The document summarizes cellular adaptation and injury. It states that cells can undergo adaptation to achieve a new steady state and preserve viability when faced with physiological stresses, but severe or persistent stress can lead to reversible or irreversible injury. It describes different types of cellular adaptation like atrophy, hypertrophy, hyperplasia and metaplasia. It also discusses various causes of cellular injury like hypoxia, chemicals, infections and genetic factors. The key mechanisms of injury involve defects in membranes, ATP production and protein/DNA integrity.

1. Chapter Two adaptation and injury

2. Adaptation & Cellular Injury : Normal cell is in a steady state “Homeostasis” Cells constantly adjust structure and function to accommodate changing demands and extracellular stress. But within a relatively narrow range of physiologic parameter. Change in Homeostasis due to stimuli - Injury

3. Irreversible Injury (cell death) Reversible Injury adaptation normal When cells encounter physiological stresses or pathological stimuli, they undergo adaptation, achieving a new a steady state and preserving viability. If the adaptive capacity is exceeded, cell injury develops. Within certain limits, injury is reversible. with severe and persistent stress, irreversible injury results.

4. adaptation A state that between normal, unstressed cell and the injured, overstressed cell.

5. General principles 1. The cellular response to injurious stimuli depends on the type of injury.

6. Incomplete occlusion of coronary artery Complete or prolonged occlusion hypertesion Prolonged starvation

7. General principles 2.The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of injured cell.

8. Skeletal muscle accommodates complete ischemia for 2 to 3 hours without irreversible injury. cardiac muscle dies after 20 to 30 minutes. Neuron dies after a few minutes.

9. General principles 3.Cellular function is far before cell death occurs, and the morphologic changes of cell injury(or death) lag far behind both.

11. General principles Cell membrane integrity, critical to cellular ionic and osmotic homeostasis; ATP generation, largely via mitochondrial aerobic respiration; Protein synthesis; Intergrity of the genetic apparatus. 4. four intracellular systems are particularly vulnerable.

16. General biochemical mechanisms Defects in plasma membrane permeability. Oxygen deprivation or generation of reactive oxygen species(free radical). Loss of calcium homeostasis. Mitochondrial damage. Chemical injury Genetic variation

17. Cellular adaptation: Atrophy Hypertrophy Hyperplasia Metaplasia Section A

18. Types of adaptation

19. CELLULAR ADAPTATION Excessive physiologic stresses. Some pathologic stimuli. A new, but altered state preserving the viability of the cell.

20. ATROPHY Decrease in mass of the cell HYPERTROPHY Increase in mass of the cell

21. ATROPHY Inadequate nutrition. Diminished blood supply. Increased compression Loss of innervation. Decreased workload Loss of endocrine stimulation. Aging malnutrational Denervative endocrine Disuse compressive Aging

22. Morphology of atrophy Brown atrophy Reduction in the number of cell organelles. Increase in the number of autophagic vacuoles. Lipofuscin granules (Brown atrophy)

23. Fig 2-5

24. Cerebral atrophy - Alzheimers:

25. Atrophy of Brain The left part of the brain diminishes in size.The gyrus is narrower and the gauge is widen.

30. Hydropic change in ischemic - kidney Microvilli

31. Muscle ischemic atrophy:

36. Hydronephrosis

40. Hormonal hypertrophy : Specific hormonal stimulation Compensatory hypertrophy : Increased functional demand HYPERTROPHY

41. Fig 2-6

44. Heart hypertrophy in hypertension: Left Ventricle

47. HYPERPLASIA

48. HYPERPLASIA Physiologic hyperplasia: Hormonal hyperplasia Compensatory hyperplasia Pathologic hyperplasia: Excessive hormonal stimulation. Effects of locally produced GFs on target cells. female breast and uterus at puberty and pregnancy.

49. Fig 2-1

50. PARTIAL HEPATECTOMY Priming Proliferation Growth lnhibition GROWTH FACTORS AND CYTOKINES HGF TGF-  EGF TNF-  IL-6 Others ADJUVANTS Norepinephrine Insulin Glucagon Thyroid hormone GROWTH INHIBITORS TGF-  Others Growth factors Adjuvanis Matrix degradation

53. Metaplasia One adult cell type is replaced by another. Genetic reprogramming of stem cells. Epithelial and mesenchymal metaplasia.

54. Intestinal glandular epithelium Squamous metaplasia Glandular metaplasia Intestinal metaplasia of gastric epithelia Bronchial epithelia Epithelia in bile duct Cervical epithelia Epithelial metaplasia Columnar epithelium Squamous epithelium Squamous epithelium Gastric glandular epithelium Barrett esophagitis

55. Connective tissue metaplasia Bone metaplasia. cartilige metaplasia. Inmatured fibroblasts Osteocytes Chondrocytes mesenchymal metaplasia

61. significance of metaplasia A two-edged sword An undesirable change Survive but some important protective mechanism is lost. The influences that predispose to such squamous metaplasia, if persistent, may promote cancer transformation in metaplastic epithelium.

62. Cell injury Section B

63. Causes of cell injury and disease Oxygen deprivation ( hypoxia, ischemia) Nutritional imbalances Physical agents Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements

65. HYPOXIA Ischemia ( loss of blood supply ). Inadequate oxygenation ( cardiorespiratory failure ). Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).

66. HYPOXIC INJURY Loss of oxidative phosphorylation and ATP generation by mitochondria. Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis. Depleted glycogen. Reduced intracellular pH: Lactic acid and inorganic phosphate. Clumping of nuclear chromatin.

67. Four biochemical themes Oxygen-derived free radicals. Loss of calcium homeostasis and increased intracellular calcium. ATP depletion. Defects in membrane permeability.

68. PHYSICAL AGENTS Trauma Heat Cold Radiation Electric shock

69. CHEMICAL AGENTS AND DRUGS Endogenous products: urea Exogenous agents: Therapeutic drugs: hormones Nontherapeutic agents: lead or alcohol

70. MECHANISMS OF CHEMICAL INJURY Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport.

71. By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals. MECHANISMS OF CHEMICAL INJURY

72. CCl 4 in SER of liver cell (P-450) – CCl 3 . – lipid peroxidation and autocatalytic reactions – swelling and breakdown of ER, dissociation of ribosome, and decreased hepatic protein synthesis ( loss of lipid acceptor protein – fatty change of liver cell) – progressive cellular swelling, plasma membrane damage, and cell death.

73. FREE RADICAL INITIATION Absorption of energy (UV light and x-rays) Oxidative metabolic reactions Enzymatic conversion of exogenous chemicals or drugs (CCl 4 >CCl 3 . ) Oxygen-derived radicals Superoxide

74. Cell injury caused by free radicals through Peroxidation of lipids. Cross linking proteins by the formation of disulfide bonds. Induction of DNA damage that has been implicated both in cell killing and malignant transformation.

75. INFECTIOUS AGENTS Viruses Rickettsiae Bacteria Fungi Parasites

76. Marfan syndrome Fibrillin, a scaffolding on which tropoelastin is deposited to form elastic fibers. FBN1, 15q21, mutations in Marfan syndrome. FBN2, 5q3, mutations in congenital contractual arachnodactyly. Genetic derangements

77. Adenomatous polyposis coli APC loci, 5q21 Adenomatous polyposis in colons (in teens). 100% malignant transformation (  40ys ). APC protein in the cytoplasm. Several partners, including  -catenin.  -catenin  entering the nucleus  activating transcription of growth-promoting genes. Causing degradation of  -catenin  maintaining low level of  -catenin in the cytoplasm.

78. CELLS REACT TO ADVERSE INFLUENCES ADAPTING SUSTAINING REVERSIBLE INJURY SUFFERING IRREVERSIBLE INJURY AND DYING

79. CELL INJURY AND NECROSIS General mechanisms: Maintenance of the integrity of cell membranes. Aerobic respiration and production of ATP. Synthesis of enzymes and structure proteins. Preservation of the integrity of the genetic apparatus.

81. Irreversible Injury Reversible Injury adaptation normal

82. Types of cell injury reversible irreversible necrosis apoptosis

83. Reversible injury Cellular swelling Fatty change Hyaline change

84. Cellular swelling

86. Excessive entry of free fatty acids into the liver (starvation, corticosteroid therapy). Enhanced fatty acid synthesis. Decreased fatty acid oxidation. Increased esterification of fatty acid to triglycerides (alcohol). Decreased apoprotein synthesis (CCl 4 ). Impaired lipoprotein secretion from the liver (alcohol). FATTY CHANGE

87. Morphology of fatty change Sudan III, Oil red O, Osmic acid Liver Heart Kidney

90. Intracellular hyaline changes Hyaline degeneration of arterioles Hyaline degeneration of connective tissue Hyaline changes (degeneration)

91. Absorption of protein causing hyaline droplets in proximal epithelial cells in the kidney. Russel bodies in plasma cells. Viral inclusions in the cytoplasm or the nucleus. Masses of altered intermediate filaments (Mallory bodies). Intracellular hyaline changes

96. Hyaline change of the central artery of the spleen (spleen of hypertension disease) The narrowing of the lumina with thickened vessel wall. Homogeneous pink hyaline material deposits under the intima.

97. Mucoid Degeneration mucopolysaccharide deposition in the stroma of connective tissue.

98. mucoid degeneration

99. A heterogeneous group of pathogenic fibrillar proteins accumulating in tissues and organs. Excess synthesis Resistance to catabolism AMYLOIDOSIS

101. Chemical nature of amyloid fibrils Two major forms: AL (amyloid light chain protein) AA (amyloid-associated protein): Derived from serum AA (12kd) synthesized in liver and elevated in inflammatory states.

102. Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.

103. Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.

104. Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.

105. Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.

106. primary (B-cell dyscrasia, AL) Secondary or reactive (AA): Collagen diseases, bronchiectasis, chronic osteomyelitis. Hemodialysis-related: Beta-2-microglobulin deposition. Hereditary (AA) Clinical forms of amyloidosis Systemic amyloidosis:

107. Nodular (tumor-forming deposits, B-cell dyscrasia, AL) Endocrine amyloidosis (procalcitonin) Amyloidosis of aging: Heart, lung, pancreas, spleen, brain. Localized amyloidosis

109. Exogenous: Carbon Tattooing Endogenous: Lipofuscin Melanin Hemosiderin Bilirubin Pigmentation

116. Dystrophic calcification Metastatic calcification Pathologic calcification

117. Necrotic tissues Atheroma Damaged heart valves Dystrophic calcification

118. Fig 2-13

120. Increased secretion of parathyroid hormone Destruction of bone tissue Vitamin D-related disorders: Sarcoidosis Renal failure Metastatic calcification Hypercalcimia

121. Metastatic calcification Affecting Interstitial tissue of gastric mucosa Kidneys Lungs Pulmonary veins Systemic arteries

122. Section C CELL DEATH

123. TYPES OF CELL DEATH necrosis Coagulation necrosis Caseous necrosis Gangrene Liquefaction necrosis( fat necrosis) Fibrinoid necrosis Apoptosis

124. Swelling, denaturation and coagulation of proteins Breakdown of cellular organelles Cell rupture Common type of necrosis after exogenous stimuli.

125. NECROSIS The sum of the morphologic changes that follow cell death in living tissue and organ: Denaturation of proteins. Enzymatic digestion of organelles and cytosol.

126. Enzymatic digestion by lysosomal enzymes of the dead cells themselves. AUTOLYSIS HETEROLYSIS Digestion by lysosomal enzymes of immigrant leukocytes.

127. Nucleus changes : The hallmarks of cell death in three patterns: Basic Pathologic Change of Necrosis Normal cell Chromatin margination karyorrhexis pyknosis karyolysis Nuclear Alteration of Necrosis

128. 1)Three pattern of nuclear changes Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of pyknotic nucleus)

129. Pyknosis : nuclear shrinkage and increased basophilia, and the DNA apparently condenses into a solid, shrunken basophilic mass.  Karyorrhexis: nucleus undergoes fragmentation, scattered about the cytoplasm. Karyolysis: the basophilia of the chromatin may fade and the nucleus disappears.

131. Cytoplasm change: increased eosinophilium and a more glassy homogeneous appearance and even vacuolated cytoplasm. The Necrosis of heptocytes

132. Types of Necrosis Coagulative Necrosis Liquefactive Necrosis Fibrinoid Necrosis Necrosis Gangrenous Necrosis

133. Morphologic appearance of necrosis Increased eosinophilia: Loss of RNA in the cytoplasm Increased binding of eosin to denatured cytoplasmic protein More glassy homogeneous appearance Loss of glycogen particles Vacuolated and moth-eaten cytoplasm Calcification of necrotic cells

134. Coagulation necrosis Denatures of both structural and enzymatic proteins by injury or the subsequent increasing intracellular acidosis.

135. Renal Infarction - Coagulative

136. Splenic Infarction - Coagulative necrosis

137. Infarction - Adrenal gland:

139. Caseous necrosis A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue architecture

140. Caseous necrosis of kidney The necrosis area is soft, white-yellow cheesy appearance.

142. Extensive Caseous necrosis Tuberculosis

144. Liquefactive necrosis Bacterial or fungal infections Central nervous system Amebiasis

145. Liver abscess: Liquifactive necrosis

146. Stroke- Liquifactive necrosis

149. Fat necrosis Traumatic Activated pancreatic lipases

150. Fat necrosis(Steatonecrosis) Only shadowy outlines of necrotic fat cells may be seen, with basophilic calcium deposits and a surrounding inflammatory reaction.

151. Fibrinoid degeneration Deeply eosinophilic Collagen diseases Necrotic vasculitis Malignant hypertension

152. Fibrinoid Necrosis homogeneous, deeply eosinophilic in necrosis.

153. Gangrene A subtype of coagulation necrosis Dry gangrene Wet gangrene Gas gangrene

154. Caseous necrosis - Tuberculosis

155. Gangrene - Amputated Diabetic foot

158. Gangrene Intestine - Thrombosis.

160. Absorption Discharge: Erosion Ulcer Sinus Fistula Cavitation Organization Encapsulation Calcification Fates of necrosis

167. Section D APOPTOSIS

168. APOPTOSIS (Programmed cell death) Programmed destruction of cells during embryogenesis. Hormone dependent involution of tissues in the adult. Cell deletion in proliferating cell popula- tions (intestinal crypt epithelium), tumors, and lymphoid organs.

169. Pathologic atrophy in parenchymal organs after duct obstruction. Cell death by cytotoxic T cells. Cell injury in certain viral diseases. Cell death produced by a variety of injurious stimuli given in low doses (e.g. mild thermal injury).

170. MORPHOLOGICAL FEATURES OF APOPTOSIS Cell shrinkage Chromatin condensation and fragmentation. Formation of cytoplasmic blebs and apoptotic bodies. Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages. Lack of inflammation.

171. Necrosis Apoptosis Stimuli Hypoxia Physical Toxins Pathological Histology Cell swelling Single cell Coagulation N Chromatin Disruption of condensation organelles Apoptotic bodies DNA Random Internucleosomal breakdown Diffuse

172. Necrosis Apoptosis Mechanism ATP depletion Gene activation Membrane Endonuclease injury Free radicals Tissue Inflammation No inflammation reaction Phagocytosis of apoptotic bodies

173. Fig 1-18

175. Biochemical features of apoptosis 1.PROTEIN CLEAVAGE: Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein 2.PROTEIN CROSS-LINKING: Transglutaminase Cytoplasmic protein  shrunken shalls  apoptotic bodies Biochemical features of apoptosis

176. 3. DNA breakdown: 50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in necrosis) 4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the surface components (phosphatidylserine, thrombospondin) on apoptotic bodies.

177. Fig 1-19

178. Apoptosis-associated genes bcl-2, c-myc, p53

179. Fig 1-20

180. Occuring conditions during embryogenesis and development; as a homeostatic mechanism to maintain normal cell populations of tissue in the face of cell turnover; as a defense mechanism such as in immune reactions; when cells are damaged by diseases or noxious agents, such as injury, tumors and inflammation; reduction cell during atrophy; in aging.

181. Morphologic features Cell shrinkage. Chromatin condensation Apoptotic bodies formation Phagocytosis of apoptotic bodies by adjacent cells or macrophages. Intacted membrane. Morphology Biochemistry of Apoptosis

182. A specific biochemical feature breakdown of DNA into large 180 to 200-kilobase pieces, by Ca 2+ /Mg 2+ dependent endogenous nucleases.

183. normalcell Cellular swelling, chromatin cluping Membrane damage Nuclear chromatin condensation and fragmentation Cytoplasmic budding and apoptosisi body Phagocytosisi of apoptosis body The sequential ultrastructual changes in necrosis and apoptosis

184. Apotosis of hepatocytes

185. Comparison of cell death by apoptosis and necrosis

186. Terminology: Necrosis: Morphologic changes seen in dead cells within living tissue. Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen) Apoptosis: Programmed cell death. Physiological, for cell regulation.

187. Types of Necrosis: Coagulative – Eg. Infarction Liquifactive - Brain, abscess Fibrinous - colleagen Caseous - Bacterial / Tuberculosis Gangrene - With infection

188. Ageing: “ Progressive time related loss of structural and functional capacity of cells leading to death” Senescence, Senility, Senile changes. Ageing of a person is intimately related to cellular ageing.

189. Factors affecting Ageing: Genetic – Clock genes, (fibroblasts) Diet – malnutrition, obesity etc. Social conditions - Diseases – Atherosclerosis, diabetes etc. Werner’s syndrome.

190. Cellular mechanisms of ageing Cross linking proteins & DNA. Accumulation of toxic by-products. Ageing genes. Loss of repair mechanism. Free radicle injury Telomerase shortening.

191. Telomerase in ageing: Germ Cells Somatic Cells

192. Ageing –changes: Gradual atrophy of tissues and organs. Dementia Loss of skin elasticity Greying and Loss of hair BV damage – atherosclerosis/bruising. Loss of Lens elasticity  opacity  vision Lipofuscin pigment deposition – Brown atrophy in vital organs.

193. Pathology of elderly

194. Factors affecting ageing: Stress Infections Diseases Malnutrition Accidents Diminished stress response. Diminished immune response. Good health.

195. Conclusions: Cellular Injury - Various causes Reversible Injury  Adaptations Hypertrophy, Hyperplasia, Atrophy Accumulations - Hydropic, hyaline, fat.. Irreversible Injury - Necrosis Coagulative, Liquifactive, Caseous Ageing - Causes, Changes, Factors