GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling.
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.
Meyer
Nuala J
NJ
Department of Medicine, W604, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., W604 Chicago, IL 60637, USA.
Huang
Yong
Y
Singleton
Patrick A
PA
Sammani
Saad
S
Moitra
Jaideep
J
Evenoski
Carrie L
CL
Husain
Aliya N
AN
Mitra
Sumegha
S
Moreno-Vinasco
Liliana
L
Jacobson
Jeffrey R
JR
Lussier
Yves A
YA
Garcia
Joe G N
JG
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
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins