Week 1 Theme Cell Injury Cell Death and Adaptations.pptx

Week 1 Theme Cell Injury Cell Death and Adaptations.pptx

1. Adaptations, Cell Injury, Cell Death

2. Adaptations When a cell is exposed to stress physiologic (pregnancy, exercise) or pathologic (hypertension), it undergoes a reversible functional and structural response during which new but altered steady states are achieved allowing the cell to survive and continue to function.

3. Adaptations

4. Hypertrophy Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ. The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components. Eg. Cells that can not multiply Muscles in body builders Cardiac muscle in hypertension

5. Hyperplasia Hyperplasia is defined as an increase in the number of cells in an organ or tissue in response to a stimulus Physiologic Female breast during pregnancy (epithelium) Liver - In individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size Bone marrow in response to supplements Endometrium – after menstruation Pathologic Endometrium – in response to hormones Hyperplasia of prostate Epidermal hyperplasia (warts) in response to viral infection

6. Mechanisms of Hyperplasia Hyperplasia is the result of growth factor-driven proliferation of mature cells and by increased output of new cells from tissue stem cells

7. Atrophy Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number Physiologic Embryonic structures – notochord, thyroglossal duct Post partum uterus Pathologic Disuse atrophy Denervation atrophy Ischemic atrophy Loss of nutrition – Marasmus, cachexia Loss of endocrine stimulation Breast after menopause Pressure atrophy Tumor compressing normal tissue

8. Mechanisms Decreased protein synthesis Increased protein degradation Through proteasomes

9. Metaplasia Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another differentiated cell type. Barret’s esophagus – squamous to columnar Respiratory epithelium – columnar to squamous Mechanism Reprogramming of stem cells that are known to exist in normal tissues.

10. Injury (ALTERED HOMEOSTASIS)

11. Most important organelles involved during cell injury Plasma membrane Mitochondria Nucleus Endoplasmic reticulum

12. Morphology of cell injury

13. Causes of cell injury Hypoxia – lack of blood supply or lack of oxygen Physical agents – Heat, Mechanical trauma Chemical agents – glucose or salt in high concentrations, PCM , poisons Microorganisms causing infections Autoimmunity Genetic derangements – accumulation of damaged DNA can trigger apoptosis Nutritional defects – Anorexia nervosa, Atheroscleosis

14. Mechanisms of cell injury Source: Robbins Textbook of pathology, 10E

15. TIMELINE Source: Robbins Textbook of pathology, 10E

16. Irreversible cell injury NECROSIS – Irreversible cell death caused due to denaturation of proteins and enzymatic digestion of cell. APOPTOSIS - Genetically programmed cell death.

17. Morphology of necrosis The morphology of necrosis can be explained in following tissue patterns Coagulative necrosis Liquefactive necrosis Gangrenous necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis

18. Coagulative necrosis (infarct) Coagulative necrosis is a form of necrosis in which the architecture of dead tissues is preserved. The injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells Cause is mainly Ischemia caused by obstruction in a vessel Source: Robbins Textbook of pathology, 10E

19. Liquefactive necrosis Liquefactive necrosis , in contrast to coagulative necrosis, is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass The necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus Best example is necrosis in brain Source: Robbins Textbook of pathology, 10E

20. Gangrenous necrosis It is a type of coagulative necrosis with superimposed bacterial infection. Best example is a limb, generally the lower leg, that has lost its blood supply Source: Robbins Textbook of pathology, 10E

21. Caseous necrosis Caseous necrosis is encountered most often in foci of tuberculous infection The term “caseous” (cheese like) is derived from the friable white appearance of the area of necrosis Source: Robbins Textbook of pathology, 10E

22. Fat necrosis It refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in acute pancreatitis Source: Robbins Textbook of pathology, 10E

23. Fibrinoid necrosis Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. Deposits of these “immune complexes,” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists. Source: Robbins Textbook of pathology, 10E

24. Source: Robbins Textbook of pathology, 10e

25. Apoptosis Apoptosis occurs normally both during development, throughout adulthood, and serves to remove unwanted, aged, or potentially harmful cells. Physiologic apoptosis Pathologic apoptosis

26. Physiologic apoptosis destruction of cells during embryogenesis Such as endometrial cell breakdown during the menstrual cycle Ovarian follicular atresia in menopause The regression of the lactating breast after weaning Prostatic atrophy after castration Involution of hormone- dependent tissues upon hormone withdrawal

27. Pathologic apoptosis DNA damage - Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA Accumulation of misfolded proteins . Improperly folded proteins may arise because of mutations. Excessive accumulation of these proteins in the ER leads to a condition called ER stress Cell death in certain infections , particularly viral infections. An important host response to viruses consists of cytotoxic T lymphocytes, which induce apoptosis of infected cells Pathologic atrophy in parenchymal organs after duct obstruction , such as occurs in the pancreas, parotid gland, and kidney

28. Morphology Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies, usually by macrophages

29. Apoptosis occur in 3 phases 1. Initiation 2.Execution 3.Removal of dead cells Enzyme involved in apoptosis Caspases Endonuclease Factors involved in apoptosis Pro apoptotic factors ( BH1-3 ) Anti-apoptotic factors ( BH1-4 ) Regulated initiators of apoptosis (BH3-only proteins )

30. Mechanisms of apoptosis

31. Necroptosis It’s a hybrid of necrosis and apoptosis. The cell start as apoptosis and ends as necrosis. Mechanism- apoptosis . Morphological features- necrosis. Also known as programmed necrosis. It is caspase independent process .

32. Pyroptosis Cell death associated with release of IL-1 Microbial products/toxins enter the infected cell. Recognized by NOD like receptors Inflammasome Activation of casp-1 Activation of IL-1 Cause death of infected cell

33. Intracellular accumulations Metabolic derangements lead to accumulation of different substances in the cytoplasm or in organelles or in nucleus

34. Intracellular accumulations Lipid Proteins Hyaline Change Glycogen Pigments Exogenous Endogenous Calcium Dystrophic calcification Metastatic calcification

35. Pathways Source: Robbins Textbook of pathology, 9E

36. Pathologic calcification Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts Types Dystrophic deposition occurs locally in dying tissues it occurs despite normal serum levels of calcium In absence of derangements in calcium metabolism Metastatic deposition of calcium salts in otherwise normal tissues results from hypercalcemia secondary to some disturbance in calcium metabolism.

37. Hayflick limit: normally cells undergo 60-70 cell divisions in entire life span. Telomeres : Telomers are short, repeat sequence of nucleotides at the end of chromosome. With each cell division telomere shortens. Telomere shortening leads to cellular aging . Telomerase : The level of telomere is maintained by an enzyme telomerase. Telomerase inhibits aging(aka immortality gene). Its activity is high in germ cells , stem cells . Low in somatic cell Cellular aging

38. Dystrophic calcification Examples in the atheromas of advanced atherosclerosis develops in aging or damaged heart valves Morphology Gross - fine, white granules or clumps, often felt as gritty deposits Microscopy – intracellular or extracellular, basophilic, amorphous granular, sometimes clumped appearance The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies – In papillary lesions of thyroid, meningiomas etc In asbestosis of the lung, iron and calcium deposition creates dumbbell shaped forms Source: Robbins Textbook of pathology, 10E

39. Metastatic calcification Causes Increased secretion of parathyroid hormone (PTH) with subsequent bone resorption hyperparathyroidism due to parathyroid tumors, and ectopic secretion of PTH-related protein by malignant tumors Resorption of bone tissue primary tumors of bone marrow (e.g., multiple myeloma, leukemia) diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease) Immobilization Vitamin D–related disorders vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor idiopathic hypercalcemia of infancy (Williams syndrome) - characterized by abnormal sensitivity to vitamin D Renal failure which causes retention of phosphate, leading to secondary hyperparathyroidism.

40. Lipid Fatty change Atherosclerosis Xanthomas Cholesterosis Neimann Pick disease type C Source: Robbins Textbook of pathology, 10E

41. Atherosclerosis In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters. Such cells have a foamy appearance (foam cells) Source: Robbins Textbook of pathology, 9E

42. Xanthomas Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons Source: Robbins Textbook of pathology, 9E

43. Cholesterosis This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder Source: Robbins Textbook of pathology, 9E

44. Neimann pick disease type C This lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs

45. Proteins Resorption droplets in proximal renal tubules in proteinuria Russel bodies α1 antitrypsin deficiency Neurofibrillary tangle found in Alzheimer’s Source: Robbins Textbook of pathology, 9E

46. Hyaline Change An alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with hematoxylin and eosin This morphologic change is produced by a variety of alterations and does not represent a specific pattern of accumulation

47. Hyaline Change Intracellular Hyaline Intracellular accumulations of protein, described earlier (reabsorption droplets, Russell bodies, alcoholic hyaline), are examples of intracellular hyaline deposits. Extracellular Hyaline Collagenous fibrous tissue in old scars may appear hyalinized In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the kidney, become hyalinized, resulting from extravasated plasma protein and deposition of basement membrane material

48. Glycogen Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism – Diabetes mellitus/Glycogen storage disorders Source: Robbins Textbook of pathology, 10E

49. Pigments Exogenous Carbon Lipofuscin Melanin Hemosiderin Melanin Homogentisic acid Bilirubin and biliverdin

50. Carbon The most common exogenous pigment is carbon (coal dust), a ubiquitous air pollutant in urban areas. ANTHRACOSIS When inhaled Carbon is picked up by macrophages within the alveoli and is then transported through lymphatic channels to the regional lymph nodes Accumulations of this pigment blacken the tissues of the lungs and the involved lymph nodes. COAL WORKER’S PNEUMOCONIOSIS In coal miners the aggregates of carbon dust may induce a fibroblastic reaction or even emphysema and thus cause a serious lung disease (Chapter 15). TATTOOING is a form of localized, exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the The pigments do not usually evoke any Inflammatory response. Source: Robbins Textbook of pathology, 10E

51. Lipofuscin It is seen in cells undergoing slow, regressive changes and is particularly prominent in the liver and heart of aging patients Tell-tale sign of free radical injury and lipid peroxidation not injurious to the cell or its functions Source: Robbins Textbook of pathology, 10E

52. Hemosiderin Hemosiderin, a hemoglobin-derived, golden yellow to-brown, granular or crystalline pigment derived from iron Under normal conditions small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver, which are actively engaged in red cell breakdown Local excesses of hemosiderin - Common bruise Systemic overload of iron - HEMOSIDEROSIS Hemochromatosis - increased absorption of dietary iron due to an inborn error of metabolism called Hemolytic anemias - premature lysis of red cells leads to release of abnormal quantities of iron Repeated blood transfusions - transfused red cells constitute an exogenous load of iron Source: Robbins Textbook of pathology, 9E

53. Melanin brown-black, pigment formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes

54. Homogentisic acid Black pigment that occurs in patients with alkaptonuria Here the pigment is deposited in the skin, connective tissue, and cartilage, and the pigmentation is known as oochronosis Source: Robbins Textbook of pathology, 10E

55. 4. Protein misfolding and DNA damage Source: Robbins Textbook of pathology, 10E

56. MORPHOLOGY OF REVERSIBLE CELL INJURY Best examples are cellular swelling and fatty change Cellular swelling Cellular swelling is the first manifestation of almost all forms of injury to cells Gross - It causes some pallor, increased turgor, and increase in weight of the organ Light microscopy - small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER Source: Robbins Textbook of pathology, 10E

57. 3. Membrane damage Source: Robbins Textbook of pathology, 10E

58. 2. Influx of calcium Source: Robbins Textbook of pathology, 10E

59. 1. Mitochondrial damage Source: Robbins Textbook of pathology, 10E

60. MECHANISMS

61. Metastatic calcification Principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins All of these tissues excrete acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification

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