Cell Injury Lecture Notes PDF

Ministry of Higher Education and Stage: 2 Scientific Research Module: mechanism of Wasit University disease College of medicine...

Ministry of Higher Education and Stage: 2 Scientific Research Module: mechanism of Wasit University disease College of medicine Lecturer Title : Cell injury Dr. Zainab abbas alquraishy M.B.Ch.B C.A.B.H.S, DipRCPath Department of pathology and forensic medicine :Cell injury results when A. cells are stressed so severely that they are no longer able to adapt or B. when cells are exposed to inherently damaging agents or.C. suffer from intrinsic abnormalities Different injurious stimuli affect many metabolic pathways and cellular organelles at the same time. Injury may progress through a reversible, then to irreversible stages and culminate in cell death :So 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 Cell injury is part of a continuum Degree of injury is a function of –Injury: type, duration, severity –Cell: type, status, adaptability Causes of cell injury Hypoxia, or oxygen deficiency, interferes with aerobic oxidative respiration and is an.1.extremely important and is the 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 ,While ischemia is the most common cause of hypoxia oxygen deficiency can also result from Inadequate oxygenation of the blood, as in pneumonia, or 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; An enormous number of chemicals can injure the cells; A. even innocuous substances such as glucose or salt, if sufficiently concentrated, can so.derange the osmotic environment that cell injury or death results.B. Oxygen at sufficiently high partial pressures is also toxic C. 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,.and exposure to these poisons can culminate in the death of the whole organism D. Other potentially toxic agents are encountered daily in our environment; these include air pollutants, insecticides, CO, asbestos, and social "stimuli" such as.ethanol E. Even therapeutic drugs can cause cell or tissue injury in a susceptible.patient or if used excessively or inappropriately Infectious agents; these range from submicroscopic viruses to meter-long.3 tapeworms; in between are the rickettsiae, bacteria, fungi, and protozoa can.cause cell injury 4. Immunological reaction; although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury. ;Examples include.A. autoimmune reactions against one's own tissues B. allergic reactions against environmental substances in genetically susceptible individuals ;Genetic defects.5 can result in pathologic changes as conspicuous as the congenital malformations associated with Down syndrome or as subtle as the single.amino acid substitution in hemoglobin S giving rise to sickle cell anemia Genetic defects may cause cell injury because of deficiency of functional proteins, such as enzymes in inborn errors of metabolism, or accumulation of damaged DNA or misfolded proteins, both of which trigger cell death when.they are beyond repair ;Nutritional imbalances includes.6 A. nutritional deficiencies remain a major cause of cell injury. Protein-calorie insufficiency among underprivileged populations is only the most obvious example; specific vitamin deficiencies are not uncommon even in developed.countries with high standards of living B. Excesses of nutrition are also important causes of morbidity and mortality. Obesity markedly increases the risk for type 2 diabetes mellitus, and diets rich in animal fat are strongly implicated in the development of atherosclerosis as well as in increased vulnerability to many disorders,.including cancer ;Physical agents; include.7.A. Trauma.B. Extremes of temperatures.C. Radiation.D. electric shock E. sudden changes in atmospheric pressure ;Aging.8 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 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 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  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 instance, heart- muscle ceases to contract within 60 seconds 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 Reversible cell injury; characterized by A. Occurs early stages of cell injury or.b. in cases of mild forms of injury c. functional and morphologic changes are reversible if the damaging.stimulus is removed d. Although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membranes damage, severe mitochondrial damage, and nuclear.dissolution Morphology of cells and tissue injury Morphology of cells and tissues with reversible cell injury ;Gross morphology of organ with reversible cell injury are A. Increased pallor, turgor, and weight of the organ affected by cellular swelling due to failure of energy-dependent ion pumps in the plasma.membrane B. Enlargement, yellowish discoloration, and organ becomes greasy on touching due to fatty changes. It is seen mainly in cells involved in and.dependent on fat metabolism, such as hepatocytes and myocardial cells ;Light microscopic findings in reversible cell injury are.a. Cellular swelling (hydropic or vacuolar degeneration).b. Fatty changes.c. Increased cytoplasmic eosinophilia.d. Surface blebbing of affected cells  Cellular swelling (hydropic change) The affected hepatocytes are distended by accumulated water.that imparts cytoplasmic pallor 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.Ischemia / Reperfusion injury Is the tissue damage caused when blood supply returns to tissue (reperfusion).after a period of ischemia or lack of oxygen (anoxia or hypoxia) Restoration of blood flow in reversibly injured cells but still viable can promote recovery but it may also paradoxically exacerbate the injury result in further injury.of the cells or even cause cell death by following mechanisms Oxidative stress. Re oxygenation increase generation of reactive oxygen and -1 nitrogen species, as a result of incomplete reduction of oxygen by damaged mitochondria and/or cellular antioxidant defense mechanisms may be.compromised by ischemia, favoring the accumulation of free radicals Increase intracellular Ca+2 due to influx of calcium resulting from cell-2 membrane damage Inflammation: production of free radicals by the inflammatory cells at -3.the perfusion area Activation of the complement system-4 :Free Radicals induced cell injury Free radicals are chemical species with a single unpaired electron in outer.orbital In such chemical state are extremely unstable & readily react with inorganic.& organic chemicals They initiate autocatalytic reactions, molecules that react with free radicles.are in turn converted into free radicles.Sources of Free Radicals Redox reactions (reduction – oxidation reaction) :This reaction normally.1.occurs in the mitochondria During this reaction small amount of toxic intermediate species are - formed include (superoxide O2. - , hydrogen peroxide H2O2 & OH. ) Nitric Oxide (NO). is normally synthesized by a variety of cell types.2 - which then act as free radicals by itself or by conversion to highly reactive.Nitrite species Absorption of radiant energy (U.V light, X-ray), these radiation can.3 -.hydrolyze the water into OH. & hydrogen free radicals (H. ).During Enzymatic Metabolism of exogenous chemicals like CCL4.4 - Free radicals can generate as a part of routine cellular activities like.5 -.respiration process, defence mechanisms  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)