Overview of Cell Injury and Cell Death Reversible Cell Injury • Hallmarks: – Reduced oxidative phosphorylation resulting in depleted ATP – Cellular swelling caused by changes in ion concentrations and water influx Cell Death • With continuing damage, injury becomes irreversible, leading to cell death. • Principal types: – Necrosis – Apoptosis Necrosis • “Accidental” and unregulated type of cell death • Damage to cell membranes and loss of ion homeostasis • Cellular contents leak into the extracellular space, eliciting inflammation • Always a pathologic process Apoptosis • When the cell’s DNA or proteins are damaged beyond repair, the cell kills itself • Characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of cell debris • No inflammatory reaction Apoptosis • Highly regulated process driven by a series of genetic pathways • “Programmed cell death” • Serves many normal functions • Not necessarily associated with cell injury Causes of Cell Injury Oxygen Deprivation • Hypoxia – Oxygen deficiency – Causes cell injury by reducing aerobic oxidative respiration Oxygen Deprivation • Hypoxia – Due to: • Reduce blood flow (ischemia) • Inadequate oxygenation (cardiorespiratory failure) • Decreased oxygen carrying capacity (anemia) • Severe blood loss Oxygen Deprivation • Depending on severity, cells may: – Adapt – Undergo injury – Die Physical Agents • Mechanical trauma • Extremes of temperature – Burn – Deep cold • Sudden changes in atmospheric pressure • Radiation • Electric shock Chemical Agents, Drugs • Too many to compile! • Simple chemicals like glucose and salt • Oxygen at high concentrations • Trace amounts of poison like arsenic and cyanide Chemical Agents, Drugs • Pollution, insecticides, herbicides • Carbon monoxide, asbestos • Alcoholic beverage • Therapeutic drugs Infectious Agents • From viruses to tapeworms • Rickettsiae, bacteria, fungi and other parasites Immunologic Reactions • Immune System: defense against infectious pathogens but may also cause cell injury in the process • Autoimmune disease Genetic Derangements • Extra chromosome: Down Syndrome • Base pair substitution: Sickle cell • Deficiency of functional proteins: inborn errors of metabolism • Polymorphisms Nutritional Imbalances • Protein-calorie deficiencies • Vitamin deficiencies • Self-imposed (bulemia, anorexia nervosa) • Nutritional excess Mechanisms of Cell Injury Depletion of ATP • Fundamental cause of necrotic cell death • Produced in two ways: – Oxidative phosphorylation (major) • Oxygen reduction in mitochondria – Glycolytic pathway • In the absence of oxygen using glucose Mitochondrial Damage • Supply ATP • Critical in cell injury and cell death • Can be damaged by: – Increases in cytosolic Ca2+ – Reactive oxygen species (ROS) – Oxygen deprivation – Mutations in mitochondrial DNA Influx of Calcium and Loss of Calcium Homeostasis • Cytosolic free calcium is normally maintained at ~0.1 umol – Extracellular at 1.3 mmol • Most intracellular calcium sequestered in mitochondria and ER • Increased in calcium: – Released from calcium stores – Influx across plasma membrane Oxidative Stress • Accumulation of oxygen-derived free radicals (reactive oxygen species) – Have a single unpaired electron – Highly reactive with adjacent molecules (organic and inorganic chemicals) • Proteins, lipids, carbohydrates, nucleic acids – Convert molecules into reactive species Defects in Membrane Permeability • Early loss of selective membrane permeability, leading ultimately to overt membrane damage • Consistent feature of cell injury (except apoptosis) • Mitochondrial, plasma and lysosomal membranes Damage to DNA and Proteins • Cells have mechanisms to repair DNA damage, however, when damage is too severe to be corrected, the cell initiates a suicide program APOPTOSIS Morphologic Alterations in Cell Injury Reversible Cell Injury • Under the light microscope: – Cellular swelling • Occurs when cells are incapable of maintaining ionic and fluid homeostasis – Fatty change • Lipid vacuoles appear in the cytoplasm • Occurs in cells involved/dependent on fat metabolism Cellular Swelling • First manifestation of almost all forms of injury to cells • Difficult to appreciate in LM more evident in gross of whole organ – Pallor – Increaser turgor – Increase in weight Cellular Swelling • Microscopy: – Small clear vacuoles in the cytoplasm • Distended/pinched-off segments of ER • Hydropic change or vacuolar degeneration – Increased eosinophilic staining Ultrastructural Changes of Reversible Cell Injury • Plasma membrane alterations (blebbing, blunting, loss of microvilli) • Mitochondrial changes (swelling, appearance of small amorphous densities) • Dilation of the ER, with detachment of polysomes) • Nuclear alterations (disaggregation of granular and fibrillar elements) Irreversible Injury • Inability to reverse mitochondrial dysfunction • Profound disturbances in membrane function Necrosis • The result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell • Necrotic cells are digested by their own lysozymes plus the lysozymes of leukocytes Necrosis • On electron microscopy: – Discontinuities in plasma and organelle membranes – Marked dilation of mitochondria – Intracytoplasmic myelin figures – Amorphous debris – Aggregates of fluffy material (denatured protein) Patterns of Tissue Necrosis Coagulative Necrosis • Architecture of dead tissues is preserved for some days • Firm texture • Injury denatures structureal proteins and enzymes NO proteolysis – Eosinophilic, anucleate cells • Removed by phagocytosis • Localized area: INFARCT • Seen in all organs except brain Liquefactive Necrosis • Characterized by digestion of dead cells • Liquid viscous tissue mass • Focal bacterial/fungal infections • Creamy yellow “pus” due to dead leukocytes • Seen in CNS infarcts Gangrenous Necrosis • Not a specific pattern of death, but used in clinical practice • Usually applied to a limb that has lost its blood supply leading to coagulative necrosis of multiple tissue planes • Wet gangrene: with superimposed bacterial infection (C. perfringens) Caseous Necrosis • Most often in tuberculous infection • “Cheese-like” • Friable white appearance • Granuloma: area of amorphous granular necrosis enclosed by a distinctive inflammatory border Fat Necrosis • Does not denote a specific pattern of necrosis • Refers to focal areas of fat destruction • E.g. Acute pancreatitis • Fat saponification: fatty acids combine with calcium • Microscopic: outlines of necrotic fat cells with basophilic calcium deposits surrounded by inflammation Fibrinoid Necrosis • Special form usually seen in immune reactions in blood vessels • Typically occurs when complexes of antigens and antibodies (“immune complexes”) are deposited in the arterial walls • Together with leaked fibrin, appears bright pink and amorphous “fibrin-like” See you next week (Prepare for a quiz) Topics: APOPTOSIS AUTOPHAGY INTRACELLULAR ACCUMULATIONS PATHOLOGIC CALCIFICATION CELLULAR AGING INFLAMMATION AND REPAIR