Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury.
BACKGROUND
Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes.


OBJECTIVE
Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2.


METHODS
To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2.


RESULTS
We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes.


CONCLUSIONS
These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.
Mochizuki
Mie
M
Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan.
Ishii
Yukio
Y
Itoh
Ken
K
Iizuka
Takashi
T
Morishima
Yuko
Y
Kimura
Toru
T
Kiwamoto
Takumi
T
Matsuno
Yosuke
Y
Hegab
Ahamed E
AE
Nomura
Akihiro
A
Sakamoto
Tohru
T
Uchida
Koji
K
Yamamoto
Masayuki
M
Sekizawa
Kiyohisa
K
D000818:Animals; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2; D009578:Nitrobenzenes / Q000627:therapeutic use; D011014:Pneumonia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use; D015534:Trans-Activators / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009578:Nitrobenzenes; D013449:Sulfonamides; D015534:Trans-Activators; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D002351:Carrageenan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2