Cell Injury and Death PDF

Cell Injury and Death Dr. Syeda Fakhra Waheed DVM, MPhil, Ph.D Pathology Post Doc. Molecular Biology  Causes of Cell Injury  Oxygen Deprivation – hypoxia - ischemia  Nutritional Deficiencies (def. proteins, Vit., Fe, Cu, etc.)  Chemical agents  Infectious agen...

Cell Injury and Death Dr. Syeda Fakhra Waheed DVM, MPhil, Ph.D Pathology Post Doc. Molecular Biology  Causes of Cell Injury  Oxygen Deprivation – hypoxia - ischemia  Nutritional Deficiencies (def. proteins, Vit., Fe, Cu, etc.)  Chemical agents  Infectious agents  Physical Agents  Immunological Reaction – Allergy and anaphylaxis – autoimmunity, – immunodeficiency  Genetic Defects –Down’s syndrome a genetic condition where a person is born with an extra copy of chromosome 21 to substitution of one amino acid in Hb resulting in sickle cell anemia  Factors Affecting Cell Injury  Cellular response to injurious stimuli depends upon type of injury, its duration, and its severity  The consequences of an injurious stimulus depend on the type of injury, status, adaptability, and genetic makeup of the injured cell  Changes following Physiological Stress or Pathological Stimuli  Cell injury – Reversible – Irreversible – cell death  Necrosisand Apoptosis  Adaptive changes  General Biochemical Mechanisms  ATP depletion – – Oxygen deprivation-hypoxia, ischemia – Non-availability of Glucose  Transport processes  Protein synthesis – Basic metabolic pathways  Generation of reactive oxygen species – Radiation, toxins, chemicals – Lipid per oxidation Cont….  Loss of calcium homeostasis – Ischemia or toxins – Activate phospholipases, proteases, and endonucleases, ATPases 10,000 times less Ca in the cells Cont…….  Mitochondrial dysfunction induced by variety of stimuli, causes a mitochondrial permeability transition, which leads to: 1. Decay of the proton gradient necessary for ATP generation 2. Releasing Cytochrome C from the mitochondria into the cytosol  Free Radical-Induced Injury How the free radicals are generated: – Reduction oxidation reactions – Nitric oxide – Absorption of radiant energy, ionizing radiation – Enzymatic metabolism of exogenous chemicals (CCl4)  Effects: – Lipid peroxidation – DNA fragmentation– thymine – Cross linking of proteins-loss of enzymatic activity  Superoxide dimutase  2O2- 2H --- H2O2 + O2 Glutathione peroxidase  2OH- +2GSH - 2H2O = GSSG Catalase  2H2O2 -- O2 + H2O  Chemical Injury  Some chemicals act directly by combining with a critical molecular component or cellular organelles – Antibiotics – antineoplastic therapeutic agents ATPase dependent transport of ions and increased membrane permeability  Many chemicals are not intrinsically biologically active but must be first converted to reactive metabolites, which then act on target cells. P-450 oxidase. CCl4  CCl3 (toxic free radical causing membrane peroxidation) Membrane damage by combining directly with lipids and proteins Main action through formation of free radicals Free Radical Cell Injury  It is another important mechanism of cell injury  Free radical injury may be the final common pathway in various processes such as chemical and radiation injury, microbial killing in all phagocytic cells, oxygen and other gaseous toxicity, cellular aging and cancer  All matter of the universe is composed of basic units known as elements  Elements are fundamental substances composed of only one type of atoms e.g. hydrogen. Nitrogen, oxygen etc..  Four elements namely; carbon, hydrogen, nitrogen and oxygen make the 96 percent of the body weight and 99 percent of the atoms of the body  Atoms are composed of three fundamental particles; electron, proton and neutron  An atom has a nucleus containing protons and neutrons and  The number of electrons is equal to protons, and the number of protons in a an atom is atomic number  A free radical is an atom or group of atoms having one or more unpaired electrons in the outer orbital  In such a state, atom is extremely reactive and unstable  Four free radicals are the most important:  1. superoxide O2; a molecule of O2 that has 13 electrons in its outer orbit  2. hydrogen peroxide H2O2; contains more oxygen than normal  3. hydroxyl radicals; produced by hydrolysis of water  4. Singlet oxygen; a form of oxygen in which one electron is shifted  Mechanism of free radical injury  1. Lipid peroxidation of membranes; in presence of O2, free radicals may cause peroxidation of lipids in the plasma membrane and membranes of cell organelles, may damage endoplasmic reticulum and mitochondria  Lipid peroxidation is initiated by hydroxyl radicals which react with unsaturated and polyunsaturated fatty acids of the membrane phospholipids  2. cross linking of proteins; free radicals act on sulphydryl bonds (-SH-HS-) of proteins  Cross linking of proteins by the formation of disulphide bonds (-S-S) in certain amino acids leads to extensive damage to the cell  3. Damage to DNA; reaction of free radicals with thymine, this leads to mutation in the genetic code  Inactivation of free radicals may be done with the help of:  1. Endogenous or exogenous antioxidants; vit. E, glutathione peroxidase  2. enzymes  Cellular Swelling  Previously known as cloudy swelling  It is disturbance of cellular metabolism in which the cells swells and the cytoplasm become more granular than normal  It is the first reaction of a cell to injury  Its caused by mildest irritants, caused by shift of extracellular water into the cell  Etiology may include; bacterial toxins, pyrogens, metabolic disease, organic and inorganic poisons (lead, arsenic, chloroform, alcohol); circulatory disturbances (anemia, infarction)  Macroscopically; organs such as liver and kidney are enlarged with round edges, increase in organ weight, the organ appears pale or anemic, when incised, cut surfaces bulges out  Microscopically; cells are swollen with rounded edges, the cytoplasm stains more with eosin, cytoplasm is more granular than normal  Cellular swelling is a reversible condition