- ATP depletion: failure of energy-dependent functions –> reversible injury –> necrosis
- Mitochondrial damage: ATP depletion –> failure of energy-dependent cellular functions –> ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis
- Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis
- Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids
- Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis
- Accumulation of damaged DNA and misfolded proteins: triggers apoptosis
Ischemic and Toxic Injury
- Mild ischemia: Reduced oxidative phosphorylation –>. reduced ATP generation -> failure of Na pump –> influx of sodium and water -> organelle and cellular swelling (reversible)
- Severe/prolonged ischemia: severe swelling of mitochondria, calcium influx into mitochondria and into the cell with rupture of lysosomes and plasma membrane. Death by necrosis and apoptosis due the release of cytochrome c from mitochondria
- Reperfusions injury follows blood flow into ischemic area is caused by oxidative stress due to release of free radicals from leukocytes and endothelial cells. Blood brings calcium that overloads reversibly injured cells with consequent mitochondrial injury. Influx of leukocytes generates free radicals and cytokines. Local activation of complement by lgM antibodies deposited in ischemic tissues.
- Chemicals may cause injury directly or by conversion into toxic metabolites. The organs chiefly affected are those involved in absorption or excretion of chemicals or others such as liver where the chemicals are converted to toxic metabolites. Direct injury to critical organelles such as mitochondria or indirect injury from free radicals generated from the chemicals/toxins is involved.
- Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction
- Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes
- Initiated by two major pathways:
- Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they activate caspases; inhibited by anti-apoptotic members of the BCL2 family, which are induced by survival signals including growth factors
- Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells.
Necroptosis and Pyroptosis:
- Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death.
- Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses.
- Necroptosis is caspase-independent but dependent on signaling by the RlP1 and RlP3 complex.
- RlP1 -RlP3 signaling reduces mitochondrial ATP generation, causes production of ROS, and permeabilizes lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis.
- Release of cellular contents evokes an inflammatory reaction as in necrosis.
- Pyroptosis occurs in cells infected by microbeslt involves activation of caspase-1 which cleaves the precursor form of lL-1 to generate biologically active lL-1. Caspase-1 along with closely related caspase-11 also cause death of the infected cell.
©Robbins Basic Pathology, Ninth edition