Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice.
BACKGROUND
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 (PPARgamma) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2(-/-)) mice compared with wild-type (Nrf2(+/+)) mice. PPARgamma has pleiotropic beneficial effects including antiinflammation in multiple tissues.


OBJECTIVE
We tested the hypothesis that PPARgamma 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 PPARgamma in hyperoxia-induced acute lung injury was determined by temporal silencing of PPARgamma via intranasal delivery of PPARgamma-specific interference RNA and by administration of a PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) in mice.


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 PPARgamma expression. Mice with decreased lung PPARgamma 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 PPARgamma induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPARgamma in airway oxidative inflammatory disorders.
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr., Building 101, MD D-201, Research Triangle Park, NC 27709, USA. cho2@niehs.nih.gov
Hye-Youn
HY
Cho
Wesley
W
Gladwell
Xuting
X
Wang
Brian
B
Chorley
Douglas
D
Bell
Sekhar P
SP
Reddy
Steven R
SR
Kleeberger
D055371:Acute Lung Injury / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D020868:Gene Silencing; D007155:Immunologic Factors / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D034741:RNA, Small Interfering
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D051267:NF-E2-Related Factor 2; D047495:PPAR gamma; D034741:RNA, Small Interfering; D015230:Prostaglandin D2