Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

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 gamma (PPAR gamma) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2(-/-)) mice compared with wild-type (Nrf2(+/+)) mice. PPAR gamma has pleiotropic beneficial effects including antiinflammation in multiple tissues. Objectives: We tested the hypothesis that PPAR gamma 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 gamma in hyperoxia-induced acute lung injury was determined by temporal silencing of PPART via intranasal delivery of PPAR-y-specific interference RNA and by administration of a PPAR gamma ligand 15-deoxy-Delta(12,14) prostaglandin J(2) 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 gamma expression. Mice with decreased lung PPAR gamma by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-Delta(12,14)- prostaglandin J(2) 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 gamma induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPAR gamma in airway oxidative inflammatory disorders.