title: Serine/threonine kinase-protein kinase B and extracellular signal-regulated kinase regulate ventilator-induced pulmonary fibrosis after bleomycin-induced acute lung injury: a prospective, controlled animal experiment.
abstract: BACKGROUND
  Lung fibrosis, reduced lung compliance, and severe hypoxemia found in patients with acute lung injury often result in a need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and fibrogeneic activity but the mechanisms regulating the interaction between high tidal volume and lung fibrosis are unclear. We hypothesized that high-tidal-volume ventilation increased pulmonary fibrosis in acute lung injury via the serine/threonine kinase-protein kinase B (Akt) and mitogen-activated protein kinase pathways.
  
  
  METHODS
  After 5 days of bleomycin administration to simulate acute lung injury, male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume mechanical ventilation (30 ml/kg) or low-tidal-volume mechanical ventilation (6 ml/kg) with room air for 1 to 5 hours.
  
  
  RESULTS
  High-tidal-volume ventilation induced type I and type III procollagen mRNA expression, microvascular permeability, hydroxyproline content, Masson's trichrome staining, S100A4/fibroblast specific protein-1 staining, activation of Akt and extracellular signal-regulated kinase (ERK) 1/2, and production of macrophage inflammatory protein-2 and 10 kDa IFNgamma-inducible protein in a dose-dependent manner. High-tidal-volume ventilation-induced lung fibrosis was attenuated in Akt-deficient mice and in mice with pharmacologic inhibition of ERK1/2 activity by PD98059.
  
  
  CONCLUSIONS
  We conclude that high-tidal-volume ventilation-induced microvascular permeability, lung fibrosis, and chemokine production were dependent, in part, on activation of the Akt and ERK1/2 pathways.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.forename: Shuen-Kuei
authors.initials: SK
authors.lastname: Liao
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Huang
authors.forename: Ming-Jui
authors.initials: MJ
authors.lastname: Hung
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Quinn
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases