Role of 15-deoxyΔ prostaglandin J 2 and Nrf 2 pathways in protection against acute lung injury

Mie Mochizuki, Yukio Ishii, Ken Itoh, Takashi Iizuka, Yuko Morishima, Toru Kimura, Takumi Kiwamoto, Yosuke Matsuno, Ahamed E. Hegab, Akihiro Nomura, Tohru Sakamoto, Koji Uchida, Masayuki Yamamoto, Kiyohisa Sekizawa

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101 Citations (Scopus)

Abstract

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-PGJ 2 ). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes. Objectives: Because 15d-PGJ 2 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-PGJ 2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ 2 reversed the exacerbating effects of NS-398 with the induction of antioxldant genes. Conclusions: These results demonstrated in vivo that 15d-PGJ 2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Original languageEnglish
Pages (from-to)1260-1266
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume171
Issue number11
DOIs
Publication statusPublished - 2005 Jun 1
Externally publishedYes

Keywords

  • Alveolar macrophages
  • Cyclooxygenase-2
  • Inflammation
  • Transcription factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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  • Cite this

    Mochizuki, M., Ishii, Y., Itoh, K., Iizuka, T., Morishima, Y., Kimura, T., Kiwamoto, T., Matsuno, Y., Hegab, A. E., Nomura, A., Sakamoto, T., Uchida, K., Yamamoto, M., & Sekizawa, K. (2005). Role of 15-deoxyΔ prostaglandin J 2 and Nrf 2 pathways in protection against acute lung injury American journal of respiratory and critical care medicine, 171(11), 1260-1266. https://doi.org/10.1164/rccm.200406-755OC