But to those who believe and do deeds of righteousness, He will give their (due) rewards, and more, out of His bounty: But those who are disdainful and arrogant, He will punish with a grievous penalty; Nor will they find, besides God, any to protect or help them. [004:173] Today’s Quranic verse

CELL INJURY

Principles of Cell Injury Dependent upon the etiology, duration, and severity of the inciting injury Dependent upon the etiology, duration, and severity of the inciting injury Dependent upon cell type, stage of cell cycle, and cell adaptability Dependent upon cell type, stage of cell cycle, and cell adaptability Cellular membranes, mitochondria, endoplasmic reticulum, and the genetic apparatus are particularly vulnerable Cellular membranes, mitochondria, endoplasmic reticulum, and the genetic apparatus are particularly vulnerable Injury at one focus often has a cascade effect Injury at one focus often has a cascade effect Morphologic reactions occur only after critical biochemical (molecular) damage Morphologic reactions occur only after critical biochemical (molecular) damage

Normal cell is in a steady state “Homeostasis” Change in Homeostasis due to stimuli - Injury Response to Injury – Reversible (adaptation)/ Irreversible (cell death) Adaptive Responses: –Atrophy –Hypertrophy –Hyperplasia –Metaplasia

Reversible vs. Irreversible Injury Cell injury is a continuum, and it is not possible to identify the exact point at which injury becomes irreversible. Cell injury is a continuum, and it is not possible to identify the exact point at which injury becomes irreversible. However, some ultrastructural and light microscopic changes are associated with each form of injury. However, some ultrastructural and light microscopic changes are associated with each form of injury. Once an irreversible injury occurs, the cell undergoes necrosis, which is the light-microscopic hallmark of cell death. Once an irreversible injury occurs, the cell undergoes necrosis, which is the light-microscopic hallmark of cell death.

In general, permanent organ injury is associated with the death of individual cells. In general, permanent organ injury is associated with the death of individual cells. By contrast, the cellular response to persistent sub-lethal injury, whether chemical or physical, reflects adaptation of the cell to a hostile environment. These changes are, for the most part, reversible on discontinuation of the stress” By contrast, the cellular response to persistent sub-lethal injury, whether chemical or physical, reflects adaptation of the cell to a hostile environment. These changes are, for the most part, reversible on discontinuation of the stress” If the acute stress to which a cell must react exceeds its ability to adapt, the resulting changes in structure and function lead to the death of the cell If the acute stress to which a cell must react exceeds its ability to adapt, the resulting changes in structure and function lead to the death of the cell

Causes of Cell Injury Hypoxia Hypoxia Physical agents including Radiations Physical agents including Radiations Chemicals and Drugs Chemicals and Drugs Microbiologic Agents Microbiologic Agents Immunologic Reactions Immunologic Reactions Genetic Defects Genetic Defects Nutritional Imbalances Nutritional Imbalances

Mechanisms of Cell Injury

Ischemia/Hypoxia Ischemia/Hypoxia Activated Oxygen Species(O 2.-, H 2 O 2, OH. ) Activated Oxygen Species(O 2.-, H 2 O 2, OH. ) –Radiation –Inflammation –Oxygen toxicity –Chemicals –Reperfusion injury OthersChemicals Infectious agents Mechanical disruption Deficiency of essential metabolites Damage to DNA

MECHANISMS OF CELL INJURY

ISCHEMIC AND HYPOXIC INJURY

Reversible Injury - Decreased oxidative phosphorylation reduced ATP reduced ATP increased cytosolic free calcium increased cytosolic free calcium reduced activity of “sodium pump” reduced activity of “sodium pump” accumulation of sodium by cell accumulation of sodium by cell is-osmotic gain of water (swelling) is-osmotic gain of water (swelling) diffusion of potassium from cell diffusion of potassium from cell

- Increased Cytosolic Calcium (activates enzymes) ATPase ATPase decreased ATP decreased ATP Phospholipase Phospholipase decreased phospholipids decreased phospholipids Endonuclease Endonuclease nuclear chromatin damage nuclear chromatin damage Protease Protease disruption of membrane and cytoskeletal proteins disruption of membrane and cytoskeletal proteins

- Increased anaerobic glycolysis glycogen depletion glycogen depletion lactic acid accumulation lactic acid accumulation accumulation of inorganic phosphates accumulation of inorganic phosphates reduced intracellular pH reduced intracellular pH

- Detachment of ribosomes reduced protein synthesis reduced protein synthesis - Worsening mitochondrial function - Increasing membrane permeability - Cytoskeleton dispersion loss of microvilli loss of microvilli formation of cell surface bl ebs formation of cell surface bl ebs

Reversible Injury results in –Swelling of mitochondria, endoplasmic reticulum, and entire cells

Irreversible Injury –Mitochondrial changes severe vacuolization severe vacuolization amorphous calcium-rich densities amorphous calcium-rich densities –Extensive plasma membrane damage –Prominent swelling of lysosomes –Massive influx of calcium (on reperfusion) –Continued loss of cell proteins, coenzymes, ribonucleic acids and other metabolites –Leakage of enzymes measured in serum

–Injury to lysosomal membranes leakage of degradative enzymes leakage of degradative enzymes –activation of acid hydrolases due to reduced intracellular pH with degradation of cell components –Prominent leakage of cellular enzymes –Influx of macromolecules from interstitium –“Myelin figures”-whorled phospholipid masses

FREE RADICAL MEDIATION OF CELL INJURY

Free Radical Injury Contributes to: Free Radical Injury Contributes to: –Chemical and radiation injury –Oxygen and other gaseous toxicity –Cellular aging –Microbial killing by phagocytic cells –Inflammatory damage –Tumor destruction by macrophages –Others

Definition Of Free Radicals Definition Of Free Radicals –Extremely unstable, highly reactive chemical species with a single unpaired electron in an outer orbital Examples Of Free Radicals Examples Of Free Radicals –OH., H., O 2.-

Source of Free Radicals Source of Free Radicals –Hydrolysis of water into OH. and H. by ionizing radiation –Redox reactions in normal physiology respiration respiration intracellular oxidase action intracellular oxidase action transition metal reactions transition metal reactions –Metabolism of exogenous chemicals

Free Radical Injury Mechanisms Free Radical Injury Mechanisms –Lipid peroxidation of membranes double bonds in polyunsaturated lipids double bonds in polyunsaturated lipids –Lesions in DNA reactions with thymine with single-strand breaks reactions with thymine with single-strand breaks –Cross-linking of proteins sulfhydryl-mediated protein cross-linking sulfhydryl-mediated protein cross-linking

Free Radical Degradation Free Radical Degradation –Unstable with spontaneous decay –Decay accelerated by superoxide dismutase superoxide dismutase glutathione glutathione Catalase Catalase –Antioxidants (vitamin E, ceruloplasmin) block formation or scavenge block formation or scavenge

CHEMICAL INJURY

Can cause: Injury to cell membrane and other cell structures Injury to cell membrane and other cell structures Block enzyme pathways (e.g cyanide) Block enzyme pathways (e.g cyanide) Coagulate cell proteins Coagulate cell proteins Upset concentration gradients and pH Upset concentration gradients and pH Direct action or Conversion to reactive toxic metabolite

RADIATION INJURY

Causes: Immediate cell death Interuption of cell replication (cancer cells) Mutation (thymidine dimers) Non-ionizing radiations can cause thermal injury

BIOLOGICAL AGENTS CAUSING INJURY

Viral injury Direct cytotoxicity Direct cytotoxicity Indirect cytotoxicity, via the immune system (activated killer T cells identify viral proteins on the cell surface and kill the cell) Indirect cytotoxicity, via the immune system (activated killer T cells identify viral proteins on the cell surface and kill the cell) Bacterial injury Mostly due to their metabolic products & secretions Mostly due to their metabolic products & secretions Host inflammatory reaction Host inflammatory reaction