Inhibition of c-Jun NH2-Terminal Kinase Activity Improves Ischemia/Reperfusion Injury in Rat Lungs

Makoto Ishii, Yukio Suzuki, Kei Takeshita, Naoki Miyao, Hiroyasu Kudo, Rika Hiraoka, Kazumi Nishio, Nagato Sato, Katsuhiko Naoki, Takuya Aoki, Kazuhiro Yamaguchi

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Abstract

Although c-Jun NH2-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-κB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4°C for 4 h followed by reperfusion at 37°C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-κB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-α into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.

Original languageEnglish
Pages (from-to)2569-2577
Number of pages9
JournalJournal of Immunology
Volume172
Issue number4
DOIs
Publication statusPublished - 2004 Feb 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ishii, M., Suzuki, Y., Takeshita, K., Miyao, N., Kudo, H., Hiraoka, R., Nishio, K., Sato, N., Naoki, K., Aoki, T., & Yamaguchi, K. (2004). Inhibition of c-Jun NH2-Terminal Kinase Activity Improves Ischemia/Reperfusion Injury in Rat Lungs. Journal of Immunology, 172(4), 2569-2577. https://doi.org/10.4049/jimmunol.172.4.2569