L4 Cell injury.pdf

CELL INJURY DR. MOHAMED SAM-AAN HUSSAIN CELL Cells are the smallest independent units of living matter A cell consists of main three parts: Nucleus Cytoplasm...

CELL INJURY DR. MOHAMED SAM-AAN HUSSAIN CELL Cells are the smallest independent units of living matter A cell consists of main three parts: Nucleus Cytoplasm Cell Membrane Cell membrane The cell membrane separates the material outside the cell (extracellular), from the material inside the cell (intracellular). Structure: Double layer of phospholipid molecules (phospholipid bi-layer) Proteins - Embedded in the phospholipid bilayer or on inner or outer surface Carbohydrates - are bound either to proteins (forming glycoproteins) or to lipids (forming glycolipids) Cholesterol - helps keep membrane fluid Cytoplasm The gel-like fluid inside the cell Sometimes the term is collectively used for the cytosol and the organelles within the colloidal suspension It is mainly composed of water but also contains salts, enzymes and other molecules. It surrounds and protects the organelles and provides a platform upon which they can operate within the cell. All of the functions for cell expansion, growth and replication are carried out in the cytoplasm of a cell. Within the cytoplasm, materials move by diffusion Organelle (“little organs”) Specialized subunit within a cell surrounded by a Lysosomes the digestive system of cell membrane and has a specific function They include: Nucleolus Control centre Mitochondria of cell Production of ATP Ribosomes Synthesis of Vacuole proteins site for the degradation of lipids, proteins, nutrient storage Golgi apparatus Packaging factory Endoplasmic reticulum RER - Synthesis and processing of proteins SER - Synthesis of steroid hormones from cholesterol and detoxification  WHAT IS CELL INJURY? Cell injury is defined as the effect of a variety of stresses due to etiologic agents a cell encounters resulting in changes in its internal and external environment. PATHOGENESIS OF CELL INJURY Type Factors pertaining to etiologic agent and host: e.g. small dose of chemical toxin or short duration of Injurious ischaemia cause reversible cell injury agent Duration Severity  Type Factors pertaining to Host cell e.g. skeletal muscle can withstand hypoxic injury for long- time while cardiac muscle suffers irreversible cell injury after persistent ischaemia due to total coronary occlusion Target >20 minutes. Cell Status Adaptability  ETIOLOGY OF CELL INJURY Genetic causes Acquired causes Hypoxia and Ischaemia (most common), Physical agents, Chemical, Microbial, Immunologic, Nutritional derangement, Ageing, Psychogenic, Iatrogenic, Idiopathic In a given situation, more than one of the above etiologic factors may be involved  Cellular responses to cell injury Mild to Moderate stress/ injury When stress is mild to Severe, persistent stress/ injury moderate, the injured Persistent and severe cell may recover form of cell injury may cause cell death When there is increased functional demand, cell may adapt to the changes which are expressed morphologically, which then revert back to normal after the stress is removed. Common underlying mechanisms of cell damage Mitochondrial damage causing ATP depletion Cell membrane damage disturbing the metabolic and trans-membrane exchanges Release of toxic free radicals  Reversible Cell Injury If the ischaemia or hypoxia is of short duration, the effects may be reversible on rapid restoration of circulation. The sequential biochemical and ultrastructural changes in reversible cell injury are: Decreased generation of cellular ATP: Damage by ischaemia from interruption versus hypoxia from other causes Intracellular lactic acidosis: Nuclear clumping Damage to plasma membrane pumps: Hydropic swelling and other membrane changes Reduced protein synthesis: Dispersed ribosomes  Irreversible Cell Injury Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of the cell (cell death). The stage at which this point of no return or irreversibility is reached from reversible cell injury is unclear but the sequence of events is a continuation of reversibly injured cell. Two essential phenomena always distinguish irreversible from reversible cell injury: Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation. Disturbance in cell membrane function Other changes include The sequential biochemical and ultrastructural changes in irreversible cell injury are: Calcium influx: Mitochondrial damage Activated phospholipases: Membrane damage Intracellular proteases: Cytoskeletal damage Activated endonucleases: Nuclear damage Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis Liberated enzymes just mentioned leak across the abnormally permeable cell membrane into the serum, the estimation of which may be used as clinical para meters of cell death.  Some enzymes liberated due to cell damage and tested for on Blood investigation Aspartate aminotransferase (AST, SGOT) - Diff use liver cell necrosis e.g. viral hepatitis, alcoholic liver disease, Acute myocardial infarction. Alanine aminotransferase (ALT, SGPT) - More specifi c for diff use liver cell damage than AST e.g. viral hepatitis Amylase - Acute pancreatitis Sialadenitis Creatine kinase-MB (CK-MB) - Acute myocardial infarction, myocarditis Skeletal muscle injury Cardiac troponin (CTn) - Specific for acute myocardial infarction Lipase - More specific for acute pancreatitis Lactic dehydrogenase (LDH) - Acute myocardial infarction Myocarditis Skeletal muscle injury  Cell injury due to Hypoxia and Ischemia Cells of different tissues essentially require oxygen to generate energy in the form of ATP and perform metabolic functions. ATP in human cell is derived from 2 sources: By aerobic respiration or oxidative phosphorylation (which requires oxygen) in the mitochondria. Anaerobic glycolytic oxidation to maintain constant supply of ATP (in which ATP is generated from glucose/glycogen in the absence of oxygen). Hypoxia may result from main 2 ways: Reduced supply of blood to cells due to interruption i.e. ischaemia. aerobic respiration as well as glucose availability are both compromised resulting in more severe and faster effects of cell injury and accumulation of metabolic waste products in the cells. myocardium, proximal tubular cells of the kidney, and neurons of the CNS are dependent solely on aerobic respiration for ATP generation and thus these tissues suffer from ill-effects of ischaemia more severely and rapidly. Impaired blood supply from causes other than interruption e.g. disorders of oxygen carrying RBC's (e.g. anaemia, carbon monoxide poisoning), heart diseases, lung diseases and increased demand of tissues. anaerobic glycolytic ATP generation continues, and thus cell injury is less severe.  WHAT ARE INTRACELLULAR ACCUMULATIONS? Presence of abnormal amounts of a substance within the cytoplasm, previously referred to as infiltration Intra-cellular accumulations in mild degree causes reversible cell injury, severe degree causes irreversible cell injury 3 groups of accumulations Accumulation of normal cell metabolites (fats, proteins, carbohydrates) Accumulation of abnormal substances Accumulation of pigments Fatty change - Fatty Liver (Steatosis) Intra-cellular accumulation of neutral fat Most commonly seen in liver but also observed in heart, skeletal muscle, kidneys etc. Etiology Conditions of excess fat: obesity, diabetes mellitus, congenital hyper-lipidaemia Liver cell damage: alcoholic liver disease, starvation, protein calorie malnutrition, chronic illness, acute fatty liver in late pregnancy, hypoxia, hepatotoxins, drug induced liver cell injury, etc. Pathogenesis Abnormal metabolism of fat in liver Morphology Cholesterol and Cholesterol Ester Accumulation Atherosclerosis Deposits of lipid vacuoles in the intima layer of arteries mostly composed of cholesterol and cholesterol ester. Foamy appearance of cells. On gross examination intima layers appears yellow with cholesterol laden atheromas. Some of the lipid rich vacuoles may rupture, releasing lipids into the blood. Atherosclerosis in brain arteries may have sudden numbness or weakness in arms or legs, difficulty speaking or slurred speech, temporary loss of vision in one eye Atherosclerosis in arms and legs arteries - may have symptoms of peripheral artery disease, such as leg Atherosclerosis in heart arteries - chest pain when walking (claudication) or decreased blood pain or pressure (angina). pressure in an affected limb. Xanthomas Intracellular accumulation of cholesterol within macrophages. Clusters of foamy cells in connective tissue in skin and tendons, appears grossly as masses knowns as xanthomas Cholesterolosis: accumulations of cholesterol laden macrophages in gallbladder Niemann-pick disease, type C: cholesterol accumulation in multiple organs due to mutations in enzyme involved in storage of cholesterol Cholesterolosis Accumulations of cholesterol laden macrophages in gallbladder Niemann-pick disease, type C Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal storage disorder resulting from mutations of either the NPC1 or the NPC2 gene, showing a wide spectrum of clinical phenotypes and a highly variable age at diagnosis. Protein accumulation Pathologic accumulation of proteins occur in: Russell’s bodies: Russell bodies are eosinophilic, homogeneous immunoglobulin (Ig)-containing inclusions usually found in cells undergoing excessive synthesis of Ig Alpha anti trypsin deficiency: A1AD is due to a mutation in the SERPINA1 gene that results in not enough alpha-1 antitrypsin (A1AT). The underlying mechanism involves unblocked neutrophil elastase and buildup of abnormal A1AT in the liver. Mallory’s bodies: are cytoplasmic hyaline inclusions of hepatocytes, once thought to be specific for alcoholic hepatitis now occur in other liver diseases which include nonalcoholic steatohepatitis (NASH) Glycogen accumulation Diabetes Mellitus: normal cellular uptake of glucose is impaired. Glycogen deposits in proximal convoluted tubule and loop of henle, hepatocytes Glycogen storage diseases: defective metabolism of glycogen due to genetic disorders Pigment accumulation Pigments are colored substances, some of which are normal constituents of cells and others are abnormal and accumulate in cells under special circumstances. They can be: Endogenus: synthesized in the body melanin, Haemoprotein derived pigments (Haemosiderin, Bilirubin, Porphyrins), Lipofuscin Exogenus: coming from outside the body inhaled pigments, ingested pigments, injected pigments (tattooing) Endogenus Pigments Melanin: brown-black pigment in hair, skin, choroid of eye, meninges and adrenal medulla. Generalized hyperpigmentation Focal hyperpigmentation Generalized hypopigmentation Localized hypopigmentation Lipofuscin (wear and tear pigment): a brown-yellow, electron-dense, autofluorescent material that accumulates progressively over time in lysosomes of postmitotic cells, such as neurons, cardiac myocytes, hepatocytes, Leydigcells of testes and in neurons in senile dementia. The exact mechanisms behind this accumulation are still unclear.. Exogenus Inhaled pigments: carbon or coal dust, asbestos, silica. Inhaled pigments can lead to pneumoconiosis. Ingested pigments: Argyria: a condition caused by excessive exposure to chemical compounds of the element silver, or to silver dust forming brownish pigmentation in skin, bowel and kidney. Karason he took a homemade silver chloride colloid and rubbing a solution of colloidal silver on his face in an attempt to treat problems with his sinuses, dermatitis, acid reflux, and other issues. Chronic lead poisoning: blue lines on teeth at the gumline Melanosis coli: dark pigment in large bowel due chronic laxative use Carotenaemia: yellowish-red coloration of skin caused by excessive ingestion of carrots (carotene) Injected pigments: Tattoing (india ink, cinnabar, carbon), presence of foreign ink particles activates the immune system of the body and are taken up by macrophages. As macrophages aren’t able to mount an immune response against the nanoparticles, macrophages contain the attack on the system by remaining in place and keeping the ink trapped in the vacuole. Free ink released upon the death of macrophages releases signals for newly formed macrophages to come to the site. The dying macrophages release the ink into the surrounding tissue, but the ink is then recaptured by the new macrophages. This release-recapture cycle continues indefinitely, causing tattoos to stay in place forever.