• Nuala J Meyer, Yong Huang, Patrick A Singleton, Saad Sammani, Jaideep Moitra, Carrie L Evenoski, Aliya N Husain, Sumegha Mitra, Liliana Moreno-Vinasco, Jeffrey R Jacobson, Yves A Lussier, and Joe G N Garcia.
• Department of Medicine, W604, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., W604 Chicago, IL 60637, USA.
• FASEB J. 2009 May 1; 23 (5): 1325-37.

AbstractWe 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.

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