Cell injury and Cell Death Bahrain version October 4 2023.pptx

LEARNING OUTCOMES • Describe cell injury and define necrosis and apoptosis • Describe the causes, mechanisms and the cellular responses to cell injury • Describe cellular adaptation • Describe the mechanism of injury • List the morphologic changes of reversible and irreversible injury • Describe the...

LEARNING OUTCOMES • Describe cell injury and define necrosis and apoptosis • Describe the causes, mechanisms and the cellular responses to cell injury • Describe cellular adaptation • Describe the mechanism of injury • List the morphologic changes of reversible and irreversible injury • Describe the types of necrosis • Describe intracellular accumulation/calcification CELL INJURY CELLULAR RESPONSE TO STRESS AND INJURY  Adaptive responses  Atrophy  Hypertrophy  Hyperplasia  Metaplasia  Reversible cell injury  Irreversible cell injury = cell death  Necrosis  Apoptosis ATROPHY Decrease in size or number of cells due to loss of cell substance (resulting in a decrease in the size of the organ)  Physiologic or pathological  Decreased workload (atrophy of disuse)  Loss of innervation  Diminished blood supply  Inadequate nutrition (cachexia)  Loss of endocrine stimulation  Aging  Foetal development (atrophy of thyroglossal duct) HYPERTROPHY  Increase in cell size- increase in the size of the organ, no new cells, just larger cells  Occurs in cells incapable of division Physiological  Skeletal muscle with exercise Pathological  Left ventricular hypertrophy in hypertension HYPERPLASIA Increase in the number of cells (and usually the size of the organ)  Occurs in organs capable of cellular division  Often associated with hypertrophy Physiological  Hormonal (breast/uterus during pregnancy)  Compensatory (partial hepatectomy) Pathological  Excessive hormonal/growth factor (thyroid, endometrial hyperplasia) ….controlled, but can increase cancer risk METAPLASIA Reversible change in which one adult cell type is replaced by another adult cell type Examples:  Cigarette smoking causes respiratory epithelium to change to stratified squamous  Barrett oesophagus-stratified squamous epithelium changes to intestinal epithelium Can be a precursor to cancer CAUSES OF CELL INJURY        Oxygen deprivation  Hypoxia - low oxygen delivery to tissue  Ischaemia - decrease in blood flow (↓ oxygen and nutrients)  Shock - decrease in perfusion Physical agents (e.g. trauma, thermal injury, radiation) Chemical agents (e.g. poisons, environmental pollutants and drugs) Infectious agents Immunologic reactions Genetic defects Nutritional deficiency or excess OUTCOME OF CELLULAR INJURY  Cellular response depends on the injury  Type  Severity  Duration  Consequence depends on the cell  Type  State  Adaptability CELLULAR INJURY Reversible changes: Cellular swelling (hydropic change, vacuolar degeneration) Plasma membrane alteration-blebbing Loss of microvilli Mitochondrial swelling Dilation of endoplasmic reticulum with detachment of ribosomes Nuclear alterations Irreversible changes: Increased mitochondrial permeability Rupture of lysosomes Membrane rupture Nuclear changes REVERSIBLE INJURY  Increased (anaerobic) glycolysis  Reduced activity of “sodium pump” leading to the accumulation of sodium and water  Reduced activity of “calcium pump” leading to increase in cytosolic free calcium which activates enzymes:  ATPase  decreased ATP  Phospholipase  decreased phospholipids  Endonuclease  nuclear chromatin damage  Protease  disruption of membrane and cytoskeletal proteins IRREVERSIBLE INJURY  Marked mitochondrial changes  Extensive plasma membrane damage-rupture  Injury to lysosomal membranes  Activation of enzymes degrades the damaged cells  Release of enzymes causes damage to the surrounding cells MECHANISMS OF INJURY MEMBRANE DAMAGE FREE RADICALS   Extremely unstable, highly reactive chemical species with a single unpaired electron in outer orbit Includes reactive oxygen species (ROS) but not all ROS are free radicals (e.g. H202) REACTIVE OXYGEN SPECIES Free radical degradation  Unstable with spontaneous decay  Inactivation by enzymes, e.g glutathione peroxidase, catalase  Antioxidants (vitamin E, C) REACTIVE OXYGEN SPECIES FREE RADICALS AND CELL INJURY  Lipid peroxidation of membranes  Free radicals and membrane lipids react to produce highly reactive lipid peroxide  Oxidative modification of proteins  Cross-linking of proteins  damage to cellular enzymes  React with DNA and cause mutation TYPES OF CELL DEATH: NECROSIS  Morphological changes that follow cell death in a living tissue   Death of a large group of cells  It is due to a pathologic process (never physiologic)  Enzymatic digestion of cell  Autolysis  Heterolysis  Inflammation in the surrounding tissue Cytoplasmic eosinophilia Pyknosis - condensation of the nucleus and clumping of the chromatin (shrinking of nuclei) Karyorrhexis - fragmentation and breakdown of the nucleus Karyolysis - pallor and dissolution COAGULATIVE NECROSIS  Specific morphologic pattern of necrosis with preservation of the structural outlines  Characteristic of hypoxic cell death except in the brain  Cell shape and organ structure are preserved  Nuclei disappear LIQUEFACTIVE NECROSIS  Transformation of solid tissue into a liquid mass; enzymatic lysis of cells  Complete digestion of the dead cells, tissue structure destroyed  Characteristic of bacterial and some fungal infection (abscess) and hypoxic cell death in the central nervous system CASEOUS NECROSIS  Distinctive form of necrosis, characteristic of tuberculous infection  Cheesy, crumbly, white gross appearance  Granular debris surrounded by a ring of granulomatous inflammation FAT NECROSIS  Necrosis of fat induced by lipases (pancreas or macrophages)  Fatty acids complex with Ca++ to create calcium soaps  Fat trauma, fat necrosis in pancreatitis FIBRINOID NECROSIS • Necrotic damage to blood vessel wall • Associated with vasculitis GANGRENOUS NECROSIS  Not a distinctive pattern of cell death (clinical term)  Coagulative necrosis (mummified tissue – ‘dry’ gangrene)  Characteristic of ischaemia of the lower limb  Ischaemia with secondary bacterial infection (liquefactive necrosis – ‘wet’ gangrene)  Gas gangrene - Clostridium infection APOPTOSIS (PROGRAMMED CELL DEATH)  Greek word for “falling off”  Involves single cells or small clusters  Physiological  Embryogenesis  Hormone (involution of breast, endometrial shedding)  Death of inflammatory cells after inflammation  Cell deletion in proliferating populations-intestinal epithelium   Deletion of autoreactive T cells in thymus (failure might result in autoimmunity) Pathological  Virus-infected cells  Cells with DNA damage  Tumour cells MORPHOLOGY OF APOPTOSIS  Involves single cells or small clusters  Cells shrink rapidly  Eosinophilia of the cytoplasm  Condensation of the chromatin  Fragmentation of DNA  Formation of apoptotic bodies  Apoptotic bodies phagocytosed or rapidly degraded  No inflammatory response APOPTOSIS APOPTOSIS APOPTOSIS VS NECROSIS INTRACELLULAR ACCUMULATIONS  Endogenous  Substance produced in excess or reduced clearance e.g. storage diseases  Lipofuscin Exogenous  Cell cannot degrade substance (carbon, tattoos) Anthracosis PATHOLOGICAL CALCIFICATION  Abnormal deposition of calcium salts with smaller amounts of iron, magnesium and other mineral salts  Two types:  Dystrophic calcification  Metastatic calcification DYSTROPHIC CALCIFICATION  Deposition of calcium in a necrotic tissue  Normal serum calcium  Areas of necrosis or injury  Intracellular or extracellular ‘METASTATIC’ CALCIFICATION Deposition of calcium in a normal tissue  Occurs with hypercalcaemia - e.g. in hyperparathyroidism, destruction of bone occurring with tumours involving bone, vitamin D intoxication, sarcoidosis, or renal failure  Primarily affects vessels, kidneys, lungs, and gastric mucosa