Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice
Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice
复制标题
DOI：
10.1053/gast.2000.16497
复制
发表时间：
2000-09-01
期刊：
影响因子：
29.4
通讯作者：
Seed, B
中科院分区：
文献类型：
--
作者：
Beck, PL;Xavier, R;Seed, B
背景和目标：非甾体抗炎药（NSAID）是常用的药物，其胃肠道副作用的发生率高，导致显著的发病率和死亡率。白细胞与NSAID诱导的损伤有关，但机制尚不清楚。我们建立了一个非甾体抗炎药诱导的胃肠道损伤的小鼠模型，以评估候选基因产物在这种损伤的发病机制中的作用。研究方法：在野生型和几种突变型小鼠系中评估吲哚美辛诱导的胃肠道损伤。使用Rag 2（-/-）小鼠，通过中性粒细胞耗竭、募集受损（由岩藻糖基转移酶VII [FTVII]的靶向破坏引起）以及缺乏成熟T和B细胞来评估白细胞参与。使用表现出正常白细胞募集但缺乏髓样细胞活化和氧自由基产生的gp 91（phox-/-）小鼠评估活化和氧自由基。结果：白细胞募集受损（FTVII/（-））和中性粒细胞耗竭导致NSAID诱导的损伤减少50%以上。然而，缺乏成熟T和B细胞的小鼠与对照小鼠相比具有NSAID诱导的损伤。白细胞活化是NSAID诱导的损伤所必需的，因为gp 91（phox-/-）小鼠对NSAID损伤的敏感性低于野生型小鼠。结论：在该鼠模型系统中，FTVII依赖性白细胞募集、通过gp 91（phox）的白细胞活化和中性粒细胞是NSAID诱导的胃肠道损伤所必需的，而T和B细胞不是必需的。
Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used agents that have a high incidence of gastrointestinal side effects resulting in significant morbidity and mortality. Leukocytes have been implicated in NSAID-induced injury, but the mechanisms are unclear. We established a murine model of NSAID-induced gastrointestinal damage to assess the roles of candidate gene products in the pathogenesis of this injury. Methods: Indomethacin-induced gastrointestinal injury was assessed in wild-type and several mutant murine lines, Leukocyte involvement was assessed by neutrophil depletion, impairment of recruitment (resulting from targeted disruption of fucosyltransferase VII [FTVII]), and the absence of mature T and B cells with the use of Rag 2(-/-) mice. Activation and oxygen free radicals were assessed using gp91(phox-/-) mice that exhibit normal leukocyte recruitment but are deficient in myeloid cell activation and oxygen free radical generation, Results: impairment of leukocyte recruitment (FTVII/(-)) and neutrophil depletion resulted in more than a 50% reduction in NSAID-induced injury. However, mice deficient in mature T and B cells had NSAID-induced damage comparable to control mice. Leukocyte activation was required for NSAID-induced damage because the gp91(phox-/-) mice were less susceptible to NSAID injury than wild-type mice. Conclusions: In this murine model system, FTVII-dependent leukocyte recruitment, leukocyte activation via gp91(phox), and neutrophils are required for NSAID-induced gastrointestinal injury, whereas T and B cells are not essential.