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.
Weblink here
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.
Weblink here