Necrosis

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Notes on General Pathology – Apoptosis….By Dr. Ashish V. Jawarkar Contact: [email protected] Website: pathologybasics.wix.com/notes

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)

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cell function

Biochemical alterations

Minutes Ultrastructural changes

Days Light Microscopic Changes

Gross Morphologic Changes

effe

ct

*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 irreversible cell injury Injury *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 Leakage of metabolites (DNAases, RNAases, Proteases etc.)

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O2

- H2O2 OH Super Hydrogen Hydroxyl Oxide Peroxide Radical

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 SOD fenton rn 2. Radiation +Fe2+ 3. Inflammn 4. CCl4 5. Transition metals (Fenton rn#) 6. NO 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

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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+ Lactic acidosis H2O Increased lipid deposition Cellular swelling Clumping of nuclear ER swelling chromatin

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*Morphology REVERSIBLE INJURY NECROSIS GROSS 1. Pallor

2. Turgor 3. Increased weight

Light Microscopy

1. Cellular swelling 2. vacuolar

degeneration/hydropic change – clear vacuoles in cytoplasm that represent pinched off segments of ER

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 3. Nucleus – a. Karyoloysis – lysis of chromatin b. Pyknosis – nuclear shrinkage c. Karyorrhexis – chromatin

condenses into solid shrunken basophilic mass

Ultra structure

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

Plasma membrane – discontinuities Cytoplasm – Myelin figures 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

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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.

Necrosis

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