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VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo

Jonathan M. Siner^*,1, Ge Jiang^*,1, Zaza I. Cohen^,1, Peiying Shan^*, Xuchen Zhang^*, Chun Geun Lee^*, Jack A. Elias^* and Patty J. Lee^*,2

^* Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and

Division of Pulmonary and Critical Care, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA

²Correspondence: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, P.O. Box 208057, New Haven, CT 06520-8057 USA. E-mail: patty.lee{at}yale.edu

Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endothelial growth factor (VEGF) has been shown to have cytoprotective effects and prolong survival in an in vivo model of HALI. Heme oxygenase-1 (HO-1) has protective effects in hyperoxia; therefore, we hypothesized that induction of HO-1 would be an important contributor to VEGF-induced cytoprotection. Using inducible, lung-specific VEGF overexpressing transgenic mice, we demonstrated that VEGF is a potent inducer of HO-1 mRNA and protein in mouse lung. To evaluate the effect of inhibition of HO-1 on injury, VEGF transgenic mice were treated with HO-1 short interfering RNA (HO-1 siRNA) and exposed to hyperoxia. Total lung lavage protein concentration, TUNEL staining, lipid peroxidation, and wet-to-dry ratio were all increased, consistent with increased injury. These findings were corroborated by survival studies in which inhibition of HO-1 function using tin-protoporphryin or silencing of HO-1 with lentiviral HO-1 short hairpin RNA (ShRNA) significantly decreased survival in hyperoxia. We conclude from these data that VEGF-induced HO-1 is an important contributor to cytoprotection in this in vivo model of acute lung injury and that alterations in VEGF function in the lung are likely to be important determinants of the outcome of acute lung injury.—Siner, J. M., Jiang, G., Cohen, Z. I., Shan, P., Zhang, X., Lee, C. G., Elias, J. A., Lee, P. J. VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo.

Key Words: oxidant injury • angiogenesis • endothelial • acute lung injury

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