GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling

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, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 ∼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.

Original languageEnglish (US)
Pages (from-to)1325-1337
Number of pages13
JournalFASEB Journal
Volume23
Issue number5
DOIs
StatePublished - May 2009

Keywords

  • Biomarker
  • Mechanical ventilation
  • Ubiquitination
  • Vascular barrier regulation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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