Cell Death Lecture Outline PDF

CELL DEATH Dr Alessandro Aldera Division of Anatomical Pathology February 2024  LECTURE OUTLINE  Necrosis  Gangrene  Apoptosis  New concepts Slides prepared by Prof. Dhirendra Govender  NECROSIS Definition: death of cells i...

CELL DEATH Dr Alessandro Aldera Division of Anatomical Pathology February 2024  LECTURE OUTLINE  Necrosis  Gangrene  Apoptosis  New concepts Slides prepared by Prof. Dhirendra Govender  NECROSIS Definition: death of cells in the living organism due to: denaturation of cellular proteins and/or enzymatic digestion of the cell Autolysis: cellular enzymatic degradation by catalytic enzymes derived from lysosomes of dead cells Heterolysis: ….catalytic enzymes derived from immigrant leucocytes and other living cells eg. neutrophils and macrophages  NECROSIS Causes: 1. Ischaemia e.g. infarct, e.g. centre of tumour - tissues vary in ability to withstand hypoxia  NECROSIS Causes: 2. Toxins e.g. snake venom & bacterial toxins 3. Infectionse.g. virus - poliomyelitis - hepatitis bacteria - diphtheria - typhoid  NECROSIS Causes: 4. Hypersensitivity reactions - caseative necrosis in TB  NECROSIS Causes: 5. Chemical poisons acids - char alkalis - liquify phenols - coagulate  NECROSIS Causes: 6. Physical factors i) irradiation ii) heat >45oC - kills cells iii) freezing - vasospasm - ice crystals  NECROSIS TYPES OF NECROSIS: 1. Coagulative necrosis 2. Liquifactive necrosis 3. Caseous necrosis 4. Fat necrosis “Fibrinoid” necrosis  NECROSIS 1. COAGULATIVE NECROSIS Commonest Preservation of basic cell shape ghost outlines Loss of nucleus Eosinophilic (pink) opaque cytoplasm Due to protein denaturation: structural proteins enzymic proteins – no proteolysis of cell Seen in all tissue except brain  COAGULATIVE NECROSIS - RENAL INFARCT Preservation of basic cell shape Loss of nuclei Eosinophilic opaque cytoplasm  NECROSIS 2. LIQUIFACTIVE NECROSIS Liquefaction of tissues Due to lytic enzymes Characteristic of infarction of brain and also in abscesses (neutrophils) High water content in brain  Infarction of brain Compound Brain infarct granular corpuscles  3. CASEATIVE NECROSIS - PULMONAR Y TB Soft friable, yellow white debris – Caseation in similar to cheese tuberculosis of the lung Hypersensitivity reaction in TB  Caseative necrosis - Microscopy Fragmented granular cellular debris surrounded by Epithelioid a granulomatous reaction histiocytes forming granuloma Caseative necrosis  NECROSIS 4. FAT NECROSIS Causes: (i) Enzymatic (ii) Traumatic (including injections) to fatty tissue (iii) Infections  NECROSIS 4. FAT NECROSIS (Contd.) Enzymatic fat necrosis Eg. Acute pancreatitis Causes: alcohol bile reflux/regurgitation Caused by pancreatic enzymes: liquify cell membranes lipases catalyse triglycerides forming free fatty acids which complex with calcium -- calcium soaps (saponification). Focal necrosis in pancreas and abdominal fat Enzymatic fat necrosis - Acute pancreatitis Enzymatic fat necrosis - Acute pancreatitis Variable Shadowy outlines of Amorphous granular inflammatory necrotic fat cells basophilic deposits reaction (lipolysed) (calcium)  NECROSIS 4. FAT NECROSIS (Contd.) Traumatic fat necrosis Trauma to fatty tissue (including injections) Sites: Breast and buttock Macroscopy: firm to hard mass Microscopy: Foam cells, giant cells, granulation tissue, haemosiderin deposits Traumatic Fat Necrosis Traumatic Fat Necrosis GANGRENE  GANGRENE Definition: necrosis with *putrefaction of a number of tissues in a body part (*digestion of dead tissue by bacterial action) Classification of gangrene: I. Primary: due to infection with pathogenic bacteria which kill tissue (exotoxins) and then invade and digest dead tissue. II. Secondary: necrosis is due to another cause Eg. ischaemia and then saprophytic bacteria digest dead tissue.  GANGRENE I. Primary gangrene Gas gangrene Anaerobic gram positive sporulating bacilli = Clostridium perfringens. Intestinal commensal Spores in soil In anaerobic environment --- exotoxins --- kill adjacent tissues which are in turn invaded --- process spreads rapidly Ferments sugars --- H2 and CO2 - bubbles in the tissues (crepitant on palpation)  GANGRENE Dry II. Secondary / Ischaemic gangrene Wet Causes: 1. Vascular disease: atherosclerosis Diabetes mellitus 2. Embolism: Left heart - atria - valves eg. infective endocarditis - ventricles eg. infarct & CMO Aorta - aneurysm - atheroma 3. Trauma to major artery 4. Frostbite ---- vascular spasm 5. Chemicals: carbolic acid causes thrombosis ergot causes vasospasm  Secondary / Dry Ischaemic gangrene Usually starts in toes and spreads proximally Shrivelled and dry = mummified Sharp line of demarcation Black (Iron sulphide) Healing above line may lead to spontaneous amputation Secondary / Wet Ischaemic gangrene Putrid, foul smelling Rapid proximal spread No clear or sharp line of demarcation APOPTOSIS  APOPTOSIS Definition: A pathway of cell death induced by regulated intracellular programmes in which the targeted cells activate enzymes that destroy DNA and other cellular proteins. Programmed cell death. Energy dependent fragmentation of DNA by endogenous endonucleases. Individual cell deletion of unwanted/defective cells induced by physiological or pathological stimuli.  APOPTOSIS Functions / Roles: I. Physiological: Embryogenesis Hormone dependent involution Cell deletion in proliferating tissues – intestine. Preventing genome instability  APOPTOSIS Functions / Roles: II. Pathological: Cell death in tumours Death of immune cells – B and T lymphocytes Atrophy of hormone dependent organs Atrophy of organs following obstruction Cell death induced by cytotoxic T cells eg. graft rejection, graft vs host disease Cell injury by viruses APOPTOSIS  APOPTOSIS Specific disease associations: 1. Reduced apoptosis ---- cell accumulation e.g. neoplasia - p53 - bcl-2 2. Increased apoptosis ---- excess cell loss e.g. atrophy AIDS neurodegenerative disorders  AUTOPHAGY Proposed third mode of cell death: Cells generate energy and metabolites by digesting their own organelles and macromolecules. Allows a starving cell to survive. Ultimately, if nutrients are not received, may potentially digest all available substrates and die.  NECROPTOSIS Definition: Form of programmed cell death – resembles necrosis morphologically and apoptosis mechanistically Genetically programmed signal Caspase independent  PYROPTOSIS Definition: Another form of programmed cell death characterised by the release of pyrogen, fever inducing IL-1 Swelling of cells, loss of plasma membrane integrity and release of inflammatory mediators Occurs in cells infected by microbes Thank you