-1 receptor antagonist, IL-4, IL-10, and IL-13.

32. i) a. Receptors with intrinsic kinase activity include growth factors such as TGF-alpha, PDGF, c-kit, and insulin. These activate receptor tyrosine kinase, which phosphorylates effector molecules such as phospholipase C-γ and PI-3 kinase.

ii) b. Receptors for many cytokines lack intrinsic tyrosine kinase activity.

iii) e. Seven transmembrane receptors are couples to G-proteins and include receptors for many physiologic peptides and hormones such as epinephrine and vasopressin as well as pharmaceutical drugs. These receptors also involve cAMP.

33. e. Epidermal growth factor, fibroblast growth factor, transforming growth factor, platelet-derived growth factor, and VEGF are major cytokines involved in wound healing.

34. i) b. Proteoglycans are components of connective tissue, retain water in the interstitial spaces, and are responsible for subcutaneous tissue turgor. Proteoglycans, especially hyaluronic acid, accumulate in patients with severe hypothyroidism “myxedema” and also in the pretibial spaces in patients with Grave disease. They are also involved in the pathology of joints. ii) e.

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