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General Pathology Notes (Robbins)

By Dr. Ashish Jawarkar Chapter 1 : CELLULAR RESPONES TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY AND CELL DEATH

TOPIC 2. CELL INJURY AND NECROSIS Overview 1. definition 2. types reversible, irreversible (necrosis,apoptosis) 3. causes 4. timeline 5. Mechanisms of cell injury (necrosis) 6. morphology 7. necrosis vs apoptosis 8. patterns of necrosis 9. molecular basis

*definition and types Cells exposed to stress

Adaptation (hypertrophy/hyperplasia/atrophy/metaplasia)

Continued stress, no more adaptation possible

Cell injury

Reversible cell injury

Irreversible cell injury (necrosis & apoptosis)

Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

*Causes of cell injury 1. O2 deprivation, nutritional imbalances 2. Physical agents trauma, heat, cold, UV light, shock 3. Chemical agents cyanide, arsenic, pollutants 4. Infectious agents 5. Deranged immunity *Timeline

Reversible Injury
cell function
effect

irreversible cell injury

Biochemical alterations Days Light Microscopic Changes

Minutes Ultrastructural changes

Gross Morphologic Changes

*Mechanisms of Cell injury (Necrosis) 1. Damage to membranes (plasma, lysosomal,mitochondrial) 2. Failure of calcium pump 3. Accumulation of free radicals 4. Mitochondrial membrane damage and depletion of ATP 5. Protein misfolding and DNA damage 1. Damage to membranes Plasma membrane damage Lysosomal membrane damage

Osmotic imbalance Leakage of metabolites

leakage of (DNAases, RNAases, Proteases etc.)

Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

2. Failure of Ca2+ pump

Calcium influx

Activation of leaked enzymes (DNAases, RNAases)

Alteration of mitochrondrial Membrane permeability

3. Accumulation of free radicals Generation of free radicals ROS

1. Redox rns in Normal metabol 2. Radiation 3. Inflammn 4. CCl4 5. Transition metals (Fenton rn#) 6. NO

O2Super Oxide

SOD

H2O2 Hydrogen Peroxide

fenton rn +Fe2+

OH Hydroxyl Radical

FENTON RN H202 + Fe2+

Fe3+ + OH + OH-

MITOCHONDRIA

Removal of free radicals done by 1. SOD (superoxide dismutase) mitochondria 2. Glutathione peroxidase mitochondria 3. Catalase peroxisome Pathologic effects of ROS 1. Fatty acid oxidation and disruption of membranes, organelles 2. Protein oxidation and loss of enzyme activity, protein misfolding 3. DNA oxidation and mutations and breaks

Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

4. Mitochondrial membrane damage and depletion of ATP Mitochondrial membrane damaged by 1. increased cytosolic calcium 2. ROS 3. hypoxia 4. mutations in mito genes Activation of caspases (apoptosis) Due to leakage of cyto c

Alteration of mitochondrial membrane permeability Due to leakage of H+

H+ leakage and Loss of membrane potential

Decreased Oxidative Phosphorylation

Decreased ATP generation

Detachment of Ribosomes

Failure of Na+ pump

Increased anaerobic Glycolysis

Decreased protein synthesis

Influx of Na +, Ca2+ H2O Cellular swelling ER swelling

Lactic acidosis

Increased lipid deposition

Clumping of nuclear chromatin

Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

*Morphology

GROSS

Light Microscopy

REVERSIBLE INJURY 1. Pallor 2. Turgor 3. Increased weight 1. Cellular swelling 2. vacuolar degeneration/hydropic change clear vacuoles in cytoplasm that represent pinched off segments of ER

NECROSIS

1. Cytoplasm a. eosinophilia due to loss of cytoplasmic RNA b. Glassy appearance due to loss of glycogen particles c. Moth eaten app due to vacuolation 2. Cell membrane a. Myelin figures membrane fragments collect in cytoplasm b. Calicification of myelin figures Nucleus Karyoloysis lysis of chromatin Pyknosis nuclear shrinkage Karyorrhexis chromatin condenses into solid shrunken basophilic mass Plasma membrane discontinuities Cytoplasm Myelin figures 3. a. b. c.

Ultra structure

Plasma membrane blebs, loss of microvilli Nucleus disaggregation of granular and fibrillar elements ER dilatation and detachment of ribosomes Mitochondria amorphous densities

Mitochondria - Large amorphous densities

*Patterns of tissue necrosis 1. COAGULATIVE NECROSIS Gross: The tissue is firm. Eg of localized coagulative necrosis is infarct. Microscopy: preserved cell outlines, loss of nuclei, inflammatory infiltrate 2. CASEOUS NECROSIS (cheese like, in TB) Gross: friable white app of necrotic area
Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

Microscopy: Granuloma central necrosis with lysed cells forming amorphous debris, surrounded by inflammatory cells and epithelioid cells 3. LIQUEFACTIVE NECROSIS (necrosis in CNS) Characterized by digestion of dead tissue transformation into liquid viscous mass Gross: Abscess cavity formation with ragged margins Microscopy: Necrotic material is creamy yellow containing dead leucocytes 4. GANGRENOUS NECROSIS 1. coagulative necrosis occurring in a limb that has lost its blood supply 2. occurs in multiple tissue planes 3. superimposed bacterial infection causes liquifactive necrosis wet gangrene 5. FAT NECROSIS Refers to focal areas of fat destruction occurring due to release of pancreatic enzymes into substance of pancreas and peritoneal cavity Seen in acute pancreatitis Gross: Pancreatic enzymes liquefy membranes of fat cells in peritoneum, split triglycerides, produce saponification and deposition of calcium, chalky white areas Microscopy: shadowy outlines of fat cells, basophilic calcium deposits, inflammatory reaction 6. FIBRINOID NECROSIS Seen in immune reactions like SLE and other vasculitic syndromes Seen in the wall of blood vessels Microscopy: The wall of the vessels show circumferential bright pink areas of necrosis and inflammation. Its basically immune complex deposition with extravasated fibrin.

Notes on General Pathology Apoptosis.By Dr. Ashish V. Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes