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
[11]   COLITIS AND COLONIC MUCOSAL BARRIER DYSFUNCTION [J].
GARDINER, KR ;
ANDERSON, NH ;
ROWLANDS, BJ ;
BARBUL, A .
GUT, 1995, 37 (04) :530-535
[12]  
GO LL, 1995, ARCH SURG-CHICAGO, V130, P53
[13]   OXIDANTS AND FREE-RADICALS IN INFLAMMATORY BOWEL-DISEASE [J].
GRISHAM, MB .
LANCET, 1994, 344 (8926) :859-861
[14]   CLOSTRIDIUM-DIFFICILE TOXIN-B DISRUPTS THE BARRIER FUNCTION OF T84 MONOLAYERS [J].
HECHT, G ;
KOUTSOURIS, A ;
POTHOULAKIS, C ;
LAMONT, JT ;
MADARA, JL .
GASTROENTEROLOGY, 1992, 102 (02) :416-423
[15]   CLOSTRIDIUM-DIFFICILE TOXIN-A PERTURBS CYTOSKELETAL STRUCTURE AND TIGHT JUNCTION PERMEABILITY OF CULTURED HUMAN INTESTINAL EPITHELIAL MONOLAYERS [J].
HECHT, G ;
POTHOULAKIS, C ;
LAMONT, JT ;
MADARA, JL .
JOURNAL OF CLINICAL INVESTIGATION, 1988, 82 (05) :1516-1524
[16]   INCREASED INTESTINAL PERMEABILITY IN PATIENTS WITH CROHNS-DISEASE AND THEIR RELATIVES - A POSSIBLE ETIOLOGIC FACTOR [J].
HOLLANDER, D ;
VADHEIM, CM ;
BRETTHOLZ, E ;
PETERSEN, GM ;
DELAHUNTY, T ;
ROTTER, JI .
ANNALS OF INTERNAL MEDICINE, 1986, 105 (06) :883-885
[17]   PEROXYNITRITE-MEDIATED TYROSINE NITRATION CATALYZED BY SUPEROXIDE-DISMUTASE [J].
ISCHIROPOULOS, H ;
ZHU, L ;
CHEN, J ;
TSAI, M ;
MARTIN, JC ;
SMITH, CD ;
BECKMAN, JS .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1992, 298 (02) :431-437
[18]   Oxidants, transcription factors, and intestinal inflammation [J].
Jourd'heuil, D ;
Morise, Z ;
Conner, EM ;
Grisham, MB .
JOURNAL OF CLINICAL GASTROENTEROLOGY, 1997, 25 :S61-S72
[19]   Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in caco-2BBe cells [J].
Kennedy, M ;
Denenberg, AG ;
Szabó, C ;
Salzman, AL .
GASTROENTEROLOGY, 1998, 114 (03) :510-518
[20]  
Le Page C, 1998, BIOCHEM BIOPH RES CO, V243, P451