Cellular Injury PDF

Cellular Injury Dr. Zainab Abbass Al quraishy Introduction Goals of this presentation…… To be a guide to key features of cell injury/death and apoptosis Outline causes and pathogenesis of cell injury/death and apoptosis Describe the morphological changes of cell injury/death and apoptosi...

Cellular Injury Dr. Zainab Abbass Al quraishy Introduction Goals of this presentation…… To be a guide to key features of cell injury/death and apoptosis Outline causes and pathogenesis of cell injury/death and apoptosis Describe the morphological changes of cell injury/death and apoptosis Cell injury Occurs when Limits of adaptive capability exceeded.1 No adaptive response is possible.2 Cell injury is divided into Reversible.1 Irreversible cell death.2  General considerations…… Cell injury is part of a continuum Degree of injury is a function of –Injury: type, duration, severity –Cell: type, status, adaptability Reversible cell injury occurs when the injurious agent is- ;mild or short lived.the functional and morphologic changes are reversible- although there may be significant structural and functional abnormalities, the injury has not progressed to severe damage of the cellular membranes and nucleus that are.equated with cell death With continuing damage, the injury becomes irreversible,.at which time the cell cannot recover and it dies Types of injurious agents ( causes of cell injury) Hypoxia a- Ischemia b- inadequate oxygenation of.1 blood.c-reduced oxygen carrying capacity of blood.Physical agents: Trauma, burns, irradiation, etc.2.Chemical agents: Poisons, drugs, alcohol, etc.3 Infectious agents.4 Immunological reactions.5 Genetic derangement.6 Nutritional imbalances.7 Aging.8 Factors influencing severity of injury Type and severity of injurious agent.1 Duration of exposure.2 Type of affected cells.3 neurons (highly susceptibility to ischemic - damage) : within 3-5 min myocardial cells-hepatocytes : 30-60 - min (intermediate susceptibility) Skeletal muscles-epidermis-fibroblast (low susceptibility)within - hours Types of insult –Hypoxia (reduced oxygen) Ischaemia –Local –Systemic Hypoxaemia –Inspired oxygen too low –Diffusion barrier abnormal –Insufficient carrying capacity in blood Interference with oxidative phosphorylation –e.g. cyanide poisoning Types of insult -chemical Drugs –e.g. paracetamol overdose Many more –e.g. alcohol, cigarette smoke Types of insult -infections Eukaryotes –Fungi, Protozoa Prokaryotes –Bacteria, Rickettsiae, Chlamydiae Viruses –DNA, RNA Types of insult -Physical Direct Physical Effects -extreme heat or cold results -Sudden changes in pressure -Electrical currents Types of insult –immune Humoral Cell-mediated Types of insult -nutrition Dietary insufficiency Dietary excess Principle structural targets for cell damage Cell membranes –Plasma membrane –Organellar membranes DNA Proteins –Structural –Enzymes Mitochondria –oxidative phosphorylation EXAMPLES OF CELL INJURY AND NECROSIS Ischemic and Hypoxic Injury Ischemia is the most common cause of cell injury in clinical -.medicine Unlike hypoxia, in which energy generation by anaerobic- glycolysis can continue, in ischemia the delivery of the substrates for glycolysis is also interfered with due to cut of.blood supply Consequently, anaerobic energy generation stops in- ischemic tissues. Therefore, ischemia injures tissues faster.than does hypoxia HYPOXIA & ISCHEMIA Loss of ATP Generation failure of many energy-dependent systems of the affected cell, including Paralysis of ion pumps (causing influx of.1 Na+ associated with Water, and exit of K+ leading to cell swelling, and influx of Ca++) Anerobic glycolysis Depletion of.2 glycogen stores with accumulation of lactic acid Reduction in protein synthesis.3  Pathogenesis of cell injury -hypoxia Reversible –Loss of ATP Failure of Na/K pump lead cell swelling –Anaerobic metabolism Increased lactic acid and phosphate lead clumped nuclear chromatin –Reduced protein synthesis Altered metabolism lead abnormal accumulations  Functional consequences may be severe at this stage. For- seconds instance, heart muscle ceases to contract within 60.of coronary occlusion ≠ mean cell death If hypoxia continues - worsening ATP depletion - loss of microvilli and the formation of blebs- the entire cell and its organelles (mitochondria, ER) are markedly swollen, with increased concentrations of water, sodium, and chloride and a decreased concentration of.potassium If oxygen is restored, all of these disturbances are.reversible  Cellular swelling (hydropic change) The affected hepatocytes are distended by accumulated water.that imparts cytoplasmic pallor This is the histologic appearance of hepatic fatty change. The lipid accumulates in the hepatocytes as vacuoles. These vacuoles.have a clear appearance with H&E staining If ischemia persists, irreversible injury and necrosis- ensue which is associated with.severe swelling of mitochondria & lysosomes ,extensive damage to plasma membranes The cell's components are progressively degraded, and there is widespread leakage of cellular enzymes into the.extracellular space -.Massive influx of calcium into the cell may occur -.Death is mainly by necrosis, but apoptosis also occur- The leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum.samples Cardiac muscle, for example, contains a unique enzyme creatine kinase and the contractile.protein troponin.Hepatocytes contain transaminases Irreversible injury and cell death in these tissues are reflected in increased serum levels of such proteins, and measurement of serum levels is.used clinically to assess damage to these tissues  Pathogenesis of cell injury -hypoxia Irreversible –Massive intra-cytoplasmic calcium accumulation –Activation of multiple degradative enzymes –Lethal cell damage  Pathogenesis of cell injury –non-ischaemic Reduced ATP synthesis/mitochondrial damage Loss of calcium homeostasis Disrupted membrane permeability Free radicals Free radicals Highly reactive, unstable chemicals Associated with cell injury in many settings –Chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity, carcinogenesis  Free radicals Free radical generation occurs by…. –Absorption of irradiation e.g. H2O lead to OH , and H –Endogenous normal metabolic reactions e.g. O2- , and H2O2 –Transition metals e.g. Fe+++ –Exogenous toxins e.g. carbon tetrachloride  Free radicals Free radicals are removed by…. –Spontaneous decay –Anti-oxidants E.g. Vitamin E, vitamin A, ascorbic acid, glutathione –Storage proteins e.g. transferrin, ferritin, ceruloplasmin –Enzymes Catalase, superoxide dismutase, glutathione peroxidase  Free radicals Injure cells by….. –Membrane lipid peroxidation Autocatalytic chain reaction –Interaction with proteins Protein fragmentation and protein-protein cross-linkage –DNA damage Single strand breaks (genomic and mitochondrial) Thank you