title: Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis.
abstract: 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 kappaB-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.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Institute for Virus Research, Kyoto University, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohashi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kido
authors.forename: Satoru
authors.initials: S
authors.lastname: Ueno
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Uza
authors.forename: Satoko
authors.initials: S
authors.lastname: Inoue
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kiriya
authors.forename: Masanori
authors.initials: M
authors.lastname: Asada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tamaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsuura
authors.forename: Kimio
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukui
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D012720:Severity of Illness Index; D013879:Thioredoxins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; C491203:TXN protein, human; D013879:Thioredoxins