Cell Injury - Pathology Lecture Notes PDF

Cell injury mechanism of disease module Session one. Prof. Dr. Hadeel karbal  Objectives. At the end of this lecture you should be able to: 1. Definitions of cell injury and cell death 2. The causes of cell injury and death 3. Cellular events associated with ce...

Cell injury mechanism of disease module Session one. Prof. Dr. Hadeel karbal  Objectives. At the end of this lecture you should be able to: 1. Definitions of cell injury and cell death 2. The causes of cell injury and death 3. Cellular events associated with cell injury and cell death 4. Structural changes of necrosis 5.Cellular events associated with apoptosis 6. Structural changes of apoptosis cell injury its a series of cellular events leading to reversible or irreversible functional and morphological changes. 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.  General considerations…… Cell injury is part of a continuum Degree of injury is a function of –Injury: type, duration, severity –Cell: type, status, adaptability Discuss the various different causes of cell injury and death There are many methods of cell injury, including Hypoxia Toxins Heat Cold. Trauma. Radiation Micro-organism Immune mechanism Hypoxia Ischaemia – Local – Systemic Hypoxaemia result from – Inspired oxygen too low – Diffusion barrier abnormal – Insufficient carrying capacity in blood Interference with oxidative phosphorylation – e.g. cyanide poisoning chemical injury Drugs e.g. paracetamol overdose Many more e.g. alcohol, cigarette smoke Physical Direct Physical Effects extreme heat or cold results Sudden changes in pressure Electrical currents infections Eukaryotes – Fungi, Protozoa Prokaryotes – Bacteria, Rickettsiae, Chlamydiae Viruses – DNA, RNA immune Humoral Cell-mediated nutrition Hypoxia Hypoxia is reduced O2. It is often due to Ischaemia, the interruption of blood supply. Ischaemia is used as a model for understanding the pathogenesis of cell injury: Principle structural targets for cell damage Cell membranes – Plasma membrane – Organellar membranes DNA Proteins – Structural – Enzymes Mitochondria – oxidative phosphorylation Reversible Changes: oxidative phosphorylation decreases Amount of ATP decreases lead to failure of Na/K pump with accumulation of intra cellular Na -----cellular swelling. This means the cell swells via osmosis Increased amount of anaerobic glycolysis, decreasing pH (Lactate) this will lead to chromatin clumping Detachment of ribosomes also leads to a decrease in protein synthesis Irreversible changes Massive accumulation of cytosolic Ca2+ Several enzymes activated resulting in cell death Different cells react differently, e.g. a neurone can only withstand Ischaemic conditions for a few minutes whereas fibroblasts can last for hours 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) Structural Changes (cell injury) Structural changes can be seen under the electron microscope Reversible Swelling Chromatin clumping Autophagy Rinosome dispersal Blebs (Little bumps on membrane surface where cytoskeleton has detached) Irreversible Nuclear changes Lysosome rupture Membrane defects Endoplasmic reticulum lysis Define Necrosis and Apoptosis Necrosis – Changes that occur after cell death in living tissue. Apoptosis – Programmed cell death Discuss cellular events associated with necrosis (types of necrosis). There are two common types of necrosis seen in clinical practice, Coagulative and Liquefactive. There are two other, rarer types, Caseous and Fat. Coagulative Necrosis More protein denaturation than enzyme release Cellular architecture is somewhat preserved, creating a ‘ghost outline’. Tends to be due to Infarcts ((Infarct in the brain = Liquefactive) Liquefactive Necrosis More enzyme release than protein denaturation Tissue is lysed and disappears Tends to be due to infection Caseous Necrosis Tissue architecture is abolished Tissue appears amorphous “Half way” between Coagulative and Liquefactive Caseous necrosis in the lung à Very likely to be TB  Fat Necrosis Occurs when cell death occurs in adipose tissue typically acute pancreatitis – pancreatitis --lipase release ---digest adipocyte membranes and fat vacuoles---- fat necrosis ----release of fatty acids--- reacts with calcium ---calcified deposits. Gangrene Clinical term for grossly visible necrosis ‘Dry’ gangrene Coagulative E.g. umbilical cord after birth ‘Wet’ gangrene Liquefactive Infection à Neutrophils à Proteolytic enzymes Infarct Necrosis due to ischaemia -coagulative e.g. myocardial infarct – liquefactive e.g. brain infarct Two further ways of describing infarcts – White Occlusion of end artery – the usual arrangement in an organ and therefore commonest pattern – Red/haemorrhagic: may occur in the following situations Venous occlusion; Dual blood supply; Loose tissues; Previously congested tissues Apoptosis single-cell death. An active process - energy consumed Derived from Greek "falling off" (as for autumn leaves) May be physiological or pathological Apoptosis - triggers Intrinsic – Withdrawal of growth stimuli, e.g. growth factors – DNA damage, e.g. p53-induced apoptosis Extrinsic – Death signals types of apoptosis Physiological type The programmed destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution and metamorphosis Hormone-dependent involution in the adult 1-prostatic atrophy after castration 2-breast atrophy after weaning Cell deletion in proliferating cell populations intestinal crypt epithelia Death of host cells that have served their useful purpose inflammatory neutrophils in acute inflammation. Elimination of potentially harmful self-reactive lymphocytes Cell death induced by cytotoxic T cells 1-cells with viral infection 2- neoplastic cells Apoptosis in pathological conditions Cell death produced by a variety of injurious stimuli. E.g.radiation and cytotoxic anticancer drugs damage DNA Cell injury in certain viral diseases , like viral hepatits. Pathological atrophy in solid parenchymal organs after duct obstruction such as occurring in prostate, parotid glands & kidney Cell death in tumors