TY - JOUR
T1 - Role of 15-deoxyΔ prostaglandin J2 and Nrf2 pathways in protection against acute lung injury
AU - Mochizuki, Mie
AU - Ishii, Yukio
AU - Itoh, Ken
AU - Iizuka, Takashi
AU - Morishima, Yuko
AU - Kimura, Toru
AU - Kiwamoto, Takumi
AU - Matsuno, Yosuke
AU - Hegab, Ahamed E.
AU - Nomura, Akihiro
AU - Sakamoto, Tohru
AU - Uchida, Koji
AU - Yamamoto, Masayuki
AU - Sekizawa, Kiyohisa
PY - 2005/6/1
Y1 - 2005/6/1
N2 - 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-Δ-prostaglandin J 2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes. Objectives: 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. Main Results: We found that ALI induced by carrageenin was markedly exacerbated in Nrf 2-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 Nrf 2-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 antioxldant genes. Conclusions: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.
AB - 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-Δ-prostaglandin J 2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes. Objectives: 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. Main Results: We found that ALI induced by carrageenin was markedly exacerbated in Nrf 2-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 Nrf 2-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 antioxldant genes. Conclusions: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.
KW - Alveolar macrophages
KW - Cyclooxygenase-2
KW - Inflammation
KW - Transcription factor
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U2 - 10.1164/rccm.200406-755OC
DO - 10.1164/rccm.200406-755OC
M3 - Article
C2 - 15750045
AN - SCOPUS:21144456105
VL - 171
SP - 1260
EP - 1266
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 11
ER -