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
• 负责人: JAMES D LILLICH
• 金额: $ 2.92万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167826
• 关键词: Attention; Calpain; Cardiovascular system; Cell Migration Inhibition function; Chronic; Computer Retrieval of Information on Scientific Projects Database; Cysteine Protease; Data; Drug toxicity; Elements; Epithelial; Epithelial Cells; Event; Funding; Gene Expression; Goals; Grant; Health Personnel; Human; Hydrophobicity; Incidence; Inflammatory; Institution; Intestines; Investigation; Knowledge; Link; Mediating; Neutrophil Infiltration; Oral; Pathway interactions; Pharmaceutical Preparations; Prevention; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Research; Research Personnel; Resources; Rofecoxib; Scientist; Source; Staging; Stomach; Surface; Ulcer; United States National Institutes of Health; Wound Healing; calpastatin; celecoxib; cell motility; design; gastrointestinal; improved; inhibitor/antagonist; migration; neutrophil; novel strategies; research study; response; wound

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goals of this project are to elucidate mechanisms that mediate non-steroidal anti-inflammtory drugs (NSAIDs) effects on cell migration during wound healing, and use the knowledge gained to develop novel strategies for treatment and prevention of gastrointestinal (GI) ulcers. Adverse GI effects of NSAIDs in humans and other species include oral, gastric, duodenal, and colonic ulceration. Despite extensive investigation, the mechanisms responsible for NSAID-associated GI damage are not completely understood. NSAIDs may promote ulcer formation, not only by inhibiting mucosal cyclooxygenase (COX) and decreasing cytoprotective prostaglandins (PG), but also by adversely influencing intestinal microflora, neutrophil recruitment, surface hydrophobicity and epithelial restitution. Recent evidence suggests that calpains (cysteine proteases) are vital to the several key pathways of fibroblastic and WBC migration. Our preliminary data indicate that ulcerogenic NSAIDs either down-regulate calpain gene expression or up-regulate the constituent inhibitor, calpastatin. From a global perspective this has led us to hypothesyze that the formation of NSAID-induced GI ulceration is due, in part, to inhibited epithelial and fibroblastic cell migration, facilitated neutrophil migration into the wound, leading to an uncoupled and uncoordinated wound healing response setting the stage for a chronic inflammatory state. The experiments proposed here are designed specifically to link NSAID inhibition of cell migration with NSAID effects on events vital to calpain function within differentiated intestinal epithelial cells (IECs). The specific aims of this project are to: 1) Demonstrate that calpains are critical to normal IEC migration. 2)Confirm that calpains are a target for NSAID-toxicity and disruption of intestinal epithelial wound healing. 3) Determine the effects of NSAIDs on the downstream substrates of the calpains, specifically cytoskeletal and intregin elements required during intestinal epithelial restitution. The results of this project will provide valuable data immediately useful not only to the health care providers who want to make rational decisions about prescribing NSAIDs, but also to the industrial scientists who strive to develop less toxic alternatives to the drugs currently available. Escalating concerns about serious cardiovascular complications linked to celecoxib and rofecoxib, the NSAIDs associated with lowest incidence of drug-induced gastropathy, draw attention to the urgent need for improved understanding of the mechanisms that underlie NSAID-induced ulcers.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的长期目标是阐明介导非甾体抗炎药（NSAID）对伤口愈合过程中细胞迁移的影响的机制，并利用所获得的知识开发治疗和预防胃肠道（GI）的新策略溃疡。非甾体抗炎药对人类和其他物种的胃肠道不良影响包括口腔、胃、十二指肠和结肠溃疡。尽管进行了广泛的研究，但与非甾体抗炎药相关的胃肠道损伤的机制尚不完全清楚。 NSAIDs 可能促进溃疡形成，不仅通过抑制粘膜环氧合酶（COX）和减少细胞保护性前列腺素（PG），而且还通过对肠道微生物群、中性粒细胞募集、表面疏水性和上皮恢复产生不利影响。最近的证据表明，钙蛋白酶（半胱氨酸蛋白酶）对于成纤维细胞和白细胞迁移的几个关键途径至关重要。我们的初步数据表明，引起溃疡的非甾体抗炎药要么下调钙蛋白酶基因表达，要么上调成分抑制剂钙蛋白酶抑制素。 从全球角度来看，这使我们推测，NSAID 诱导的胃肠道溃疡的形成部分是由于抑制了上皮细胞和成纤维细胞迁移，促进了中性粒细胞迁移到伤口中，导致了不耦合和不协调的伤口愈合反应环境慢性炎症状态的阶段。这里提出的实验专门设计用于将 NSAID 对细胞迁移的抑制与 NSAID 对分化肠上皮细胞 (IEC) 内钙蛋白酶功能至关重要的事件的影响联系起来。 该项目的具体目标是： 1) 证明钙蛋白酶对于正常的 IEC 迁移至关重要。 2)确认钙蛋白酶是NSAID毒性和肠上皮伤口愈合破坏的靶标。 3) 确定 NSAID 对钙蛋白酶下游底物的影响，特别是肠上皮恢复过程中所需的细胞骨架和整合素元件。 该项目的结果将提供有价值的数据，不仅对想要就非甾体抗炎药处方做出合理决定的医疗保健提供者有用，而且对努力开发现有药物毒性较小的替代品的工业科学家也有用。人们对塞来考昔和罗非考昔（这两种非甾体抗炎药与药物性胃病发病率最低）相关的严重心血管并发症的担忧不断升级，引起人们对迫切需要加深对非甾体抗炎药引起的溃疡机制的了解的关注。