CELL ADAPTATION ,INJURY AND DEATH.pptx death

CELL ADAPTATION ,INJURY AND DEATH.pptx death

1. CELLULAR ADAPTATIONS DR ATWINE RAYMOND

2. PATHOLOGY FUNDAMENTALS 4 aspects of a disease process: Etiology or Cause Pathogenesis Morphologic changes Functional Abnormalities in Cells ---> Clinical Manifestations

3. INTRODUCTION

4. CELLULAR ADAPTATION Adaptations are reversible functional and structural responses to changes in physiologic states (e.g., pregnancy) and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function. Adaptations are reversible changes in the size, number, metabolic activity, or functions of cells in response to changes in their environment.

5. TYPES OF ADAPTATION HYPERPLASIA HYPERTROPHY ATROPHY METAPLASIA

6. ATROPHY HYPERTROPHY HYPERPLASIA METAPLASIA

7. HYPERTROPHY DEFINITION; Increase in size of cells Increases tissue or organ size and weight Increased synthesis of intracellular structural components produces increased cell size Response to stimuli in cells which have limited capacity to divide

8. Examples of Hypertrophy Physiologic : Increased size of myometrial (uterine smooth muscle) cells in pregnancy (hormonal stimulation) Pathologic : Enlargement of cardiac muscle cells ( myocardiocytes ) in patients under hemodynamic stress (hypertension)

9. Normal muscle Hypertrophied muscle

10. COMPARISON OF NORMAL & HYPERTROPHIED MYOCARDIUM (HP)

11. GRAVID VS. NON-GRAVID UTERUS

12. HYPERPLASIA DEFINITION; Hyperplasia is an increase in the number of cells in an organ or tissue usually increasing tissue/organ mass Hyperplasia occurs in tissues or organs with the capacity to divide Hyperplasia and hypertrophy often occur together Physiological hyperplasia aims to increase the functional capacity or increase tissue mass after damage or partial resection Pathologic hyperplasia is a controlled response to excessive hormonal or growth factor stimulation

13. Examples of Hyperplasia Physiologic: Lactating breast in pregnancy (hormonal stimulation) Liver regeneration after partial resection (compensatory) Pathologic: Thyroid hyperplasia (TSH stimulation) Benign prostatic hyperplasia (androgen stimulation)

14. NON-LACTATING VS. LACTATING BREAST

15. ATROPHY Atrophy is reduced size of organ or tissue due to decreased cell size and number. As with hypertrophy and hyperplasia, atrophy can be physiologic as well as pathologic Physiologic atrophy includes: Disappearance of embryonic structures (thyroglossal duct) Involution of thymus Involution of uterus, post partum Involution of breast, post lactation

16. CELLULAR MECHANISMS of ATROPHY Decreased protein synthesis: reduced metabolic activity Increased protein degradation: Increased autophagy

17. CAUSES OF PATHOLOGIC ATROPHY Failure of endocrine stimulation : endometrial and uterine cervical atrophy after menopause Decreased workload (disuse atrophy) : atrophy of leg muscles in immobilized patient Loss of innervation (denervation atrophy) : leg muscles of paraplegic Decreased blood supply (ischemia) : atrophy of brain downstream from occluded artery Inadequate nutrition : marasmus and cachexia Pressure atrophy (probably ischemic) : Atrophy of normal tissues surrounding expansive tumor mass

18. PRE-MENOPAUSAL VS. POST-MENOPAUSAL ATROPHIC ENDOMETRIUM: PHYSIOLOGIC ATROPHY

19. PATHOLOGIC BRAIN ATROPHY

20. METAPLASIA Reversible change of cells from one adult cell type to another cell type. Metaplasia is an adaptive response to noxious influences allowing the cell to better withstand stressful stimuli at the expense of loss of some function. When persistent, the influences may initiate malignant transformation Most significant metaplasias occur in epithelial cells and are clearly adaptive. Mesenchymal cells can also undergo metaplasia is not so clearly an adaptive response (e.g. bone formation in skeletal muscle—myositis ossificans )

21. METAPLASIA FROM COLUMNAR TO SQUAMOUS EPITHELIUM IN AIRWAY

22. IMPORTANT METAPLASIAS IN EPITHELIAL CELLS Columnar to squamous epithelium: Bronchi of tobacco smokers—may lead to squamous cell carcinoma Nasopharynx and bronchi in chronic upper and lower respiratory tract infection Uterine cervix—may lead to HPV induced squamous cell carcinoma Squamous to columnar epithelium: Lower esophagus due to gastric reflux (Barrett esophagus)—may lead to adenocarcinoma

23. CELL INJURY AND DEATH

24. CELLULAR RESPONSE TO STRESS AND INJURIOUS STIMULI

25. TEST OF REVERSIBILITY DESTINGUISHES ADAPTATION FROM INJURY When stresses or irritants are eliminated, adapted cell may recover original states, injured cells cannot

26. CAUSES OF CELL INJURY-1 HYPOXIA : Oxygen deprivation, especially due to ischemia (decreased blood flow) PHYSICAL AGENTS : Mechanical trauma, temperature extremes, extremes in atmospheric pressure, electric current, radiation CHEMICAL AGENTS AND DRUGS : Hyper/hypotonic electrolyte concentrations, direct toxins, toxic metabolites, environmental pollution, tobacco INFECTIOUS AGENTS : From viruses to helminthes

27. CAUSES OF CELL INJURY-2 Immunologic reactions eg autoimmune Genetic derangements eg down’s syndrome, sickle cell Nutritional imbalances eg PEM, Vit def

28. MECHANISMS OF CELL INJURY Cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity. Consequences of cell injury depend on the type, state, and adaptability of the injured cell(s). Cell injury results from different mechanisms acting on several cellular components.

29. Principle structural targets for cell damage Cell membranes Plasma membrane Organelle membranes DNA Proteins Structural Enzymes Mitochondria Oxidative phosphorylation

30. MECHANISMS OF CELLULAR INJURY Depletion of ATP Damage to mitochondria Influx of calcium with loss of calcium homeostasis Accumulation of oxygen derived free radicals Defects in membrane permeability Damage to DNA and proteins

31. Functional and morphologic consequences of decreased intracellular ATP during cell injury

32. Depletion of ATP Loss of ATP Failure of Na/K pump Anaerobic metabolism Increased lactic acid and phosphate Reduced protein synthesis

33. Depletion of ATP/loss of calcium homeostasis If ATP levels reduced to 5-10% of normal levels: Reduced function of plasma membrane sodium pump Increased rate of anerobic glycolysis Glycogen store depletion, accumulation of lactic acid lowers intracellular pH Failure of Ca2+ pump Further reduction in protein synthesis Irreversible damage to mitochondria and lysosomal membranes  cell death

34. Mitochondrial damage Mitochondria supply ATP Sensitive to nearly all injurious stimuli AND mutations in mitochondrial genes are causes of certain inherited defects Major consequences: Creation of mitochondrial permeability transition pore leading to loss of mitochondrial membrane potential, failure of oxidative phosphorylation, and ATP depletion Formation of reactive oxygen species Proteins normally sequestered in mitochondrial wall may leak into cytosol and initiate cell death pathways

35. Oxygen-derived free radicals (oxidative stress) Highly reactive, unstable chemicals; single unpaired electron Accumulation of free radicals is called oxidative stress Free radicals are removed by: Spontaneous decay, scavenging; Anti-oxidants ( Vitamin E, vitamin A, ascorbic acid, glutathione); Storage proteins ( transferrin, ferritin, ceruloplasmin); Enzymes ( Catalase, superoxide dismutase, glutathione peroxidase) Injure cells by: Membrane lipid peroxidation- Autocatalytic chain reaction; Interaction with proteins- Protein fragmentation and protein-protein cross-linkage; DNA damage- Single strand breaks (genomic and mitochondrial)

36. TYPES OF CELL INJURY Reversible Irreversible

37. Cell injury - morphology Reversible Only few of these visible with light microscope: nuclear & chromatin changes, karyorrhexis, quantity of cytoplasm Irreversible

38. REVERSIBLE CELL INJURY MARKERS Biochemical markers of reversible cell injury : Depletion of adenosine triphosphate (ATP) Changes in ion concentrations and water influx Morphological markers of reversible cell injury Cellular swelling (Light microscopy) Fatty change and membrane blebs (LM) Alterations in shape and integrity of mitochondria, & components of cytoskeleton (Electron microscopy)

39. IRREVERSIBLE CELL INJURY End state of irreversible cell injury: cell death. Cell death has two mechanisms: NECROSIS: Un-programmed destruction of cell structures APOPTOSIS: Programmed disassembly of cell structures

40. NECROSIS Features: Invariably pathologic process Loss of membrane integrity Lysis of cellular contents Leakage of cellular contents Dissolution of nucleus with DNA breakdown Usually an inflammatory response

41. Morphologic changes in reversible cell injury and necrosis.

42. Important terminology in necrosis Pyknosis : Shrinking of chromatin (increased basophilia) Karyorrhexis: Fragmentation of pyknotic nucleus Karyolysis: Fading/dissolution of nucleus

43. Patterns of Tissue Necrosis 1. Coagulative necrosis is a form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days. The affected tissues exhibit a firm texture. Presumably, the injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. A localized area of coagulative necrosis is called an infarct .

44. Coagulative Necrosis: Kidney Infarction

45. 2. 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. It is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells. The necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus .

46. Liquefactive Necrosis: Brain

47. 3. Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly used in clinical practice. It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) When bacterial infection is superimposed there is more liquefactive necrosis because of the actions of degradative enzymes in the bacteria and the attracted leukocytes (giving rise to so-called wet gangrene ).

48. 4. Caseous necrosis is encountered most often in tuberculous infection. The term “caseous” ( cheeselike ) is derived from the friable white appearance of the area of necrosis On microscopic examination, the necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma

49. Caseous necrosis.

50. 5. Fat (saponifying) necrosis 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. In this disorder pancreatic enzymes leak out of acinar cells and liquefy the membranes of fat cells in the peritoneum. The released lipases split the triglyceride esters contained within fat cells. The fatty acids, so derived, combine with calcium to produce grossly visible chalky-white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions

51. Saponifying Fat Necrosis: The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.

52. 6. 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)

53. Fibrinoid necrosis: artery

54. APOPTOSIS Cell death caused by activation of degrading enzymes within the cell itself. Usually physiological process of organized cell removal that can become pathologic: Nuclear dissolution Cell fragmentation Preservation of membrane integrity Rapid removal of the relatively little debris by macrophages (phagocytes) No inflammatory response

55. APOPTOSIS IN PHYSIOLOGIC SITUATIONS Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues. The destruction of cells during embryogenesis Involution of hormone-dependent tissues upon hormone withdrawal , such as endometrial cell breakdown during the menstrual cycle, the regression of the lactating breast after weaning Elimination of potentially harmful self-reactive lymphocytes Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response , and lymphocytes at the end of an immune response .

56. APOPTOSIS IN PATHOLOGIC STATES Cell death by injurious stimuli such as chemotherapeutic drugs, radiation Cell injury in viral disease Atrophy after duct obstruction Graph versus host disease Cell death in tumors

57. NECROSIS APOPTOSIS

58. INTRACELLULAR ACCUMULATIONS AND PIGMENTS Cause of accumulations: Metabolic derangements Nature of substances: Harmless or cytotoxic Normal cellular constituent or abnormal substance which cannot be further degraded

59. INTRACELLULAR ACCUMULATIONS AND PIGMENTS Types of substances: Proteins: e.g. Alpha-1-antitrypsin in liver cells; immunoglobulins in plasma cells Lipids (triglycerides, cholesterol, phospholipids): e.g. triglycerides in fatty liver change; cholesterol esters in gallbladder Glycogen: e.g. Genetic glycogen storage diseases Pigments—exogenous (carbon, tattooing pigments) endogenous (lipofuscin, melanin, hemosiderin)

60. Mechanisms of intracellular accumulations

61. LIPID ACCUMULATIONS STEATOSIS : Accumulation of triglycerides in parenchymal cells (liver, heart, kidney) CHOLESTEROLOSIS: Accumulation of cholesterol in gallbladder or xanthomas of the skin ATHEROSCLEROSIS : Accumulation of cholesterol in smooth muscle cells and macrophages (in vessel walls)

62. HEPATIC STEATOSIS—FATTY LIVER

63. Normal Muscle vs. Muscle in Glycogen Storage Disease

64. PIGMENT DEPOSITION EXOGENOUS (Carbon): First in macrophages ENDOGENOUS : Both in parenchymal cells and macrophages

65. EXOGENOUS CARBON IN PULMONARY MACROPHAGES

66. PIGMENT DEPOSITION: ENDOGENOUS MISPLACED SUBSTANCES & DEBRIS PHYSIOLOGICAL PIGMENTS THAT MAY BE PATHOLOGICALLY MISPLACED * Melanin (brown-black) Primary adrenal insufficiency increasing melanocyte-stimulating hormone * Bilirubin (yellow) Blocked bile ducts increasing retention of bilirubin in hepatocytes (jaundice) PATHOLOGICAL PIGMENTS THAT ARE MADE UP OF CELLULAR DEBRIS * Lipofuscin (brown) made up of lipid fragments * Hemosiderin (yellow) made up of products of hemoglobin catabolism

67. BILIRUBIN IN BILE CANALICULI & HEPATOCYTES

68. LIPOFUSCIN GRANULES: CARDIOMYOCYTES

69. HEMOSIDERIN LADEN MACROPHAGES IN LUNG

70. PATHOLOGIC CALCIFICATION Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts. There are two forms of pathologic calcification. When the deposition occurs locally in dying tissues it is known as dystrophic calcification ; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism. In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification , and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism.

71. DYSTROPHIC CALCIFICATION Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost always present in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function. Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits.

72. DYSTROPHIC CALCIFICATION OF AORTIC VALVE

73. METASTATIC CALCIFICATION Metastatic calcification may occur in normal tissues whenever there is hypercalcemia . Hypercalcemia also accentuates dystrophic calcification. There are four principal causes of hypercalcemia : (1) increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism due to parathyroid tumors, (2) resorption of bone tissue , secondary to primary tumors of bone marrow (e.g., multiple myeloma, leukemia) or diffuse skeletal metastasis (e.g., breast cancer), or immobilization; (3) vitamin D–related disorders , including vitamin D intoxication (4) renal failure ,

74. Metastatic calcification appears primarily in interstitial tissues of: Stomach mucosa Kidneys Lungs Systemic arteries Pulmonary veins

75. METASTATIC CALCIFICATIONS IN GASTRIC MUCOSA, KIDNEY