INTRODUCTION TO HEALTH AND DISEASE BLOCK

Transcription

1 MBBS 1 st Yr. Lecture Dr. Annie Cheung September 25, 2002, 8:30AM 9:30 AM LT1, G/F, Academic and Administration Block Faculty of Medicine Building INTRODUCTION TO HEALTH AND DISEASE BLOCK CELL INJURY AND CELL DEATH Learning Objectives: To identify stimuli that may cause injury to cells To understand the concept of reversible & irreversible cell damage To understand possible mechanisms of cell injury To appreciate morphological features found in common types of reversible and irreversible cell injury and their pathological association To understand complications of cell death Effects of Cellular Injury Cells are maintained in a normal "steady state" by homeostatic mechanisms. Excessive external stresses or stimuli may bring about cellular adaptations i.e. hypertrophy, atrophy, hyperplasia and metaplasia. Cell injury occurs when the limits of adaptive capability are exceeded or when no adaptive response is possible. Cell injury is reversible up to a certain point, but persistent or severe stimulus causes irreversible cell injury and cell death. Causes of cell injury 1

2 1. Hypoxia (most common cause of cell injury): impairment of blood supply (ischaemia) loss of oxygen-carrying capacity of blood (e.g. Carbon monoxide poisoning) poisoning of oxidative enzymes within the cell (e.g. cyanide poisoning) 2. Physical agents: mechanical trauma sudden change in atmospheric pressure extremes of temperature radiation electricity 3. Chemical agents including poison and drugs. 4. Biological agents: bacteria-toxins; immunopathic. virus - cytopathic; incorporation into host's genome; immunopathic. fungus; parasite. 5. Immunological reactions: hypersensitivity states autoimmunity 6. Others: genetic defects; nutritional imbalance. Pathogenesis of cell injury The biochemical site and mechanisms of action of many injurious agents are unknown. No known common final pathway of cell injury resulting from the various causes. 4 intracellular systems are particularly vulnerable to the action of injurious agents:- 1. intracellular aerobic respiration, 2. cell membranes, 3. enzymatic and structural protein synthesis, and 4. genetic apparatus. The structural changes of cell injury become apparent only after some critical biochemical derangement has occurred. eg. Hypoxia anaerobic glycolysis structural membrane damage cellular swelling. The result of cell injury depends on the injury (i.e. the type, duration and severity of the stimulus) and on the cell (i.e. the type, state and adaptability of the cell). Susceptibility of cells to ischaemic necrosis High Neurons (3 5 min) Intermediate Myocardium, hepatocytes, renal epithelium (30 min 2 hr) Low Fibroblasts, epidermis, skeletal muscle (many hours) 2

3 I. REVERSIBLE INJURY (CELL DEGENERATION) Degeneration refers to morphological changes in cells caused by sublethal injury. The cell can revert to the former state of homeostasis if the noxious agent is removed. The changes are seen frequently in the cytoplasm. 1. Intracellular oedema (cellular swelling, hydropic degeneration) Due to entry of excessive isotonic fluid into the cell as a result of functional derangements in the mitochondria and plasma membrane. The organ shows pallor, increased turgor and increased weight. Individual cells are swollen with accumulation of Na+ and water, and loss of glycogen. With progressive influx of water, clear vacuoles appear in the cytoplasm. 2. Fatty change Fatty change refers to any abnormal accumulation of fat within parenchymal cells. Liver cells, heart muscle cells and renal tubular cells are most commonly affected. The organ is large, pale and greasy. Individual cells contain in their cytoplasm membrane-bound fat droplets as clear vacuoles may fuse displace the nucleus to the periphery of the cell. Causes of fatty change a) Hypoxia, including anaemia b) Starvation and wasting disease c) Chemicals and toxins, including alcohol, carbon tetrachloride, and bacterial toxin d) Metabolic disorders e.g. uncontrolled diabetes mellitus 3. Hyaline degeneration 'Hyaline' describes a non-specific, homogeneous glassy, pink appearance due to alterations within cells or in the extracellular space e.g. alcoholic hyaline in alcoholic liver disease, viral inclusions; hyaline arteriolosclerosis. 4. Intracellular accumulations e.g. pigment of aging (lipofuscin); lysosomal storage diseases; haemosiderin (iron) Sublethal nuclear damage Morphological changes in the nucleus exposed to sublethal injury are often not recognizable in light microscopy Sublethal damage to chromosomes is the basis of many heritable diseases (in germ cells) and neoplasm (in somatic cells). II. IRREVERSIBLE INJURY (CELL DEATH) Two morphological patterns of cell death in a living tissue or organ are recognized: 3

4 (A) Apoptosis (literally "falling off") Affects scattered single cells. Characterized by DNA fragmentation and chromatin condensation induced by and endonuclease activity. Shrinkage and condensation of the nucleus and cytoplasm occur rapidly break up into membrane-bound apoptotic bodies phagocytosed by adjacent cells degraded inside phagolysosomes. Apoptotic body is recognized in tissue sections as rounded or oval masses of intensely eosinophilic cytoplasm, frequently contain some dense nuclear chromatin fragments. May be a physiologic, active self-destructive process by which cells are eliminated when they are no longer required by the body, e.g. in normal cell turnover in various organs and in programmed destruction of cells during embryonic development. Also occurs in pathological states such as cell death induced by UV or ionizing radiation, cell mediated immunity, cytotoxic anticancer drugs, tumour cell death, toxic or viral hepatitis. (B) Necrosis Necrosis may be defined as the morphologic changes that follow cell death in a living tissue or organ, resulting from the progressive degradative action of enzymes on the lethally injured cell. Necrosis is death of cells or groups of cells while they are still part of a living body the living tissue develops a reaction towards the necrotic tissue. Cell death release of the lysosomal hydrolases self-digestion and structural disintegration of the necrotic cells (autolysis) or digested by phagocytosis and proteolytic enzymes immigrant leukocytes (heterolysis). Necrosis is often recognized macroscopically when large groups of cells die. Cytoplasmic changes are variable. Nuclear changes characteristically include: a) pyknosis i.e. dense haematoxylinophilic mass of chromatin, b) karyorrhexis i.e. chromatin material breaks up into fragments, and c) karyolysis i.e. complete dissolution of the nuclear matter so that the whole cell stains uniformly with eosin. Morphologic types of necrosis: 1. Coagulative necrosis Most common pattern of necrosis eg. Infarction caused by deprivation of blood supply The dead tissue is yellowish, firm, dull and lusterless. Histologically the tissue architecture and cell outlines are preserved with loss of nucleus. Characterized by conversion of the cell to an acidophilic, opague "tombstone". Formation of fibrin and the denatured cellular protein (structural & enzymatic proteins) blocks the proteolysis of the cell firmness of the necrotic tissue This kind of necrosis occurs usually in solid organs such as spleen, kidney and myocardium. 2. Liquefaction (colliquative) necrosis The lesion is soft and liquid. Results from the action of powerful hydrolytic enzymes (autolysis and heterolysis) Structure of the tissue is lost removal of debris fluid filled space 4

5 Occurs in ischaemic necrosis of brain e.g. cystic infarct of brain. Also found in bacterial infections: bacterial and leucocytic enzymes digestion of dead cells. 3. Caseous necrosis This lesion resembles cream cheese because of its whiteness, crumbling character and high lipid content. Caseation is characteristic of tuberculosis (due to the capsule of the tubercle bacillus Mycobacterium tuberculosis). Histologically, cellular outlines cannot be seen, and the tissue is changed into amorphous masses enclosed within a granulomatous inflammatory wall. 4. Fat necrosis a) Enzymatic fat necrosis (eg. acute pancreatitis) Triglycerides in fat cells are hydrolyzed by pancreatic lipase fatty acids and glycerol. Fatty acids then react with calcium to form soaps (saponification) which are deposited in the tissues as opague and chalky white patches. This causes patchy necrosis of the pancreas and of fatty spots throughout the abdomen. b) Traumatic fat necrosis Lipids released from fat cells provoke a chronic inflammatory and giant cell reaction. Usually seen in the breast where it presents as an indurated mass. 5. Fibrinoid necrosis Eosinophilic degeneration of collagen e.g. in a rheumatoid nodule Tissue death is accompanied by fibrin deposition, e.g. in Arthus reaction, in the arteriolar lesions of malignant hypertension. Effects of necrosis 1. Loss of function 2. Release of cell contents, e.g. aminotransferases released into the plasma from necrotic liver or myocardial cells 3. Acute inflammation 4. Effects of repair and regeneration, e.g. fibrous scar, cyst-like spaces 5. Dystrophic calcification 6. Infection, e.g. gangrene, abscess References 1. Chapter I: Cellular Pathology I: Cell Injury and Cell Death. Pathologic Basis of Disease. Robbins, Cotran & Kumar. 6th Edition. 2. Chapter III: Cell Injury and Death. Oxford Textbook of Pathology. Vol Chapter I: Cells and Tissues in Health and Disease. Muir's Textbook of Pathology. 13th Edition. 5