Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis.
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.
Ohashi
Shinya
S
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Institute for Virus Research, Kyoto University, Japan.
Nishio
Akiyoshi
A
Nakamura
Hajime
H
Kido
Masahiro
M
Ueno
Satoru
S
Uza
Norimitsu
N
Inoue
Satoko
S
Kitamura
Hiroshi
H
Kiriya
Keiichi
K
Asada
Masanori
M
Tamaki
Hiroyuki
H
Matsuura
Minoru
M
Kawasaki
Kimio
K
Fukui
Toshiro
T
Watanabe
Norihiko
N
Nakase
Hiroshi
H
Yodoi
Junji
J
Okazaki
Kazuichi
K
Chiba
Tsutomu
T
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
D016207:Cytokines; D011994:Recombinant Proteins; C491203:TXN protein, human; D013879:Thioredoxins