Blockade of poly(ADP-ribose) synthetase inhibits neutrophil recruitment, oxidant generation, and mucosal injury in murine colitis
Blockade of poly(ADP-ribose) synthetase inhibits neutrophil recruitment, oxidant generation, and mucosal injury in murine colitis
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多聚（ADP - 核糖）合成酶的阻断抑制小鼠结肠炎中的中性粒细胞募集、氧化剂产生和黏膜损伤
DOI：
10.1016/s0016-5085(99)70130-7
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发表时间：
1999-02
期刊：
影响因子：
29.4
通讯作者：
B. Zingarelli;C. Szabó;A. Salzman
中科院分区：
文献类型：
--
作者：
B. Zingarelli;C. Szabó;A. Salzman
背景与目的炎症性肠病以氧化和亚硝化应激、白细胞浸润和细胞间粘附分子1（ICAM-1）表达上调为特征。最近的数据表明，在分离的肠上皮细胞的氧化和亚硝化应激产生DNA单链断裂，激活核酶聚（ADP-核糖）合成酶（PARS），导致细胞内能量消耗和细胞旁通透性增加。本研究的目的是检查在体内的相关性，这种损伤pathway.MethodsColitis是由直肠滴注三硝基苯磺酸（TNBS）在小鼠与遗传缺陷的PARS（PARS-/-）和野生型littermates.ResultsIn野生型小鼠，TNBS治疗导致结肠糜烂和溃疡，维持长达7天。神经元浸润（由粘膜中的髓过氧化物酶活性指示）与ICAM-1的上调以及高水平的丙二醛和硝基酪氨酸相关。TNBS处理的PARS−/−小鼠经历了类似的结肠损伤，但在6天内完全消退。解决的损害是与ICAM-1的上调，减少中性粒细胞浸润，脂质过氧化，和亚硝化damage.ConclusionsThese数据表明，PARS起着至关重要的作用，结肠炎症可能通过调节ICAM-1的表达，中性粒细胞的招聘，和随后的氧化剂的产生。《胃肠病学》1999;116：335-345
Background & AimsInflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. Recent data show that oxidative and nitrosative stress in isolated enterocytes produces DNA single-strand breaks that activate the nuclear enzyme poly(ADP-ribose) synthetase (PARS), resulting in depletion of intracellular energetics and increased paracellular permeability. The aim of the present study was to examine the in vivo relevance of this injury pathway.MethodsColitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in mice with a genetic deficiency of PARS (PARS−/−) and in wild-type littermates.ResultsIn wild-type mice, TNBS treatment resulted in colonic erosion and ulceration that was maintained up to 7 days. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and high levels of malondialdehyde and nitrotyrosine. TNBS-treated PARS−/−mice experienced a similar colonic injury that was, however, completely resolved by 6 days. Resolution of the damage was associated with absence of ICAM-1 up-regulation, reduction of neutrophil infiltration, lipid peroxidation, and nitrosative damage.ConclusionsThese data show that PARS plays a critical role in colonic inflammation possibly by regulating ICAM-1 expression, neutrophil recruitment, and the subsequent oxidant generation. GASTROENTEROLOGY 1999;116:335-345