reversible

irreversible

• ischemia/hypoxia (decrease blood flow/oxygen)
• trauma/environmental hzard (ex: hyperthermia and hypothermia)
• infectious agents
• immune responses
• toxins
• free radicles
• directed stimulus ("programmed" cell death)

1. ischemia decrease O2
2. decrease ETC in mit
3. decrease ATP
   1. decrease Na/K pump
      1. decrease influx of Ca and H20, and increase exit of K
      2. cause cell swelling, loss of microvilli, bleebs, ER swelling, myelin figures
   2. increase glycolysis
      1. decrease pH cause clumping of nuclear chromatin
         1. can become irreversible
      2. decrease glycogen
   3. detachment of ribosomes
      1. decrease protein synthesis
      2. lipid deposition

• swelling
• ribosome detach
• cloudy swelling on LM

• pt of irreversible injury
• membrane breaks
• calcium entry activates proteases and autodigestion

1. increase time of decrease pH leads to intracellular relase of lysosomal enzymes
   1. basophilia
   2. nuclear changes
   3. protein digestion

• swelling on cell as whole "cloudy swelling"
  • advanced form: hydrophic degeneration (organelles look like vacuoles as water continues to come in)
• swelling of SER and RER with detachment of ribosomes from RER on TEM
• mitochondria and cristae swelling with electron dense granular deposits of calcium
• periperhal clumping of nuclear chromatin
• plasma membrane blebs

• calcium precipitates to form electron dense granular deposits
• pyknotic nucleus (condenses into little ball)
  • VERY basophilic (loss of RNA, degradation of proteins)
• nucleus eventually fragments (karyorhexis) and is lost from cell (karyolysis)

• apoptosis
  • death by design
  • energy active process requirs new RNA and protein syn.
  • cell membranes remain intact around subcellular fragments
  • prompt phagocytosis of fragments reoves cell without exposing neighbor tissues to injury
• necrosis
  • disruption of homeostasis
  • energy delpletion
  • cell membrane dissolves as cell dies
  • release of proteases and inflammatory substances damages neighboring tissues

1. induction via:
   • extrinsic: receptor ligand interaction (FAS, TNF receptor)
   • intrinsic: withdrawal of GF's, hormones
   • injury: radiation, toxins, free radicals
     • damage DNA
   • Tc cells
2. all pathways meet at mitochondrial permeability increasing
3. activate pro-apoptotic
4. activates initiator caspases
5. activate executioner capsases
   1. cysteine residues act at Asp residues of proteins
   2. leads to breakdown of cytoskel. and endonuclease activation
      • endonuclease cause DNA fragmentation

• specific death ligands
• withdrawl of GF's, hormones
• injurous agents (ex: radiation)
• cytotoxic T cells can directly activate execution caspes

• induction with enzyme synthesis
• execution via activation of proteases, endonucleases
• degeneration- form apoptotic bodies
• phagocytosis via macrophages

• apoptosis- active form of cell death
• necrosis- death in response to injury

• apoptosis- gene activation (BCL-2, c-myc, p53)
• necrosis- no gene activation

• apoptosis- ATP dependent, may require protein and/or RNA syn.
• necrosis- ATP depletion, no protein or RNA syn./ NO ENERGY REQUIRED

• apoptosis- pathological conditions, physical and toxic insults
• necrosis- wide range of causes (some overlap with apoptosis)

• apoptosis- often single cells
• necrosis- mostly clusters of cells

• coagulative
• liquifactive
• enzymatic/fat
• caseous
• fibrinoid

• cell death without dissolution of tissue architecture
  • shapes of cells, tissues same while nuclei and intracellular organelles are lysed
  • cells, tissue stain uniformly pink (no nucleic acids remain)
• cause- sudden ischemia
  • sudden loss of blood, O2 lead to
  • denaturation of proteolytic enzymes and structural proteins, BUT
  • lysosomal and protease activity is insufficient to dissolve cells and tissues

• dry- infarction involving several tissue planes, characterized by coagulative necrosis involving several tissue planes, without infection
• wet- same as dry, but complicated by infection and superimposed liquifactive necrosis

Gangrene is infarct (death of tissue due to loss of blood supply) in an extremity.

• Def- necrosis resulting in lysis of cell with loss of tissue and associated accumulation of pus (bunch of neutrophils)
• commonly seen in: brain, abscess
  • cause of abscess usually infection induced in dense and localized influx of netrophils
  • cause in brain usually hypoxia (and brain can't do wound healing)

• def
  • loss of lipid content and loss of membrane integrity of lipocytes within and surrounding pancrease
  • precipitation of insoluble calcium salts in areas of cell damage (saponification)
    • appear as chalk white deposits on gross exam and fine, blue black percipitate on LM)
• cause- acute inflam. of pancreatitis due to alcohol related injury or gallstones
• mechanism
  • pancreatic lipase leak from injured pancreatic acinar cells
  • digests lipocytes and pancreatic cells

• def.
  • occurs in granuloma
  • complete loss of cells and tissue architecture at center of granuloma
  • replacement of cells with debri that appears friable, white, cottage cheese deposit in tuissue on gross exam
  • granular accum. thats pink in HE with border of macrophages and fibrosis on LM
• cause- TB
• mechanism
  • apoptosis
  • necrosis of macrophages at center of granuloma
  • effects of cytokines (TNF) macrophages
  • effects of CD8 T cell activation via FAS-FASL ligand death receptor

• loc.- arterial walls
• features
  • deeply eosinophilic
  • amorphis, fibrin like strands seen in vessel walls via HE stain on LM with variable frag. of smooth muscle
• cause- most commonly vascular injury due to immune complex associated vasculitis or accelerated HTN
• mechanism
  • vascular damage lead to:
  • injury to vessel wall causing leak of protein and fibrin from circulation to become entrapped in wall
  • ex: vasculitis (complement activated by entrapped immun complexes causes vascular injuury)
  • ex: malignant/accelerated HTN (excessive pressure damage endothelium and vessel wall)

• apoptosis- internucleosomal fragmentation of DNA by calcium, magnesium dependent endonuclease into discrete fragments
• necrosis- lysosomal DNase degradation of DNA into randomly sized fragments

• apoptosis- key event may be cytoplasmic initation of endogenous proteases
• necrosis- progressive membrane damage and calcium influx are critical

• apoptosis- peripheral crescent like chromatin condesation
• necrosis- peripheral chromatin clumping

• apoptosis- loss of cell volume, shrinkage
• necrosis- cell and organelle swelling

• apoptosis- intact cell membrane ion gradient
• necrosis- loss of ion gradient

• apoptosis- nuclear fragmentation, surface and organelle blebbing
• necrosis- rupture of nuclear membrane and leakage

• apoptosis- cytoplasmic budding yields membrane bound apoptotic bodies rapidly phagocytized by macrophages or parenchymal cells (no inflammatory response)
• necrosis- inflammatory response and phagocytosis of debris by macrophages and PMNL

• apoptosis- cells shrink and fragment
• necrosis- cells swell and burst