Paper I
Question
Apoptosis in pathologic conditions
Answer
Apoptosis is a regulated, energy-dependent form of programmed cell death characterized by cell shrinkage, chromatin condensation, nuclear fragmentation, and formation of membrane-bound apoptotic bodies, without eliciting an inflammatory response.
Physiological pathologic roles
- Deletion of cells during embryogenesis (implantation, organogenesis, developmental involution)
- Hormone-dependent involution in the adult (endometrial cell breakdown during menstrual cycle, lactating breast involution after weaning)
- Cell deletion in proliferating cell populations to maintain constant cell numbers (intestinal crypt epithelium)
- Elimination of potentially harmful self-reactive lymphocytes (both in the thymus and periphery — central and peripheral tolerance)
- Death of host cells that have served their useful purpose (neutrophils in an acute inflammatory response, lymphocytes at the end of an immune response)
Pathologic conditions involving apoptosis
- DNA damage — radiation, cytotoxic anticancer drugs, hypoxia (if damage is mild, triggers apoptosis via p53 activation; severe damage causes necrosis)
- Accumulation of misfolded proteins — ER stress response
- Cell injury in certain viral infections — viral hepatitis (councilman bodies), where the immune system induces apoptosis of infected cells
- Pathologic atrophy in parenchymal organs after duct obstruction — pancreas, parotid gland, kidney
- Tumour cell death — particularly in response to chemotherapy/radiotherapy, and immune-mediated tumour cell killing by cytotoxic T lymphocytes
Mechanisms
- Intrinsic (mitochondrial) pathway: Triggered by growth factor withdrawal, DNA damage, or protein misfolding — mitochondrial outer membrane permeabilization releases cytochrome c, activating caspase-9 and downstream executioner caspases
- Extrinsic (death receptor) pathway: Triggered by ligand binding to death receptors (Fas/FasL, TNF receptor), activating caspase-8 and downstream executioner caspases
- Both pathways converge on activation of executioner caspases (caspase-3, -6, -7), which cleave cellular substrates, leading to the morphological features of apoptosis