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Am J Physiol Gastrointest Liver Physiol 290: G772-G781, 2006. First published December 1, 2005; doi:10.1152/ajpgi.00425.2005
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INFLAMMATION/IMMUNITY/MEDIATORS

Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis

Shinya Ohashi,1 Akiyoshi Nishio,1 Hajime Nakamura,3 Masahiro Kido,1 Satoru Ueno,1 Norimitsu Uza,1 Satoko Inoue,1 Hiroshi Kitamura,1 Keiichi Kiriya,1 Masanori Asada,1 Hiroyuki Tamaki,1 Minoru Matsuura,1 Kimio Kawasaki,1 Toshiro Fukui,1 Norihiko Watanabe,1 Hiroshi Nakase,1 Junji Yodoi,2 Kazuichi Okazaki,4 and Tsutomu Chiba1

1Department of Gastroenterology and Hepatology, Graduate School of Medicine and 2Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto; 3Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan; and 4Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan

Submitted 8 September 2005 ; accepted in final form 28 November 2005

Severe acute pancreatitis is a disease with high mortality, and infiltration of inflammatory cells and reactive oxygen species have a crucial role in the pathophysiology of this disease. Thioredoxin-1 (TRX-1) is an endogenous redox-active multifunctional protein with antioxidant and anti-inflammatory effects. TRX-1 is induced in various inflammatory conditions and shows cytoprotective effects. The aim of the present study was to clarify the protective roles of TRX-1 in the host defense mechanism against severe acute pancreatitis. Experimental acute pancreatitis was induced by intraperitoneal administration of cerulein, a CCK analog, and aggravated by lipopolysaccharide injection in transgenic mice overexpressing human TRX-1 (hTRX-1) and control C57BL/6 mice. Transgenic overexpression of hTRX-1 strikingly attenuated the severity of experimental acute pancreatitis. TRX-1 overexpression suppressed neutrophil infiltration as determined by myeloperoxidase activity, oxidative stress as determined by malondialdehyde concentration, and cytoplasmic degradation of inhibitor of {kappa}B-{alpha}, thereby suppressing proinflammatory cytokines, tumor necrosis factor-{alpha}, interleukin-1beta, and interleukin-6; a neutrophil chemoattractant, keratinocyte-derived chemokine; and inducible nitric oxide synthase in the pancreas. Administration of recombinant hTRX-1 also suppressed neutrophil infiltration, reduced the inflammation of the pancreas and the lung, and improved the mortality rate. The present study suggests that TRX-1 has potent antioxidant and anti-inflammatory actions in experimental acute pancreatitis and might be a new therapeutic strategy to improve the prognosis of severe acute pancreatitis.

thioredoxin-1; acute pancreatitis; reactive oxygen species; redox-regulation; antioxidant


Address for reprint requests and other correspondence: A. Nishio, Dept. of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Univ., 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan (e-mail: anishio{at}kuhp.kyoto-u.ac.jp)




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