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Role of 15-Deoxy^12,14 Prostaglandin J₂ and Nrf2 Pathways in Protection against Acute Lung Injury

Department of Respiratory Medicine, and Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba; and Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan

Correspondence and requests for reprints should be addressed to Yukio Ishii, M.D., Ph.D., Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan. E-mail: ishii-y{at}md.tsukuba.ac.jp

Rationale: 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-^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. 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 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.

Key Words: alveolar macrophages • cyclooxygenase-2 • inflammation • transcription factor

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