Cell Injury and Death - Dr. Atikah PDF

Cell injury and death Dr. Noratikah Othman  Overview of cell injury Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities  Reversible Injury In ear...

Cell injury and death Dr. Noratikah Othman  Overview of cell injury Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities  Reversible Injury In early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membrane damage and nuclear dissolution.  Irreversible Injury With continuing damage, the injury becomes irreversible, at w h i ch t i m e t h e ce l l ca nnot recover and it dies. There are two types of cell death—necrosis and apoptosis—which differ in their mechanisms, morphology, and roles in disease and physiology. Necrosis
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Apoptosis NECROSIS CAUSES OF CELL INJURY Most injurious stimuli can be grouped into the following categories: 1. Oxygen Deprivation 2. Chemical Agents 3. Infectious Agents 4. Immunologic Reactions 5. Genetic Factors 6. Nutritional Imbalances 7. Physical Agents 8. Aging 1. Oxygen Deprivation Hypoxia, or oxygen deficiency, interferes with aerobic oxidative respiration and is an extremely important and common cause of cell injury and death. Hypoxia should be distinguished from ischemia, which is a loss of blood supply in a tissue due to impeded arterial flow or reduced venous drainage. oxygen deficiency can also result from inadequate oxygenation of the blood, as in pneumonia, or from reduction in the oxygen- carrying capacity of the blood, as in blood loss anemia or carbon monoxide (CO) poisoning. (CO forms a stable complex with hemoglobin that prevents oxygen binding.) 2. Chemical Agents potentially toxic agents are encountered daily in the environment; these include air pollutants, insecticides, CO, asbestos, and “social stimuli” such as ethanol. Even innocuous substances such as glucose, salt, or even water, if absorbed or administered in excess, can so derange the osmotic environment that cell injury or death results. Agents commonly known as poisons cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the integrity of an enzyme or cofactor that will lead to death. Even oxygen at sufficiently high partial pressures is toxic. 3. Infectious Agents Agents of infection range from submicroscopic viruses to meter-long tapeworms; in between are the rickettsiae, bacteria, fungi, and protozoans. 4. Immunologic Reactions Although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury. Examples are autoimmune reactions against one’s own tissues and allergic reactions against environmental substances in genetically susceptible individuals  5. Genetic Factors Genetic defects may cause cell injury as a consequence of deficiency of functional proteins, such as enzymes in inborn errors of metabolism, or accumulation of damaged DNA. Genetic variations (polymorphisms) contribute to the development of many complex diseases and can influence the susceptibility of cells to injury by chemicals and other environmental insults. E.g: Down syndrome and sickle cell anaemia  6. Nutritional Imbalances nutritional deficiencies remain a major cause of cell injury. Protein calorie insufficiency. specific vitamin deficiencies. disorders of nutrition rather than lack of nutrients are also important causes of morbidity and mortality; for example, obesity markedly increases the risk for type 2 diabetes mellitus. Moreover, diets rich in animal fat are strongly implicated in the development of atherosclerosis as well as may cause cancer. 7. Physical Agents Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells. 8. Aging Cellular senescence leads to alterations in replicative and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to damage and, eventually, the death of cells and of the organism.  The Morphology Of Cell And Tissue Injury 1. Reversible injury 2. Necrosis 3. Patterns of tissue necrosis  The Morphology of Cell and Tissue Injury All stresses and noxious influences exert their effects first at the molecular or biochemical level. Cellular function may be lost long before cell death occurs, and the morphologic changes of cell injury (or death) lag far behind both. For example, myocardial cells become non contractile after 1 to 2 minutes of ischemia, although they do not die until 20 to 30 minutes of ischemia have elapsed.  Reversible injury The two main morphologic correlates of reversible cell injury are: 1. cellular swelling and 2. fatty change. Cellular swelling is the result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis. Fatty change occurs in hypoxic injury and in various forms of toxic or metabolic injury and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. Cause by failure to oxidise fatty acid. Morphologic changes in reversible and irreversible cell injury (necrosis). A: Normal kidney tubules with viable epithelial cells. B: Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. C: Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents. Morphology of Necrosis Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells. Cytoplasmic changes. Necrotic cells show increased eosinophilia (i.e., pink staining from the eosin dye—the E in the hematoxylin and eosin [H&E] stain). Hematoxylin – blue. Bind to RNS or DNA Eosin – red/orange, bind to protein  Nuclear changes. Nuclear changes assume one of three patterns, all due to breakdown of DNA and chromatin. The basophilia of the chromatin may fade (karyolysis), presumably secondary to deoxyribonuclease (DNase) activity. pyknosis, characterized by nuclear shrinkage and increased basophilia. karyorrhexis, the pyknotic nucleus undergoes fragmentation. Patterns of tissue necrosis Liquefactive necrosis Liquefactive necrosis (or colliquative necrosis) is a type of necrosis which results in a transformation of the tissue into a liquid viscous mass. Caseous necrosis Caseous necrosis is encountered most often in foci of tuberculous infection. Caseous means “cheese-like,” referring to the friable yellow- white appearance of the area of necrosis Fat necrosis Fat necrosis refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Summary of cell injury morphology  1. Mechanisms of cell injury 1. Depletion of ATP 2. Influx of Calcium 3. Mitochondrial Damage and Dysfunction 4. Defects in Membrane Permeability 5. Damage to DNA and Proteins 1. Depletion of ATP The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage, and the actions of some toxins (e.g., cyanide). https://www.youtube.com/watch?v=JcGKDDvk5AQ  Significant depletion of ATP has widespread effects on many critical cellular systems: 1. The activity of plasma membrane ATP- dependent sodium pumps is reduced, causing cell swelling and dilation of the ER. 2. There is a compensatory increase in anaerobic glycolysis in an attempt to maintain the cell’s energy sources. lactic acid accumulates, leading to decreased intracellular pH and decreased activity of many cellular enzymes. 3. Failure of ATP-dependent Ca2+ pumps leads to influx of Ca2+, with damaging effects on numerous cellular components, described later. 4. Prolonged or worsening depletion of ATP causes structural disruption of the protein synthetic apparatus, with a consequent reduction in protein synthesis. 2. Mitochondrial Damage and Dysfunction Mitochondrial damage may result in several biochemical abnormalities: ATP depletion failure of energy dependent cellular functions ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis 3. Influx of Calcium depleting extracellular Ca2+ delays cell death after hypoxia and exposure to some toxins. Ischemia and certain toxins cause an increase in cytosolic calcium concentration, initially because of release of Ca2+ from the intracellular stores, and later resulting from increased influx across the plasma membrane. Increased cytosolic Ca2+ activates a number of enzymes, with potentially deleterious cellular effects. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and adenosine triphosphatases (ATPases) (thereby hastening ATP depletion). Increased intracellular Ca2+ levels may also induce apoptosis, by direct activation of caspases and by increasing mitochondrial permeability.  4. Defects in Membrane Permeability The plasma membrane can be damaged by ischemia, various microbial toxins, lytic complement components, and a variety of physical and chemical agents. Several biochemical mechanisms may contribute to membrane damage: Decreased phospholipid synthesis. Increased phospholipid breakdown. Cytoskeletal abnormalities. Activation of proteases by increased cytosolic Ca2+ may cause damage to elements of the cytoskeleton, leading to membrane damage. Lipid breakdown products. Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis Cytoskeleta l 5. Damage to DNA and Proteins Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g., after radiation injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis. Accumulation of damaged DNA and misfolded proteins: triggers apoptosis APOPTOSIS – programmed cell death Apoptosis Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins. Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off”). The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes. Causes of Apoptosis Causes of Apoptosis Morphology of apoptosis cells In H&E-stained tissue sections, the nuclei of apoptotic cells show various stages of chromatin condensation and aggregation and, ultimately, karyorrhexis. at the molecular level this is reflected in fragmentation of DNA into nucleosome- sized pieces. The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytosol and organelles Mechanism of apoptosis Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes Initiated by two major pathways: 1. Mitochondrial (intrinsic) pathway. 2. Death receptor (extrinsic) pathway. 1. Mitochondrial (intrinsic) pathway. is triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress). associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activation. 2. Death receptor (extrinsic) pathway. In the extrinsic pathway, signal molecules known as ligands, which are released by other cells, bind to transmembrane death receptors on the target cell to induce apoptosis. Mechanism of Apoptosis Intrinsic pathway Mechanism of Apoptosis Extrinsic pathway  Mechanism of Apoptosis Activation of caspases & apoptotic cell clearance Autophagy – self- degradation Autophagy Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components. It is a survival mechanism in times of nutrient deprivation, such that the starved cell subsists by eating its own contents and recycling these contents to provide nutrients and energy. Autophagy process 1. In this process, intracellular organelles and portions of cytosol are first sequestered (isolated) within an autophagic vacuole. 2. The vacuole fuses with lysosomes to form an autophagolysosome. 3. The lysosomal enzymes digest the cellular components. INTRACELLULAR ACCUMULATIONS Intracellular accumulation Under some circumstances cells may accumulate abnormal amounts of various substances, which may be harmless or associated with varying degrees of injury. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be synthesized by the affected cells or may be produced elsewhere. There are four main pathways of abnormal intracellular accumulations: 1. Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport, as in fatty change in the liver. 2. Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin. 3. Failure to degrade a metabolite due to inherited enzyme deficiencies. The resulting disorders are called storage diseases. 4. Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration  Cellular Aging Cellular aging is the result of a progressive decline in the life span and functional capacity of cells. Results from combination of accumulating cellular damage (e.g., by free radicals), reduced capacity to divide (replicative senescence), and reduced ability to repair damaged DNA. Several mechanisms are thought to be responsible for cellular aging: 1.Accumulation of DNA damage: defective DNA repair mechanisms; conversely DNA repair may be activated by calorie restriction, which is known to prolong aging in model organisms 2.Replicative senescence: reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres) 3.Other factors: progressive accumulation of metabolic damage; possible roles of growth factors that promote aging in simple model organisms