Hye-Youn Cho1, Wesley Gladwell1, Xuting Wang2, Brian Chorley2, Douglas Bell2, Sekhar P. Reddy3 and Steven R. Kleeberger1. Published ahead of print on March 11, 2010, doi:10.1164/rccm.200907-1047OC. American Journal of Respiratory and Critical Care Medicine Vol 182. pp. 170-182, (2010)
Rationale: The NF-E2 related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is essential for protection against oxidative injury and inflammation including hyperoxia-induced acute lung injury. Microarray expression profiling revealed that lung peroxisome proliferator activated receptor (PPAR) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2–/–) mice compared with wild-type (Nrf2+/+) mice. PPAR has pleiotropic beneficial effects including antiinflammation in multiple tissues.
Objectives: We tested the hypothesis that PPAR is an important determinant of pulmonary responsivity to hyperoxia regulated by Nrf2.
Methods: A computational bioinformatic method was applied to screen potential AREs in the Pparg promoter for Nrf2 binding. The functional role of a potential ARE was investigated by in vitro promoter analysis. A role for PPAR in hyperoxia-induced acute lung injury was determined by temporal silencing of PPAR via intranasal delivery of PPAR-specific interference RNA and by administration of a PPAR ligand 15-deoxy-12,14-prostaglandin J2 in mice.
Measurements and Main Results: Deletion or site-directed mutagenesis of a potential ARE spanning -784/-764 sequence significantly attenuated hyperoxia-increased Pparg promoter activity in airway epithelial cells overexpressing Nrf2, indicating that the -784/-764 ARE is critical for Nrf2-regulated PPAR expression. Mice with decreased lung PPAR by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-12,14-prostaglandin J2 administration significantly reduced hyperoxia-induced lung inflammation and edema in Nrf2+/+, but not in Nrf2–/– mice.
Conclusions: Results indicate for the first time that Nrf2-driven PPAR induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPAR in airway oxidative inflammatory disorders.
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