Session 2 Cellular and Tissue Response to Damage B.M.C.Randika Wimalasiri B.Sc in MLS(Peradeniya) Lecturer(Probationary) Department of Medical Laboratory Sciences • The changes that occur in the various cellular organelles and cytoskeleton Cellular response to damage • Non lethal damage- changes in organelles and in the cytoskeleton. • The type of response - type of the injurious agent. • Different cellular organelles - different types of damage. • More common reactions. Changes in Mitochondria • Function: mediate cellular respiration • Non lethal damage to mitochondria -alterations in number, size, shape and function. • Examples 1. Hypertrophy - increased demand causes increase in workload ad increase in the number of mitochondria. 2. Atrophy - decrease the number of mitochondria in a cell 3. Megamitochondria - are very large, sometimes abnormally shaped. Ex : alcoholic liver disease nutritional deficiencies 4. Mitochondrial myopathies - group of genetic disorders causing metabolic disease of skeletal muscle. • Increased numbers of unusually large mitochondria containing abnormal cristae filled with crystalloids • muscle fibers do not work due to mitochondrial defects) Smooth endoplasmic reticulum • Functions - detoxification and metabolism of various drugs and chemicals including alcohol, barbiturates, insecticides, steroids etc. • Examples 1. Barbiturates- • metabolized in the liver by the cytochrome P-450 oxidase system found in the SER. • Prolonged usage leads to a state of tolerance, with a decrease in the effects of the drug and the need to use increasing doses. This adaptation is due to increased volume (hypertrophy) of the SER of hepatocytes and increased P-450 enzymatic activity. • More of the enzyme is produced the drugs and toxins are metabolized quicker and the patients ‘adapt’ to the drug . • As more and more of the drug is metabolized a higher dosage is necessary to maintain therapeutic levels and effectiveness. • I.e. when barbiturates are ingested more and more of the drug is needed to be taken at a higher dosage to achieve similar effects. • Alcohol - increase the activity of p-450 oxidase system by increasing the SER. • When this happens other drugs which use the same p-450 system for their metabolism loses the effectiveness at lower dosage and need higher doses to maintain effective therapeutic levels. Lysosomes • Enzyme filled membrane bound vesicles that contain a variety of enzymes like acid phosphatases, glucuronidases, collagenases, ribonucleases etc. • May be primary or secondary. • When there is material to be digested the primary lyzosomes fuse with the material and form secondary lysosomes or polyphagosomes. Lysosomes breakdown particulate material in one of the two methods. Heterophagy – • Process of takeing up particulate material from the extracellular compartment to the cell - endocytosis. • Uptake of soluble smaller particles - pinocytosis. • These materials are then engulfed by the cells which form vacuoles which eventually fuse with lysosomes to form phagolysomes where the engulfed material is digested by the lysosomal enzymes. • Examples: digestion of necrotic cellular debris by macrophages and bacteria by polymorphonuclear leucocytes. • Autophagy – – cells own components need to be eliminated as in reduction of organelles in atrophic tissue or elimination of organelles damaged in cell injury, an autophagic vacuole is formed. – This vacuole fuses with a lysosome. – The contents are digested by the formation of an autophagolysosome. • Most proteins and carbohydrates are digested but a fragment of lipid may remain undigested as residual bodies. • Ex : lipofuscin pigment • Deficiencies of the lysosomal enzymes - accumulation of various substances in the cell, cause many diseases. • Lysosmal storage disorders - A hereditary group of disorders, accumulation of various molecules within the cells, especially neurons causing severe disease. • Certain drugs disturb lysosomal function . Ex quinine increases the internal pH of the lysosome inactivating its enzymes. Cytoskeletal abnormalities • Functions- maintaining structural stability, cell movement and movement of organelles within the cell. • Contain microtubules, actin filaments, myosin filaments, intermediate filaments and contractile proteins. • Abnormalities of the cytoskeleton causes functional defects – i.e. in cell movement and movement of intracellular organelles. • Intracellular fibrillar material may accumulate within the cell and cause disease. Examples 1. Mallory bodies in • Neurofibrillary tangles liver cells in in the brain in Alcoholic liver Alzheimers disease : disease: microtubule accumulations of associated proteins intermediate and neurofilaments. filaments. 2.2 Intracellular accumulations • May be found in the cytoplasm, within organelles (typically lysosomes), or in the nucleus • 3 types of accumulations/ substances 1. Normal endogenous substances in abnormal amounts eg: lipid, protein, water and carbohydrates 2. Abnormal substances eg: products of abnormal synthesis or metabolism, minerals and products of infectious agents 3. Pigments Normal endogenous substances in abnormal amounts 1. Fatty change ( steatosis ) Fatty change • All major classes of lipids such as triglycerides, cholesterol, cholesterol esters and phospholipids can accumulate within cells. • Mild change - no effect on cell function. • Severe change - can lead to chronic liver disease, cirrhosis and even liver cancer. Macroscopic and microscopic changes in fatty liver • Steatosis - The process of abnormal accumulation of triglycerides within parenchymal cells of organs. • Triglycerides can accumulate in the heart, muscle and kidney • Mainly occurs in the liver - the major organ involved in fat metabolism. • Causes for steatosis : injury due to – toxins, obesity , malnutrition, diabetes and anoxia. – The most common toxic cause - alcohol abuse. • Alcohol alters mitochondrial and microsomal functions and decreases formation of apoproteins which are lipid binding proteins which bind triglycerides. Cholesterol accumulation: Atherosclerosis • Accumulation of cholesterol in smooth muscle cells and macrophages are filled with lipid vacuoles containing cholesterol and cholesteryl esters result in formation of atherosclerotic plaques within vessels. Protein accumulation : Hyaline change • Deposition of a glassy pink homogenous substance within the cell is termed hyaline change. • This change is common and is produced by a variety of alterations and does not represent a specific pattern of accumulation. Accumulation of glycogen • Excessive intracellular deposits of glycogen are seen in abnormalities of either glucose or glycogen. Diabetes mellitus is the common example of a disorder in glucose metabolism. In poorly controlled diabetes glycogen is accumulated in liver cells, Beta cells of the islets of Langerhann, heart muscle cells and in cells of the collecting duct system of the kidney. • Glycogen storage diseases are a group of genetic disorders where enzymatic defects in synthesis or breakdown of glycogen results in massive accumulation causing secondary cell injury and death. Pigments • Pigments are colored substances and collect in cells under special circumstances. • Some are normal constituents of cells like melanin. • Pigments can be – exogenous :coming from outside the body or – endogenous: synthesized from the body itself Exogenous pigments 1. Carbon or coal dust : The most common • This is found everywhere in the air. • When it is inhaled the alveolar macrophages pick up the pigment and it is accumulated within them. As a result the lungs become black (Anthracosis). • When the carbon dust is increased a fibroblastic reaction is raised and may cause a disease called coal workers pneumoconiosis. 2. Tattooing Endogenous pigments 1.Lipofuscin • Insoluble pigment • Seen normally in ageing cells. • Also called the wear and tear pigment. • Derived from polymers of lipids and phospholipids by peroxidation of polyunsaturated lipids of cellular membranes. • Yellow brown finely granular intracytoplasmic perinuclear pigment • mostly seen in the liver and heart. 2. Melanin • Endogenous • Non hemoglobin derived • Brown black pigment in melanocytes. • Result of oxidation of tyrosine to dihydroxyphenylalanine by tyrosinase. 3. Haemosiderin • haemoglobin derived • golden yellow to brown granular pigment in tissues • local or systemic excess of iron • Iron is released in red cell breakdown and stored in liver, bone marrow and spleen as ferritin and haemosiderin. • When there is bleeding into tissues excess hemosiderin deposition takes place locally. • Haemosiderosis – deposition of hemosiderin in many organs and tissues in the conditions of systemic overload of iron. • Haemochromatosis – A genetic defect in iron metabolism results in a disease that absorb too much iron from the diet resulting heavy deposition of haemosiderin in tissues • Iron can be demonstrated by Perl’s stain. Calcification • Calcification is pathologic deposition of calcium salts with smaller amounts of iron, magnesium and other minerals. There are 2 types of pathologic calcification. Thank You!!!! .