title: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome.
abstract: BACKGROUND
  Recent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy.
  
  
  OBJECTIVE
  To examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction.
  
  
  METHODS
  In vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11).
  
  
  METHODS
  In vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand.
  
  
  RESULTS
  The injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P =.03) and 8 hours (P =.002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P =.002).
  
  
  CONCLUSIONS
  Mechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.
authors.affiliation: Department of Critical Care, St Michael's Hospital, University of Toronto, Toronto, Ontario.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Jean
authors.initials: J
authors.lastname: Parodo
authors.forename: Osamu
authors.initials: O
authors.lastname: Kajikawa
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.forename: Vern
authors.initials: V
authors.lastname: Edwards
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D018925:Chemokines / Q000097:blood; D003404:Creatinine / Q000097:blood; D004847:Epithelial Cells / Q000166:cytology; D053222:Fas Ligand Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D007421:Intestine, Small / Q000166:cytology; D007668:Kidney / Q000166:cytology; D007684:Kidney Tubules / Q000166:cytology; D017093:Liver Failure / Q000097:blood / Q000209:etiology / Q000473:pathology; D008168:Lung / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism; D023421:Models, Animal; D009102:Multiple Organ Failure / Q000097:blood / Q000209:etiology* / Q000473:pathology*; D011817:Rabbits; D051437:Renal Insufficiency / Q000097:blood / Q000209:etiology / Q000473:pathology; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018925:Chemokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D003404:Creatinine