Robbins Chapter 1: Cell Injury & Death
Robbins Chapter 1: Cell Injury & Death
Four aspects of disease process:
I. Etiology or cause
III. Morphologic changes (structural alterations in cells or tissues)
IV. Functional derangements and clinical significance
Cellular adaptions: hypertrophy, atrophy
When the limits of adaptive responses are exceeded cell injury occurs, initially reversibl, then irreversible leading to cell death.
Necrosis: severe cell swelling or cell rupture, denaturation and coagulation of cytoplasmic proteins and breakdown of cell organelles
Apoptosis: internally controlled cell death, chromtin condensation and fragmentation.
Oncosis: prelethal changes preceding necrotic cell death, characterized by cell swelling
Causes of Cell Injury:
- Hypoxia (loss of aerobic oxidative respiration) vs. Ischemia (loss of blood supply: also cuts off metabolic substrates, injures tissue faster)
- Physical agents (temperature, trauma, radiation)
- Chemical agents and drugs
- Infectious agents
- Immunologic reactions
- Genetic derangements
- Nutritional imbalances
General Biochemical Mechanisms
Particularly vulnerable are glycolysis, the citric acid cycle and oxidative phosphorylation.
- ATP depletion: ouabain-sensitive Na+,K+-ATPase in plasma membrane stops working, Na+ accumulates intracellularly, cell swells; cell switches to anaerobic metabolism (glycolysis) and glycogen stores are depleted, pH goes down.
- Oxygen and oxygen-derived free radicals/reactive oxygen species
- Loss of intracellular calcium homeostasis: activates phospholopases, proteases, ATPases, endonucleases
- Defects in membrane permeability
- Irreversible mitochondrial damage: leakage of cytochrome c triggering apoptotic cell death
Reversible cell injury: cell swelling, detachment of ribosomes from granular e.r. and dissociation of polysomes into monosomes. Fatty change encountered in cells invloved in fat metabolism (hepatocyte, myocardium). Histologically characterized by pallor, hydropic change, vacuolar degeneration. EM: plasma membrane blebbing, blunting, villous distortion, myelin figures, mitochondrial swelling, rarefaction, nuclear disaggregation of granular and fibrillar elements.
Irreversible cell injury: mitochondria swell, lysosomes swell, damage to plasma membrane and lysosomal membranes leads to enzyme leakage; acidosis somewhat protective by inhibiting enzymatic reactions.
Ischemia/Reperfusion Injury: new damage on reperfusion mediated by oxygen free radicals and cytokine/adhesion molecules furthering immune-mediated injury.
Free radicals: def. chemical species with a single unpaired electron in outer orbit.
Cause injury by: lipid peroxidation of membranes, oxidative modification of proteins, lesions in DNA (single strand breaks).
Inactivated by: antioxidants (vit A, E, glutathione), binding to storage and transfer proteins (transferrin, ferritin, lactoferrin, ceruloplasmin), enzymes (catalase, SOD, glutathione peroxidase)
mercuric chloride – binds sulfhydryl groups of proteins
cyanide – poisons mitochondrial cytochrome oxidase
CCl4 – conversions to free radical CCl3· causing lipid peroxidation
Acetaminophen – P450 catalyzed oxidation to toxic metabolite
Necrosis: def. spectrum of morphologic changes that follow cell death in living tissue that result from progressive degredative action of enzymes on the lethally injured cell. Morphologic appearance of necrosis is the result of enzyme digestion & denaturation of proteins. Histologically: increased eosinophilia, karyolysis (nuclear pallor), pyknosis (nuclear shrinkage), karyorrhexis (nuclear fragmentation).
- Coagulative: e.g. myocardial infarct
- Liquefactive: e.g. bacterial or fungal infections, CNS hypoxia
- Gangrenous: e.g. limb ischemia (usually a combination of coagulative and liquefactive necrosis), surgical term
- Caseous: e.g. tuberculosis. characterized by granular debris w/obliteration of tissue architecture (gross: white & cheesy)
- Fat necrosis
Apoptosis: def. programmed cell death.
Chracterized by cell shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, phagocytosis by macrophages or adjacent cells. Does not elicit inflammation (in contrast to necrosis).
- Protein cleavage (caspases)
- Protein cross-linking
- DNA breakdown (endonuclease)
- Phagocytic recognition (mediated by phosphatidylserine and thrombospondin expression)
- ced genes
- Fas-Fas ligand model: CD95 receptor on cell surface, TNF and TNFR-mediated apoptosis
- Bcl-2: supresses apoptosis by direct action on mitochondria (preventing increased permeability) & by binding other proteins (Apaf-1)
- caspase (cysteine proteases that cleave after aspartic acid) mediated proteolytic cascade
heterophagy and autophagy
lipofuscin pigment represents undigested material that results from lipid peroxidation
cloroquine – raises lysosomal pH inactivating its enzymes
amiodarone – binds lysosomal phospholipids inhibiting breakdown
barbiturates – hypertrophy of smooth e.r. and P450 upregulation
megamitochondria – liver in alcoholic liver disease and in nutritional deficiencies
Thin filaments – actin (6-8 nm), myosin (15 nm). Amabita phalloides toxin binds actin fillaments
Microtubules (20-25 nm) – involved in motility (cilia), leukocyte migration, phagocytosis. Colchicine and vinca alkaloids bind tubulin and prevent assembly.
Intermediate filaments (10 nm) – keratin, neurofilaments, desmin, vimentin, glial filaments. Mallory body composed of keratin intermediate filaments. Alterations in keratin filament genes cause skin disorder epidermolysis bullosa simplex.