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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 and Joe G. N. Garcia^*,1

^* Section of Pulmonary and Critical Care Medicine and

Section of Genetic Medicine, Department of Medicine, and

Department of Pathology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA

¹ Correspondence: Department of Medicine, W604, Pritzker School of Medicine University of Chicago, 5841 S. Maryland Ave., W604 Chicago, IL 60637, USA. E-mail: jgarcia{at}medicine.bsd.uchicago.edu

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.—Meyer, N. J., Huang, Y., Singleton, P. A., Sammani, S., Moitra, J., Evenoski, C. L., Husain, A. N., Mitra, S., Moreno-Vinasco, L., Jacobson, J. R., Lussier, Y. A., Garcia, J. G. N. GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling.

Key Words: mechanical ventilation • biomarker • vascular barrier regulation • ubiquitination

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