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1 Department of Gastroenterology and Hepatology, Kyoto University, Graduate School of Medicine, Kyoto, Japan
2 Department of Experimental Therapeutics, Kyoto University Hospital, Translational Research Center, Kyoto, Japan
3 Department of Biological Responses, Kyoto University, Institute for Virus Research, Kyoto, Japan
4 Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
* To whom correspondence should be addressed. E-mail: anishio{at}kuhp.kyoto-u.ac.jp.
Severe acute pancreatitis is a disease with high morbidity, 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 anti-oxidant 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 cholecystokinin analogue, 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 
B-
, thereby suppressing pro-inflammatory cutokines, tumor necrosis factor-, interleukin-1
, 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 anti-oxidant and anti-inflammatory actions in experimetal acute pancreatitis, and might be a new therapeutic strategy to improve the prognosis of severe acute pancreatitis.
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