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CELL INJURY

CELL INJURY. CONTENTS. TISSUE HYPOXIA CELL INJURY CELL ACCUMULATIONS GROWTH ALTERATIONS. TISSUE HYPOXIA. What are the most common causes of tissue hypoxia [inadequate oxygenation of tissue]

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CELL INJURY

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  1. CELL INJURY

  2. CONTENTS • TISSUE HYPOXIA • CELL INJURY • CELL ACCUMULATIONS • GROWTH ALTERATIONS

  3. TISSUE HYPOXIA

  4. What are the most common causes of tissue hypoxia [inadequate oxygenation of tissue] • Ischemia, Hypoxemia, Hemoglobin-related problems, Defective or uncoupled oxidative phosphorylation • What are the most common sites in the central nervous system most susceptible to tissue hypoxia • Neurons in the hippocampus, Purkinje cells in the cerebellum, Neurons in layers 3, 5, and 6 of the cerebral cortex • What are the most common causes of ischemia [reduction of arterial blood flow to tissue] • Atherosclerosis [less common causes: vessel compression (e.g., expanding mass), Torsion of vessels (e.g., volvulus (twisting of bowel around mesentery]), Decreased cardiac output (e.g., Left-sided heart failure)]

  5. What are the most common consequences of ischemia • Infarction [localized cell necrosis], Atrophy [reduction in cell/tissue mass], Organ dysfunction • What are the most common causes of hypoxemia [low partial pressure of oxygen in plasma; Pa02] • Respiratory acidosis [hypoventilation; increased partial pressure of arterial CO2, PaCO2], Ventilation defect (e.g., atel-ectasis [collapse of alveoli]), Perfusion defect (e.g., pulmonary embolus), Diffusion defect (e.g.,interstitial fibrosis) • What are the most common causes of Hemoglobin-related problems • Anemia, Methemoglobinemia [heme iron in ferric condition], Carbon monoxide poisoning, Left-shifted Oxygen dissociation curve [Hemoglobin with a high affinity for oxygen]

  6. What are the most common alterations in O2(oxygen) content in anemia [O2 content = (1.34 X Hb) X O2 saturation + PaO2] • Decreased oxygen content owing to a reduction in hemoglobin concentration; SaO2 [percentage of heme groups occupied by oxygen] and PaO2 (partial pressure of arterial oxygen) are normal • What are the most common alterations in oxygen content in respiratory acidosis • Decreased oxygen content owing to a reduction in SaO2 (oxygen saturation in hemoglobin) and PaO2 (partial pressure of arterial oxygen) • What are the most common alterations in oxygen content in methemoglobinemia and carbon monoxide poisoning • Decreased oxygen content owing to a reduction in SaO2 ; Hemoglobin concentration and PaO2 are normal

  7. What are the most common causes of a left-shifted Oxygen Dissociation Curve • Carbon monoxide poisoning, Methemoglobin (MetHb), Alkalosis, Fetal hemoglobin (HbF), Hypothermia • What are the most common treatment for methemoglobinemia • Methylene blue, which activates a normally inactive methemoglobin reductase system that converts ferric to ferrous ions [Ascorbic acid is used as an ancillary treatment, since it reduces ferric to ferrous ions.] • What are the most common treatment for carbon monoxide poisoning • Oxygen, which displaces carbon monoxide from the heme group

  8. What are the most common causes of uncoupled oxidative phosphorylation [uncoupling: increased permeability of the inner mitochondrial membrane to protons] • Block of cytochrome oxidase (e.g., cyanide, carbon monoxide), Uncoupling agents (e.g., salicylates, alcohol, dinitrophenol) • What are the most common organelle and biochemical process altered in tissue hypoxia • Mitochondria and generation of adenosine triphosphate (ATP) by oxidative phosphorylation • What are the most common biochemical consequence of tissue hypoxia • Decrease in adenosine triphosphate (ATP) synthesis

  9. What are the most common initial light microscopic finding in tissue hypoxia • Cellular swelling due to loss of the sodium/ potassium ATPase pump • What are the most common reversible consequences of reduction in adenosine triphosphate (ATP) • Cellular swelling due to loss of the sodium/ potassium ATPase pump (correlates with dilatation of endoplasmic reticulum), Detachment of ribosomes leading to decreased protein synthesis (fatty liver from decreased apolipoproteins), Increased anaerobic glycolysis

  10. What are the most common causes of enhanced anaerobic glycolysis in tissue hypoxia • Allosteric enhancement of Phosphofructokinase: increased Adenosine monophosphate (AMP) and decreased citrate • What are the most common irreversible consequences of reduction in adenosine triphosphate (ATP) • Cell membrane and mitochondrial injury due to free radical injury and increase in cytosolic calcium [Nuclear pyknosis is the most common light microscopic change.] • What are the most common effects of calcium in tissue hypoxia • Activates phospholipase in the cell membrane, endonuclease in the nucleus; Enters the mitochondria to produce large amorphous densities that are visible with electron microscopy

  11. What are the most common lab marker of tissue injury • Serum enzymes (e.g., Creatine Kinase in acute myocardial infarction, transaminases in hepatitis) • What are the most common lab finding indicating anaerobic glycolysis • Increased anion gap metabolic acidosis due to lactic acidosis from anaerobic glycolysis

  12. Question • Which of the following causes tissue hypoxia without altering the oxygen content of blood? • (A) Respiratory acidosis • (B) Carbon monoxide poisoning • (C) Methemoglobinemia • (D) Cyanide poisoning • (E) Anemia

  13. CELL INJURY

  14. What are the most common free radicals [unpaired electron in outer orbit] • Superoxide, Hydroxyl ions, Drugs (e.g., acetaminophen, carbon tetrachloride), Hydrogen peroxide • What are the most common sources for free radicals • Ionizing radiation, Damaged mitochondria, Oxidase reactions (e.g., xanthine oxidase), Drugs, Chemicals, Granulocytes/macrophages • What are the most common metal associated with generation of free radicals • Iron [The Fenton reaction generates hydroxyl free radicals, which are the mechanism of injury in iron overload diseases (e.g., hemo-chromatosis and hemosiderosis).]

  15. What are the most common site for generation of drug/chemical free radicals • Cytochrome P450 system in the liver • What are the most common injuries associated with free radicals • Lipid peroxidation of cell membranes, Reper-fusion injury (e.g., post-infusion tissue plasminogen activator), Retinopathy of prematurity (superoxide free radicals), Bronchopulmonary dysplasia (superoxide free radicals), Cancer (free radical-induced point mutations) • What are the most common antioxidants that neutralize free radicals • Superoxide dismutase (superoxide), Catalase (peroxide), Glutathione (peroxide, acetaminophen), Vitamin E (cell membrane lipid peroxidation), Selenium (co-factor in glutathione peroxidase), Ascorbic acid (free radical scavenger), beta-carotenes.

  16. What are the most common cause of individual cell necrosis [cell death] • Apoptosis [Apoptosis is important in programmed cell death, involution of wolffian and miillerian duct remnants, Atrophy, Toxin-induced injury, Cell death by cytotoxic T cells (e.g., Councilman bodies in viral hepatitis).] • What are the most common cause of coagulation necrosis [necrotic tissue with cell structures intact] • Ischemia secondary to atherosclerosis [Less common causes include radiation and heavy metals (e.g., lead).] • What are the most common site of coagulation necrosis • Heart [Acute myocardial infarction is the leading cause of death in the United States.]

  17. What are the most common sites of pale infarctions [localized areas of tissue necrosis without hemorrhage] • Heart, Kidneys, Liver (least likely to infarct owing to a dual blood supply), Spleen, Brain (atherosclerotic stroke; liquefactive not coag-ulative necrosis) • What are the most common sites of hemorrhagic (red) infarctions [localized areas of tissue necrosis with hemorrhage • Lungs, Bowel, Ovaries, Testicles, Brain (embolic stroke) • What are the most common cause of gangrene in the toes of a diabetic • Atherosclerotic peripheral vascular disease [Dry gangrene is primarily coagulative necrosis (no infection). Wet gangrene begins as coagulative necrosis, but superimposed infection results in liquefactive necrosis.]

  18. What are the most common sites for watershed infarcts [infarctions in areas between two overlapping blood supplies] • Cerebral cortex and splenic flexure (overlap area between the superior and inferior mesenteric arteries) • What are the most common mechanism of liquefactive necrosis • Destructive effect of proteolytic enzymes (neutrophils, macrophages, cells in the cental nervous system) • What are the most common cause of enzymatic fat necrosis • Acute pancreatitis [It is most commonly secondary to alcoholism and biliary tract disease. Fatty acids and calcium combine (saponification) and form chalky white areas in the tissue.]

  19. What are the most common cause of calcifications in the left upper quadrant on a radiograph • Dystrophic calcification [calcification of damaged tissue] in a patient with recurrent pancreatitis • What are the most common site of traumatic fat necrosis • Pendulous breast tissue [It is often confused with cancer owing to calcifications and induration of the tissue.]

  20. What are the most common tissue manifestation of caseous necrosis [combination of coagulative and liquefactive necrosis] • Granulomas [Granulomas are a localized collection of activated macrophages (epithelioid cells) and CD4 T helper cells (type IV cellular immune reaction). Caseation (cheesy appearance) is lipids released from the cell walls of dead organisms (Tuberculosis, systemic fungi).] • What are the most common causes of caseation necrosis • Tuberculosis, Systemic fungal infections (his-toplasmosis) • What are the most common causes of noncaseating necrosis • Sarcoidosis, Crohn's disease

  21. What are the most common cause of fibrinoid necrosis [eosinophilic staining fibrin-like material] • Immune complex vasculitis (e.g., Henoch-Schonlein Purpura) [other examples: vegetations in rheumatic fever, rheumatoid nodules] • What are the most common cause and sites of gummatous necrosis [granulomatous variant of caseous necrosis] • Tertiary syphilis with the skin and bone representing the most common sites [Gummas have a rubbery consistency and have a necrotic center surrounded by macrophages.]

  22. Question • Which of the following is an example of liquefactive necrosis? • (A) Myocardial infarction • (B) Cerebral infarction • (C) Apoptosis • (D) Acute tubular necrosis • (E) Gummatous necrosis

  23. CELL ACCUMULATIONS

  24. What are the most common lipid accumulation • Cholesterol in an atherosclerotic plaque • What are the most common cause of a fatty liver • Alcohol [Substrates from alcohol metabolism that increase very low density lipoprotein, VLDL synthesis (lipid of fatty change) include nicotinamide adenine dinucleotide, NADH (increases production of Dihydroxyacetone phosphate, DHAP in the glycolytic cycle — » glycerol 3-PO4, the carbohydrate backbone of very low density lipoprotein), acetate (fatty acid), Acetyl coenzyme A (substrate for fatty acid synthesis).] • What are the most common cause of hepatomegaly in kwashiorkor • Fatty change [A decreased protein intake decreases apoprotein synthesis and secretion of very low density lipoprotein from the liver (Very low density lipoprotein must be coated by protein to be soluble in plasma).]

  25. What are the most common skin lesions associated with Cholestrol accumulation • Xanthelasma (yellow patches on eyelids; type II hyperlipidemia), Tendon xanthomas (familial hypercholesterolemia) • What are the most common protein associated with amyloid formation • Light chains in primary amyloidosis due to plasma cell dyscrasias (e.g., multiple myeloma) • What are the most common examples of protein accumulations in tissue • Hyaline arteriolosclerosis (small vessel disease of Diabetes Mellitus and hypertension), Amyloid, Immunoglobulin (e.g., red globules in reactive plasma cells)

  26. What are the most common lesions with melanin accumulation • Nevocellular nevi, Malignant melanoma • What are the most common causes of excess melanin deposition in skin • Increased release of adrenocorticotropic hormone from hypocortisolism: Addison's disease, Adrenogenital syndrome (enzyme deficiencies) increased production of adrenocorticotropic hormone: ectopic cushing's syndrome (small cell carcinoma of lung) • What are the most common disorders with absence of melanin • Vitiligo (autoimmune destruction of melanocytes), Albinism (Autosomal recessive; deficiency of tyrosinase), Phenylketonuria (decreased production of tyrosine — » decreased melanin)

  27. What are the most common disorders associated with melanin look-alikes • Coal worker's pneumoconiosis (anthracotic pigment), Melanosis coli (pigment from laxatives discolors colon), Alcaptonuria (Autosomal recessive; deficiency of homogentisate oxidase; accumulation of homogentisate) • What are the most common pigments derived from Hemoglobin • Bilirubin, Hemosiderin (packets of ferritin), Hematin (oxidized heme that has a black color; melena in stools [acid pH in the stomach converts hemoglobin into hematin])

  28. What are the most common disorders associated with glycogen accumulation • Diabetes mellitus (deposition in renal tubules called Armanni-Ebstein anomaly; deposition in the nuclei of hepatocytes), Glycogen storage diseases (e.g., von Gierke's [hepatorenomegaly], Pompe's disease [restrictive cardiomyopathy], McArdle's disease [absence of muscle phosphorylase with accumulation of glycogen in muscle]) • What are the most common mechanism of dystrophic calcification • Calcification of damaged tissue in the presence of a normal serum calcium level (e.g., atherosclerotic plaque) • What are the most common mechanism of metastatic calcification • Calcification of tissue secondary to an increase in calcium or phosphate (e.g., primary hyperparathyroidism)

  29. What are the most common pigment associated with free radical injury and atrophy • Lipofuscin, which is a brown pigment representing the undigestible end-product of lipid peroxidation • What are the most common cause of Glycosaminoglycan accumulations • Mucopolysaccharidoses, which are predominantly Autosomal recessive lysosomal storage diseases (e.g., Hurler's disease)

  30. Question • Which of the following materials other than bilirubin accumulates in blood or tissue in intrahepatic obstruction to bile flow? • (A) Hematin • (B) Lipofuscin • (C) Cholesterol • (D) Triglyceride • (E) Melanin

  31. GROWTH ALTERATIONS

  32. What are the most common cell cycle regulators in cell growth • Cyclins and kinases [Cyclins are proteins that activate kinases, which regulate the progression from one phase of the cycle to the next (Gl -> S -h> G2 -> M -> Gl with repeat of the cycle or from Gl to GO [resting phase]).] • What are the most common suppressor gene controlling cell growth • p53 suppressor gene [This gene produces a protein that controls kinase activity.] • What are the most common cell cycle phase that controls whether the cell divides again or terminally differentiates itself • Gl phase [This is also the most variable phase of the cycle (all the other phases remain constant).]

  33. What are the most common cell cycle phase for chromosomal replication • S phase [DNA and organelles double in this phase.] • What are the most common cell cycle phase for synthesis of components required for mitosis • G2 phase • What are the most common cell cycle phase blocked by vinca alkaloids • M phase (mitosis) [Vinca alkaloids (e.g., vin-cristine, vinblastine) bind to tubulin (protein forming the mitotic spindle), hence disrupting the spindle apparatus in mitosis.]

  34. What are the most common cell cycle phase blocked by antimetabolites interfering with DNA synthesis • S phase (e.g., methotrexate) • What are the most common growth alteration • Atrophy [reduced cell/tissue mass] • What are the most common causes of atrophy • Normal aging, Ischemia (e.g., cerebral atrophy), Disuse (e.g., decreased muscle workload), Loss of trophic stimulation (e.g., denervation of muscle), Malnutrition (e.g., marasmus), Compression (e.g., renal cortex in hydronephrosis)

  35. What are the most common cell alterations in atrophy • Destruction of cell organelles and structural proteins (called autophagy; leaves lipofuscin behind) • What are the most common underdevelopment of an organ • Hypoplasia, where there is incomplete or partial development of an organ or tissue (e.g., hypoplasia of the left ventricle) [Agenesis is absence of the primordial tissue (no organ). Aplasia is presence of primordial tissue without any further development.] • What are the most common type of tissue containing stem cells • Labile tissue, where >1.5% of the cells are in active mitosis [Stem cells rather than all the cells in the tissue are involved in mitosis. Examples: basal cells in the skin, bone marrow stem cells, cells in the intestinal crypts, lymphoid tissue.]

  36. What are the most common theory for cell hypertrophy [increase in cell size] • Block prior to the G2 phase of the cell cycle by transforming growth factor • What are the most common theory for cell hyperplasia [increase in cell number] • Block after mitosis causing cells to remain in the cell cycle and not enter the GO phase • What are the most common types of tissue capable of undergoing both hyperplasia and hypertrophy • Labile (see above) and stable cells [Stable cells are normally in the GO phase of the cycle and do not have stem cells. They must be stimulated (e.g., hormones, growth factors) to enter the Gl phase of the cell cycle (e.g., smooth muscle, hepatocytes).]

  37. What are the most common muscle types that undergo only hypertrophy • Cardiac and skeletal muscle [These are permanent cells (cannot enter the cell cycle), hence they cannot divide. Smooth muscle cells undergo hypertrophy and hyperplasia.] • What are the most common examples of permanently differentiated tissue • Skeletal and cardiac muscle, neurons • What are the most common cause of left ventricular hypertrophy (LVH) • Essential hypertension [Increased peripheral resistance increases the afterload the muscle must contract against.]

  38. What are the most common example of equal proportions of hypertrophy and hyperplasia • Gravid uterus, where there is both smooth muscle hyperplasia (estrogen-induced) and hypertrophy • What are the most common cause of bone marrow erythroid hyperplasia • Hypoxemia [A reduced PaO2, partial pressure of arterial oxygen, is a stimulus for erythropoietin release, which stimulates the erythroid stem cell to undergo mitosis.] • What are the most common growth alteration predisposing to endometrial cancer • Endometrial hyperplasia, which may progress into carcinoma in situ, and invasive adenocarcinoma [Endometrial hyperplasia is due to unopposed estrogen.]

  39. What are the most common cause of squamous metaplasia of the respiratory tract [metaplasia: replacement of one adult cell type by another] • Smoking [Both the true vocal cords and the mainstem bronchus are lined by ciliated pseudostratified columnar epithelium. Toxins in smoke cause irritation, leading to squamous metaplasia.] • What are the most common cause of glandular metaplasia of the distal esophagus • Gastroesophageal reflux disease [A relaxed Lower esophageal sphincter leads to acid injury of squamous epithelium and subsequent glandular metaplasia (Barrett's esophagus), which predisposes to adenocarcinoma.] • What are the most commom cause of intestinal metaplasia in the stomach • Chronic atrophic gastritis secondary to Helicobacter pylori. [Intestinal metaplasia refers to the presence of goblet cells and Paneth cells in the stomach.]

  40. What are the most common infectious agent causing squamous metaplasia in the bladder • Schistosoma hematobium [The eggs deposited by adult worms in the venous plexus of the bladder cause inflammation and squamous metaplasia of the overlying transitional epithelium. Squamous cancer may also occur.] • What are the most common vitamin deficiency producing squamous metaplasia • Vitamin A deficiency [Vitamin A normally prevents squamous metaplasia.]

  41. What are the most common growth alteration predisposing to cancer • Dysplasia (atypical hyperplasia), which, in mild cases, may regress with removal of the offending agent. [Irreversible lesions progress into carcinoma in situ and then invasive cancer.] • What are the most common cause of squamous dysplasia of the cervix [dysplasia: atypical hyperplasia] • Human Pappiloma Virus type 16, which produces squamous metaplasia that may progress into dysplasia, carcinoma in situ, and invasive cancer

  42. QUESTION • An increase in goblet cells in the nonrespiratory terminal bronchioles is an example of which of the following? • (A) Metaplasia • (B) Hyperplasia • (C) Hypertrophy • (D) Dysplasia • (E) Mesenchymal metaplasia

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