Cell Death | Chapter 2 | ROBBINS PATHOLOGY Based Audio Podcast

ROBBINS PATHOLOGY CHAPTER 2 - Cell Injury, Cell Death, and Adaptations Cell Death - Cell death represents the culmination of persistent or excessive cellular injury, marking the transition from potentially reversible damage to irreversible damage. Injurious stimuli target essential cellular components, including mitochondria, cell membranes, and DNA. The cellular response depends on the nature, duration, and severity of the injury. The two principal mechanisms of cell death are necrosis and apoptosis, which differ significantly in their morphology, mechanisms, and physiological roles. Necrosis Necrosis is a pathological process resulting from severe injury, such as ischemia, trauma, or exposure to toxins. Historically, it is viewed as "accidental" cell death. It is characterized by severe mitochondrial damage, ATP depletion, and the rupture of lysosomal and plasma membranes. Morphology and Consequences: Necrotic cells are enlarged (swelling). A key feature is the breakdown of the plasma membrane, allowing cellular contents to leak out into the extracellular space. This leakage elicits a local host reaction: inflammation. Leakage of intracellular proteins (e.g., cardiac troponin) into the circulation serves as a biomarker for tissue-specific injury. Microscopically, necrotic cells show increased eosinophilia due to loss of RNA and accumulation of denatured proteins. The nucleus breaks down in three patterns: fading (karyolysis), shrinkage (pyknosis), or fragmentation (karyorrhexis), ultimately disappearing within 1 or 2 days. Patterns of Tissue Necrosis: Necrosis can manifest in specific tissue patterns: 1. Coagulative necrosis: The architecture of the dead tissue is preserved for days, resulting in a firm texture (e.g., an infarct). 2. Liquefactive necrosis: Dead cells are digested, transforming the tissue into a viscous liquid (pus), often seen in bacterial infections or hypoxic death in the CNS. 3. Caseous necrosis: Characterized by a friable, yellow-white, "cheeselike" appearance, common in tuberculosis. 4. Fat necrosis: Focal fat destruction, typically caused by activated pancreatic lipases, leading to chalky-white deposits. 5. Fibrinoid necrosis: Vascular damage where immune complexes deposit in artery walls, appearing amorphous and bright pink. 6. Gangrenous necrosis: Applied to a limb that has lost blood supply and undergone necrosis, usually coagulative. Apoptosis Apoptosis is a highly regulated mechanism of cell death ("suicide program") serving to eliminate unwanted cells, maintaining homeostasis, or eliminating cells injured beyond repair (e.g., those with DNA damage or misfolded proteins). It kills cells without eliciting an inflammatory reaction. Morphology and Mechanism: Apoptotic cells are reduced in size (shrinkage), contrasting with necrosis. The most characteristic feature is chromatin condensation. The cell fragments into plasma membrane-bound apoptotic bodies containing cytoplasm and organelles. Although the plasma membrane remains intact, surface components change (e.g., externalized phosphatidylserine) to serve as "eat me" signals for rapid phagocytic removal (efferocytosis). Apoptosis is mediated by caspases (proteases). Two distinct pathways converge on caspase activation: 1. Mitochondrial (Intrinsic) Pathway: The most common pathway, triggered by loss of survival signals or DNA damage. Insults activate pro-apoptotic BAX/BAK proteins, which increase mitochondrial membrane permeability, causing proteins like cytochrome c to leak into the cytosol. Cytochrome c binds to APAF-1 to activate initiator caspase-9. 2. Death Receptor (Extrinsic) Pathway: Initiated by engagement of plasma membrane death receptors (e.g., Fas or TNFR1). This leads to the activation of initiator caspase-8. Both pathways activate executioner caspases (e.g., caspase-3 and caspase-6). Other Mechanisms Other forms of cell death include: • Necroptosis: A hybrid form that morphologically resembles necrosis (swelling, membrane rupture, inflammation) but is genetically controlled and caspase-independent. It relies on the RIPK1 and RIPK3 complex, which leads to MLKL phosphorylation and plasma membrane disruption. • Pyroptosis: Occurs in infected cells and involves activation of caspase-1, causing cell death and releasing the inflammatory cytokine IL-1 (fever-inducing). • Ferroptosis: An iron-dependent pathway triggered by excessive membrane lipid peroxidation, leading to loss of plasma membrane permeability. • Autophagy: Primarily a survival mechanism where cells degrade their own contents (autophagosomes fuse with lysosomes) to recycle metabolites during nutrient deprivation, but can lead to cell death if inadequate to cope with stress.