Inhibition of poly( ADP-ribose) polymerase attenuates inflammation in a model of chronic colitis

被引:111
作者
Jijon, HB
Churchill, T
Malfair, D
Wessler, A
Jewell, LD
Parsons, HG
Madsen, KL
机构
[1] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2C2, Canada
[2] Univ Alberta, Surg Med Res Inst, Edmonton, AB T6G 2C2, Canada
[3] Univ Alberta, Div Gastroenterol, Edmonton, AB T6G 2C2, Canada
[4] Univ Calgary, Calgary, AB T2N 1N4, Canada
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2000年 / 279卷 / 03期
关键词
interleukin-10; 3-aminobenzamide; inflammatory bowel disease; intestinal permeability;
D O I
10.1152/ajpgi.2000.279.3.G641
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.
引用
收藏
页码:G641 / G651
页数:11
相关论文
共 50 条
[1]   ENERGY CHARGE OF ADENYLATE POOL AS A REGULATORY PARAMETER . INTERACTION WITH FEEDBACK MODIFIERS [J].
ATKINSON, DE .
BIOCHEMISTRY, 1968, 7 (11) :4030-&
[2]   REGULATION OF TIGHT-JUNCTION PERMEABILITY DURING NUTRIENT ABSORPTION ACROSS THE INTESTINAL EPITHELIUM [J].
BALLARD, ST ;
HUNTER, JH ;
TAYLOR, AE .
ANNUAL REVIEW OF NUTRITION, 1995, 15 :35-55
[3]  
BANASIK M, 1992, J BIOL CHEM, V267, P1569
[4]   Oxidative damage and tyrosine nitration from peroxynitrite [J].
Beckman, JS .
CHEMICAL RESEARCH IN TOXICOLOGY, 1996, 9 (05) :836-844
[5]   Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses [J].
Berg, DJ ;
Davidson, N ;
Kuhn, R ;
Muller, W ;
Menon, S ;
Holland, G ;
ThompsonSnipes, L ;
Leach, MW ;
Rennick, D .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (04) :1010-1020
[6]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[7]  
Briviba K, 1999, METHOD ENZYMOL, V301, P301
[8]  
CASELLAS F, 1986, AM J GASTROENTEROL, V81, P767
[9]   Formation of nitric oxide derived inflammatory oxidants by myeloperoxidase in neutrophils [J].
Eiserich, JP ;
Hristova, M ;
Cross, CE ;
Jones, AD ;
Freeman, BA ;
Halliwell, B ;
van der Vliet, A .
NATURE, 1998, 391 (6665) :393-397
[10]   Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia [J].
Eliasson, MJL ;
Sampei, K ;
Mandir, AS ;
Hurn, PD ;
Traystman, RJ ;
Bao, J ;
Pieper, A ;
Wang, ZQ ;
Dawson, TM ;
Snyder, SH ;
Dawson, VL .
NATURE MEDICINE, 1997, 3 (10) :1089-1095