module 3 - detailed

• cells actively control the composition of their immediate environment and intracellular milieu within a narrow range of physiological parameters
• under physiological stresses or pathological injury cells can undergo adaptation to achieve a new steady state that would be compatible with their new environment

  if injury is too severe, chronic, or rapid, the affected cells die
• what are the characteristics of cell injury?

  not an all or nothing phenomenon, response depends on type, status, and genetic makeup of the injured cell, local injuries can result in multiple secondary and tertiary effects, cell function may be lost long before biochemical and clinical manifestations occur
• what are some causes of cell injury?

  hypoxia, ischemia, chemical agents, physical agents, infections, immunological reactions, genetic defects, nutritional defects, aging
• what is hypoxia?

  inadequate supply of oxygen to tissues
• what is ischemia?

  inadequate blood flow to tissues
• what are the key aspects of the pathogenesis of cell injury?

  ATP depletion, permeabilization of cell membranes, disruption of protein synthesis and other metabolic processes, and DNA damage
• what causes ATP depletion in the pathogenesis of cell injury?

  decreased ATP production, calcium induced mitochondrial permeability, and calcium activation of ATPase
• what causes permeabilization of cell membranes in the pathogenesis of cell injury?

  calcium activation of phospholipase A, ROS peroxidation of membrane lipids, and protease degradation of cytoskeleton
• what causes disruption of protein synthesis and other metabolic processes in the pathogenesis of cell injury?

  calcium activated proteases, lysosomal enzyme release, ATP and NADPH depletion, disaggregation of ribosomes, and ROS damage to enzymes
• what causes DNA damage in the pathogenesis of cell injury?

  activation of endonucleases, ROS damage to DNA and RNA
• what are the sequence of events in reversible and irreversible ischemic cell injury?

  ischemia blocks blood flow, decrease oxidative phosphorylation in mitochondria, ATP depletion

  inhibit Na pump --> influx of calcium, water and sodium, efflux of potassium --> cellular swelling, loss of microvilli, blebs, ER swelling, myelin figures

  increase glycolysis --> decrease pH and increase glycolysis --> intracellular release and activation of lysosomal enzymes --> decrease basophilia, nuclear changes, and protein digestion

  detachment of ribosomes --> decrease protein synthesis --> lipid deposition
• what marks the transition from reversible to irreversible cell injury?

  membrane damage and increased cytoplasmic calcium
• what intracellular enzymes does calcium activate?

  ATPase, phospholipase, protease, endonuclease
• what are the sources and effects of calcium?

  sources: extracellular, ER, mitochondria

  effects: membrane damage, chromatin damage, reduced ATP
• what is the role of reactive oxygen species in cell injury?

  free radicals cause cell injury
• what induces reactive oxygen speceis?

  inflammation, radiation, oxygen toxicity, chemicals, reperfusion, injury
• what are examples of reactive oxygen species?

  superoxide (O2), hydrogen peroxide (H2O2), hydroxyl radical (OH)
• what is the cytoarchitecture of cellular necrosis?

  cytoplasmic swelling, rupture of plasma membrane, swelling of cytoplasmic organelles, and nuclear changes
• what is pyknosis?

  chromatin condensation
• what is karyorrhexis?

  nuclear fragmentation
• what is karyolysis?

  nuclear lysis
• what are the morphological features of reversible cell damage?

  cell swelling, mitochondrial swelling, endoplasmic reticulum swelling, clumping of nuclear chromatin, myelin figures, loss of microvilli, surface blebs, and lipid deposition
• what are the morphological features of irreversible cell damage?

  pyknosis, karyorrhexis, karyolysis, fragmentation of cell and nuclear membranes, loss of basophilia/ribosomes, membrane disruption, detachment of ribosomes, lysosome rupture
• what are the characteristics of coagulation necrosis?

  homogenous eosinophilic cytoplasm, retained cell outlines, pyknosis and karyolysis
• what is the default pattern of necrosis associated with ischemia or hypoxia in every organ in the body except the brain?

  coagulation necrosis
• what happens in coagulative necrosis?

  cellular degradation is principally dependent on enzymes from nearby intact cells, this process is slower and thus dead cells remain somewhat intact and recognizable
• what are the characteristics of caseous necrosis?

  pale yellow, crumbly exudate, cell walls disrupted, tissue architecture lost, mineralization
• what causes caseous necrosis?

  typical of infections with organisms that are difficult to degrade, leads to activation of macrophages and recruitment of additional macrophages, residual material from infectious agent and cell debris produces the cheese like exudate
• what are the characteristics of liquefactive necrosis?

  near total loss of cells and tissue, grossly has a fluid consistency
• what is the necrosis pattern seen following ischemic and other injury in the brain and other CNS?

  liquefactive necrosis
• what are the three major factors that contribute to liquefactive necrosis?

  enzymatic digestion of cellular debris in dead or dying tissues (proteases, DNases, lysosomal enzymes), enzymatic digestion of surrounding tissues, and denaturation of cellular proteins
• necrosis leads to inflammation, apoptosis does not
• what is the morphology of apoptosis?

  rounding up of the cell, reduction of cellular volume, pyknosis, karyorrhexis, plasma membrane blebbing, engulfment by resident phagocytes
• what are the mechanisms of apoptosis?

  the extrinsic and intrinsic pathways
• what is the extrinsic death receptor initiated pathway of apoptosis?

  involves TNF and Fas, initiator caspase 8 is activated by dimerization, involved in bystander apoptosis
• what is the intrinsic mitochondrial pathway of apoptosis?

  forms an apoptosome
• what is the final common pathway of apoptosis?

  executioner caspases
• what kind of apoptosis is androgen dependent epithelial apoptosis in the epididymis and why?

  intrinsic, due to removal of hormones
• why do executioner caspases break down chromatin?

  executioner caspase takes away inhibitor of CAD, and allows caspase activated DNase to work causing DNA fragmentation