title: Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs.
abstract: Although c-Jun NH(2)-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-kappaB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4 degrees C for 4 h followed by reperfusion at 37 degrees 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-kappaB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-alpha 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.
authors.affiliation: Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Yukio
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kei
authors.initials: K
authors.lastname: Takeshita
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyao
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kudo
authors.forename: Rika
authors.initials: R
authors.lastname: Hiraoka
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishio
authors.forename: Nagato
authors.initials: N
authors.lastname: Sato
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.forename: Takuya
authors.initials: T
authors.lastname: Aoki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002352:Carrier Proteins / Q000378:metabolism / Q000627:therapeutic use; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C110528:Mapk8ip1 protein, rat; D016328:NF-kappa B; D011506:Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D002392:Catechin; C045651:epigallocatechin gallate; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases