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.
Cho
Hye-Youn
HY
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
Gladwell
Wesley
W
Wang
Xuting
X
Chorley
Brian
B
Bell
Douglas
D
Reddy
Sekhar P
SP
Kleeberger
Steven R
SR
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