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

Molecular mechanisms of cell death: Apoptosis: ◦Programmed cell death ◦Active process - energy dependent ◦Type of cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins ◦Affect a...

Molecular mechanisms of cell death: Apoptosis: ◦Programmed cell death ◦Active process - energy dependent ◦Type of cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins ◦Affect a single cell or group of cells ◦Characteristic microscopic appearance ◦Enzymes activated that degrade nuclear DNA and protein ◦Membrane integrity is maintained ◦Lysosomal enzymes are not involved ◦Quick - cells gone in a few hours ◦Pathological or physiological When does apoptosis occur physiologically?: ◦1) In order to maintain a steady state ◦2) Hormone-controlled involution ◦3) Embryogenesis ‣ Removal of tissue ‣ Organ sculpting ◦Signalling events in involution. One example is breast gland epithelium after lactation, in which the number of cells in the epithelium becomes reduced. Induction of apoptosis and shedding of dying cells into the alveolar lumen. When does apoptosis occur pathologically?: ◦Cytotoxic T cell killing of virus-infected cells ◦Removal of neoplastic cells ◦When cells are damaged, particularly with damaged DNA ◦Graft vs host disease Apoptosis:  How do apoptotic cells look like?: Initiation and execution of apoptosis: ◦ Triggered by two mechanisms ‣ Intrinsic ‣ Extrinsic ◦Both result in activation of caspases ‣ Enzymes that control and mediate apoptosis ‣ Cause cleavage of DNA and proteins of the cytoskeleton How is the intrinsic pathway initiated and carried out?: ◦Initiating signal comes from within the cell. ◦Triggers: ‣ Most commonly irreparable DNA damage ‣ Withdrawal of growth factors or hormones ◦p53 protein is inactivated and this results in the outer mitochondrial membrane becoming leaky ◦Cytochrome C is released from the mitochondria and this causes activation of caspases How is the extrinsic pathway initiated and carried out?: ◦Initiated by extracellular signals ◦Triggers: ‣ Cells that are a danger e.g. tumour cells, virus-infected cells ◦One of the signals is TNFalpha: ‣ Secreted by T killer cells ‣ Binds to cell membrane receptor (‘death receptor’) ‣ Results in activation of caspases Clearance of apoptotic bodies: ◦Both intrinsic and extrinsic pathways cause the cells to shrink and break up into apoptotic bodies ◦The apoptotic bodies express proteins on their surface ◦They can now be recognised by phagocytes or neighbouring cells ◦Finally degradation takes place within the phagocytes  Apoptotic vs necrotic cells: Comparison of structural changes in oncosis/necrosis and apoptosis: