Lecture 1.2b - Cell injury and cell death 2.pdf

Abnormal cellular accumulations: ◦Seen when metabolic processes become unbalanced ◦Often occur with sublethal or chronic injury ◦Can be reversible ◦Can be harmless or toxic ◦They can derive from the: ‣ Cell’s own metabolism ‣ The extracellular space, e....

Abnormal cellular accumulations: ◦Seen when metabolic processes become unbalanced ◦Often occur with sublethal or chronic injury ◦Can be reversible ◦Can be harmless or toxic ◦They can derive from the: ‣ Cell’s own metabolism ‣ The extracellular space, e.g. spilled blood ‣ The outer environment, e.g. dust What kind of things can accumulate in cells?: ◦There are five main groups of intracellular accumulations: ‣ Water and electrolytes ‣ Lipids ‣ Carbohydrates ‣ Proteins ‣ ‘Pigments’ When does fluid accumulate in cells?: ◦Hydropic swelling ◦Occurs when energy supplies are cut off, e.g. hypoxia ◦Indicates severe cellular distress ◦Na+ and water flood into cell ◦Particular problem in the brain-cerebral oedema ‣ Oedema is recognised as an area of lucency or hypodense or hypoattenuation by CT imaging When do lipids accumulate in cells?: ◦Steatosis (accumulation of triglycerides) ◦Often seen in liver (major organ of fat metabolism) ◦If mild - asymptomatic ◦Causes: ‣ Alcohol (reversible in about 10 days) ‣ Diabetes mellitus ‣ Obesity ‣ Toxins (e.g. carbon tetrachloride) High fat diet-induced hepatic steatosis:  When do lipids accumulate in cells?: ◦Cholesterol: ‣ Cannot be broken down and it is insoluble ‣ Can only be eliminated through the liver ‣ Excess stored in cells in vesicles ‣ Accumulates in smooth muscle cells and macrophages in atherosclerotic plaques = foam cells ‣ Present in macrophages in skin and tendons of people with hereditary hyperlipidaemias = xanthomas In what conditions do proteins accumulate in cells?: ◦Seen as eosinophilic droplets or aggregations in the cytoplasm ‣ Alcoholic liver disease - Mallory’s hyaline (damaged keratin filaments) What do accumulated proteins look like?: ◦Alpha-1 antitrypsin deficiency: ‣ Liver produces incorrectly folded alpha 1-antitrypsin protein (a protease inhibitor) ‣ Cannot be packaged by ER, accumulates within ER and is not secreted ‣ Systemic deficiency - proteases in lung act unchecked, resulting in emphysema When do pigments accumulate in cells?: ◦Exogenous: ‣ Carbon/coal dust/soot - urban air pollutant ‣ Inhaled and phagocytosed by alveolar macrophages ‣ Anthracosis and blackened peribronchial lymph nodes ‣ Usually harmless, unless in large amounts = fibrosis and emphysema = coal worker’s pneumoconiosis ‣ Tattooing - pigments pricked into the skin ‣ Phagocytosed by macrophages in dermis and remains there ‣ Some pigment will reach draining lymph nodes Endogenous pigment accumulation: ◦Haemosiderin: ‣ Iron storage molecule ‣ Derived from haemoglobin, yellow/brown ‣ Forms when there is a systemic or local excess of iron, e.g. bruise ‣ With systemic overload of iron, haemosiderin is deposited in many organs = haemosiderosis ‣ Seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis.  What is hereditary haemochromatosis?: ◦Genetically inherited disorder - results in increased intestinal absorption of dietary iron ◦Iron is deposited in skin, liver, pancreas, heart and endocrine organs - often associated with scarring in liver (cirrhosis) and pancreas ◦Symptoms include liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas. ◦Treatment is repeated bleeding. Accumulation of bilirubin in Jaundice: ◦Accumulation of bilirubin - bright yellow ◦Breakdown product of heme, stacks of broken porphyrin rings ◦Formed in all cells of the body (cytochromes contain heme) but must be eliminated in bile ◦Taken from tissues by albumin to liver, conjugated with bilirubin and excreted in bile ◦If bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results ◦Deposited in tissues extracellularly or in macrophages Calcification of tissues: ◦Abnormal deposition of calcium salts within tissues. ◦Can be localised (dystrophic) or generalised (metastatic) ◦Dystrophic: ‣ Occurs in an area of dying tissue, atherosclerotic plaques, ageing or damaged heart valves, in tuberculus lymph nodes and some malignancies Why does dystrophic calcification occur?: ◦No abnormality in calcium metabolism, or serum calcium or phosphate concentrations ◦Local change/disturbance favours nucleation of hydroxyapatite crystals ◦Can cause organ dysfunction, e.g. atherosclerosis, calcified heart valves Why does metastatic calcification occur?: ◦Due to hypercalcaemia secondary to disturbances in calcium metabolism ◦Hydroxyapatite crystals are deposited in normal tissues throughout the body ◦Usually asymptomatic but it can be lethal ◦Can regress if the cause of hypercalcaemia is corrected What causes hypercalcaemia?: ◦Increased secretion of parathyroid hormone (PTH) resulting in bone resorption: ‣ Primary - due to parathyroid hyperplasia or tumour ‣ Secondary - due to renal failure and the retention of phosphate ‣ Ectopic - secretion of PTH-related protein by malignant tumours (e.g. carcinoma of the lung) ◦Destruction of bone tissue: ‣ Primary tumours of bone marrow e.g. leukaemia, multiple myeloma ‣ Diffuse skeletal metastases ‣ Pager’s disease of bone - when accelerated bone turnover occurs  ‣ Immobilisation Cellular ageing: ◦As cells age, they accumulate damage to cellular constituents and DNA ◦After a certain number of divisions they reach replicative senescence - related to the length of chromosomes ◦Ends of chromosomes are called telomeres, with every replication the telomere is shortened. When the telomeres reach a critical length, the cell can no longer divide.