Novel Mechanisms of NSAID-induced GI Toxicity

NSAID 引起胃肠道毒性的新机制

基本信息

  • 批准号:
    8232604
  • 负责人:
  • 金额:
    $ 33.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide for the relief of inflammation and pain. However, NSAIDs cause adverse gastrointestinal (GI) side-effects in a large proportion of people who use them, many of whom require hospitalization to recover. Traditionally, NSAID- induced GI toxicity was associated with the inhibition of cyclooxygenase (COX) enzymes, particularly COX-1. Recent evidence however, indicates that COX inhibition does not account for the full range of toxic effects observed in the GI tract. Additionally, the discovery of the adverse cardiovascular effects of COX-2 specific NSAIDs has demonstrated the importance of identifying mechanisms through which NSAIDs cause GI toxicity. Accordingly, we propose to investigate the molecular mechanisms underlying inhibition of restitution by NSAIDs, one of the negative effects that NSAIDs have on GI epithelia. GI epithelia form a barrier that separates the internal milieu from the harsh conditions of the lumen of the GI. Restitution is the cell proliferation-free process by which wounds or gaps in the epithelial barrier are repaired by the spreading and migration of neighboring cells into the wound. NSAIDs with ulcerogenic potential inhibit cell migration in intestinal epithelial cells. Our research group has shown that this inhibition is associated with a decrease in the expression and activity of calpain proteases and depolarization of membrane potential (Em). On the basis of these data, we hypothesize that NSAIDs impair intestinal epithelial cell migration and inhibit calpain activity through a signaling pathway that is highly sensitive to drug-induced changes in Em. Therefore, in Specific Aim 1 we will determine if NSAIDs impair de-adhesion of cell contacts by measuring the number and distribution of cellular adhesions as well as the expression and rate of turnover of specific adhesion components. In Specific Aim 2, we will determine if NSAIDs or Em depolarization modulate calpain activity through disruption of EGF-stimulated phosphorylation of calpains or disruption of PIP balance by measuring expression and activation of the EGF pathway, PIP levels, and calpain activity and localization to the membrane. In Specific Aim 3, we will extend our in vitro experiments by determining the effects of NSAIDs on cell migration, calpain and Kv channel expression, and calpain participation in membrane localized complexes in rats treated with NSAIDs. These innovative experiments have the potential to identify molecular mechanisms through which NSAIDs decrease calpain activity, in addition to determining the effects of reductions in calpain activity on cellular de-adhesion during migration both in vitro and in vivo. This project will provide basic information on wound healing processes in intestinal cells that are applicable to other tissues, document the effects of NSAIDs on these processes, and give insight into how NSAIDs may affect the healing process in other tissues. The research also has great potential for aiding in the development of new drugs in this class capable of ameliorating pain without the adverse side effects of current drugs. PUBLIC HEALTH RELEVANCE: The widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the alleviation of inflammation and pain poses a major medical risk to patients due to the common toxic effects these drugs have on the gastrointestinal tract. Our research is designed to elucidate novel mechanisms through which these toxic effects occur in order to eliminate the side effects associated with NSAID use and enhance the safety of future drugs of this class. This research may help reduce or eliminate the loss of billions of dollars per year due to medical complications resulting from NSAID-induced GI toxicity.
描述(由申请人提供):非甾体类抗炎药(NSAIDS)是全世界使用最广泛的药物之一,可缓解炎症和疼痛。但是,NSAID会在很大一部分使用它们的人中引起不良胃肠道(GI)的副作用,其中许多人需要住院才能恢复。传统上,NSAID诱导的GI毒性与抑制环氧酶(COX)酶,尤其是COX-1有关。然而,最近的证据表明,Cox抑制作用并不能说明GI道中观察到的全部毒性作用。此外,发现COX-2特异性NSAID的不良心血管效应的发现证明了识别NSAID引起GI毒性的机制的重要性。因此,我们建议研究NSAID抑制恢复原状的分子机制,这是NSAID对GI上皮菌的负面影响之一。胃肠道上皮形成了一个障碍,将内部环境与gi管腔的恶劣条件分开。恢复原状是无细胞增殖的过程,通过该过程通过邻近细胞进入伤口的扩散和迁移来修复上皮屏障中的伤口或间隙。具有溃疡性潜力的NSAID抑制肠上皮细胞中的细胞迁移。我们的研究小组表明,这种抑制与钙蛋白酶蛋白酶的表达和活性降低以及膜电位(EM)的去极化有关。根据这些数据,我们假设NSAIDS会损害肠上皮细胞迁移,并通过对药物诱导的EM变化高度敏感的信号传导途径抑制钙蛋白酶活性。因此,在特定的目标1中,我们将通过测量细胞粘附的数量和分布以及特定粘附成分的周转率来确定NSAID是否会损害细胞接触的粘附。在特定目标2中,我们将通过破坏EGF刺激的钙蛋白酶磷酸化或通过测量EGF途径,PIP水平,钙蛋白酶的活性以及对膜上的位置来确定NSAIDS或EM去极化是否通过破坏Calpains的磷酸化或破坏PIP平衡的破坏来调节钙蛋白酶活性。在特定的目标3中,我们将通过确定NSAID对细胞迁移,CALPAIN和KV通道表达的影响以及在用NSAID处理的大鼠中参与膜局部化合物的影响来扩展体外实验。这些创新的实验具有鉴定NSAIDS降低钙蛋白酶活性的分子机制的潜力,除了确定钙蛋白酶活性减少对体外和体内迁移过程中细胞脱粘的影响。该项目将提供有关适用于其他组织的肠细胞伤口愈合过程的基本信息,记录NSAID对这些过程的影响,并深入了解NSAID如何影响其他组织中的愈合过程。该研究还具有巨大的潜力,可以帮助在此类中开发新药,能够改善疼痛,而不会产生当前药物的不利副作用。 公共卫生相关性:非甾体类抗炎药(NSAIDS)的广泛使用缓解炎症和疼痛,由于这些药物对胃肠道的常见毒性影响,对患者构成了主要的医疗风险。我们的研究旨在阐明这些有毒作用发生的新型机制,以消除与NSAID使用相关的副作用,并增强该类别的未来药物的安全性。这项研究可能有助于减少或消除由于NSAID引起的GI毒性导致的医学并发症,每年损失数十亿美元。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Inhibition of Kv channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling.
  • DOI:
    10.1016/j.bcp.2015.10.017
  • 发表时间:
    2015-12-15
  • 期刊:
  • 影响因子:
    5.8
  • 作者:
    Silver K;Littlejohn A;Thomas L;Marsh E;Lillich JD
  • 通讯作者:
    Lillich JD
Suppression of calpain expression by NSAIDs is associated with inhibition of cell migration in rat duodenum.
  • DOI:
    10.1016/j.tox.2017.03.017
  • 发表时间:
    2017-05-15
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Silver K;Littlejohn A;Thomas L;Bawa B;Lillich JD
  • 通讯作者:
    Lillich JD
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JAMES D LILLICH其他文献

JAMES D LILLICH的其他文献

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{{ truncateString('JAMES D LILLICH', 18)}}的其他基金

INTESTINAL EPITHELIAL WOUND HEALING: NSAIDS AND CALPAIN INHIBITION
肠上皮伤口愈合:NSAIDS 和钙蛋白酶抑制
  • 批准号:
    8167826
  • 财政年份:
    2010
  • 资助金额:
    $ 33.3万
  • 项目类别:
INTESTINAL EPITHELIAL WOUND HEALING: NSAIDS AND CALPAIN INHIBITION
肠上皮伤口愈合:NSAIDS 和钙蛋白酶抑制
  • 批准号:
    7959796
  • 财政年份:
    2009
  • 资助金额:
    $ 33.3万
  • 项目类别:
INTESTINAL EPITHELIAL WOUND HEALING: NSAIDS AND CALPAIN INHIBITION
肠上皮伤口愈合:NSAIDS 和钙蛋白酶抑制
  • 批准号:
    7720928
  • 财政年份:
    2008
  • 资助金额:
    $ 33.3万
  • 项目类别:
NSAIDS, POLYAMINE-DEPLETION & DEPOLARIZED MEMBRANE POTENTIAL
非甾体抗炎药、多胺消耗
  • 批准号:
    7610456
  • 财政年份:
    2007
  • 资助金额:
    $ 33.3万
  • 项目类别:
NSAIDS, POLYAMINE-DEPLETION & DEPOLARIZED MEMBRANE POTENTIAL
非甾体抗炎药、多胺消耗
  • 批准号:
    7381862
  • 财政年份:
    2006
  • 资助金额:
    $ 33.3万
  • 项目类别:
NSAIDS, POLYAMINE-DEPLETION & DEPOLARIZED MEMBRANE POTENTIAL
非甾体抗炎药、多胺消耗
  • 批准号:
    7171090
  • 财政年份:
    2005
  • 资助金额:
    $ 33.3万
  • 项目类别:
NSAIDS, POLYAMINE-DEPLETION & DEPOLARIZED MEMBRANE POTENTIAL
非甾体抗炎药、多胺消耗
  • 批准号:
    6981769
  • 财政年份:
    2004
  • 资助金额:
    $ 33.3万
  • 项目类别:

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