title: GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling.
abstract: We explored the mechanistic involvement of the growth arrest and DNA damage-inducible gene GADD45a in lipopolysaccharide (LPS)- and ventilator-induced inflammatory lung injury (VILI). Multiple biochemical and genomic parameters of inflammatory lung injury indicated that GADD45a(-/-) mice are modestly susceptible to intratracheal LPS-induced lung injury and profoundly susceptible to high tidal volume VILI, with increases in microvascular permeability and bronchoalveolar lavage levels of inflammatory cytokines. Expression profiling of lung tissues from VILI-challenged GADD45a(-/-) mice revealed strong dysregulation in the B-cell receptor signaling pathway compared with wild-type mice and suggested the involvement of PI3 kinase/Akt signaling components. Western blot analyses of lung homogenates confirmed approximately 50% reduction in Akt protein levels in GADD45a(-/-) mice accompanied by marked increases in Akt ubiquitination. Electrical resistance measurements across human lung endothelial cell monolayers with either reduced GADD45a or Akt expression (siRNAs) revealed significant potentiation of LPS-induced human lung endothelial barrier dysfunction, which was attenuated by overexpression of a constitutively active Akt1 transgene. These studies validate GADD45a as a novel candidate gene in inflammatory lung injury and a significant participant in vascular barrier regulation via effects on Akt-mediated endothelial signaling.
authors.affiliation: Department of Medicine, W604, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., W604 Chicago, IL 60637, USA.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Evenoski
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Sumegha
authors.initials: S
authors.lastname: Mitra
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000503:physiopathology; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins