title: A potential role of the JNK pathway in hyperoxia-induced cell death, myofibroblast transdifferentiation and TGF-β1-mediated injury in the developing murine lung.
abstract: BACKGROUND
  Transforming growth factor-beta 1 (TGF-β1) has been implicated in hyperoxia-induced cell death and impaired alveolarization in the developing lung. In addition, the c-JunNH2-terminal kinase (JNK) pathway has been shown to have a role for TGF-β1-mediated effects. We hypothesized that the JNK pathway is an important regulator of hyperoxia-induced pulmonary responses in the developing murine lung.
  
  
  RESULTS
  We used cultured human lung epithelial cells, fetal rat lung fibroblasts and a neonatal TGF-β1 transgenic mouse model. We demonstrate that hyperoxia inhibits cell proliferation, activates cell death mediators and causes cell death, and promotes myofibroblast transdifferentiation, in a dose-dependent manner. Except for fibroblast proliferation, the effects were mediated via the JNK pathway. In addition, since we observed increased expression of TGF-β1 by epithelial cells on exposure to hyperoxia, we used a TGF-β1 transgenic mouse model to determine the role of JNK activation in TGF-β1 induced effects on lung development and on exposure to hyperoxia. We noted that, in this model, inhibition of JNK signaling significantly improved the spontaneously impaired alveolarization in room air and decreased mortality on exposure to hyperoxia.
  
  
  CONCLUSIONS
  When viewed in combination, these studies demonstrate that hyperoxia-induced cell death, myofibroblast transdifferentiation, TGF-β1- and hyperoxia-mediated pulmonary responses are mediated, at least in part, via signaling through the JNK pathway.
authors.affiliation: Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Li
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.forename: Huanxing
authors.initials: H
authors.lastname: Sun
authors.forename: Angara
authors.initials: A
authors.lastname: Sureshbabu
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakurai
authors.forename: Virender K
authors.initials: VK
authors.lastname: Rehan
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000254:growth & development* / Q000648:ultrastructure; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1