Cell Injury and Cell Death

Cell Injury If the cells fail to adapt under stress, they undergo certain changes called cell injury. The affected cells may recover from the injury (reversible) or may die (irreversible).

Causes of Cell Injury Oxygen deprivation (hypoxia) Physical agents Chemical agents Infections agents Immunologic reactions Genetic defects Nutritional imbalances

Hypoxia & Ischaemia

Morphology of Cell Injury Reversible: Cellular swelling and vacuoles formation (Hydropic changes) Changes at this stage EM - blebbing of the plasma membrane, swelling of mitochondria and dilatation of ER Nuclear alterations Fatty change

Sequence of events in reversible injury reduced oxidative phosphorylation and ATP production in the mitochondria increased anaerobic metabolism (glycolysis)  reduced glycogen stores and increased production of Lactic acid decreased intracellular pH - clumping of nuclear DNA decreased activity of Na+ pump (ATP-dependent) generalized edema (increased intracellular Na+ and H20) detachment of ribosomes from ER - reduced protein synthesis surface blebs, mitochondrial swelling

Cloudy swelling, Kidney Hydropic change or vacuolar degeneration. Appears whenever cells are incapable of maintaining ionic and fluid homeostasis. The first manifestation of almost all forms of cell injury. Reversible injury.

Fatty Change Hepatic lipid accumulation is characterized by intracellular accumulation of triglycerides, and due to the failure of metabolic removal. Defects in fat metabolism are often induced by alcohol consumption, and also associated with diabetes, obesity, and toxins. Fatty change is most often seen in the liver (and heart), and is generally reversible.

Morphology of Cell Injury Irreversible (Necrosis): The changes are produced by enzymatic digestion of dead cellular elements, denaturation of proteins and autolysis (by lysosomal enzymes) Cytoplasm - increased eosinophilia Nucleus - nonspecific breakdown of DNA leading to pyknosis (shrinkage), karyolysis (fading) and karyorrhexis (fragmentation).

Irreversible Injury disruption of plasma membrane disintegration of DNA, RNA, and phospholipids rupture of lysosomes and leakage of lysosomal enzymes into the cytoplasm  enzymatic digestion of cellular components influx of Ca+2 into the intracellular space

Irreversibility Inability to reverse mitochondrial dysfunction Profound disturbances in membrane function

Reversible Injury: Cellular Swelling, Vacuolar Degeneration, “Hydropic Change” – appearance of clear, vacuolated cytoplasm (due to generalized edema, mitochondrial edema, dispersion of ribosomes, and presence of surface blebs) “Fatty Change” – appearance of lipid vacuoles in the cell cytoplasm Irreversible Injury: binding of eosin to denatured proteins causes increased cytoplasmic eosinophilia  more pink loss of DNA, RNA, glycogen causes decreased basophilia  less blue nuclear changes: karyolysis (faded), karyorrhexis (fragmentation), pyknosis (shrinkage)

MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY Free radicals are chemical species with a single unpaired electron in an outer orbit. Free radicals are highly reactive with cell membranes and nucleic acids. They may by initiated by: absorption of radiant energy enzymatic metabolism of exogenous chemicals or drugs redox reactions of normal metabolism: superoxide anion radical from mitochondria and cytochrome p450 hydrogen peroxide from peroxysome catylases hydroxyl ions from ionization of water transition metals nitric oxide

MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY Free radicals cause: lipid peroxidation of membranes oxidation of proteins DNA damage

Cells can be damaged by a variety of mechanisms. Hypoxia causes loss of ATP production secondary to oxygen deficiency and can be caused by ischemia, cardiopulmonary failure, or decreased oxygen-carrying capacity of the blood. The response of cells can range from adaptation to reversible injury to irreversible injury with cell death. Intracellular sites and systems particularly vulnerable to injury include DNA, ATP production, cell membranes, and protein synthesis. Reversible cell injury is primarily related to decreased ATP synthesis by oxidative phosphorylation, leading to cellular swelling and inadequate protein synthesis. Irreversible cell injury often additionally involves severe damage to membranes, mitochondria, Iysosomes, and nucleus.