MECHANISMS OF NOVEL ANTI-INFLAMMATORY ACTIONS OF SLPI

SLPI 的新型抗炎作用机制

• 批准号: 6781461
• 负责人: Aihao Ding
• 金额: $ 35.64万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781461
• 关键词: antiinflammatory agents; biological signal transduction; cell surface receptors; clinical research; disease /disorder model; gene expression; gene targeting; genetic regulation; genetically modified animals; human subject; interferons; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; macrophage; microarray technology; mutant; neutralizing antibody; neutrophil; pathologic process; protease inhibitor; protein structure function; tissue /cell culture; transfection; vascular endothelium

DESCRIPTION (provided by applicant): Secretory leukocyte protease inhibitor (SLPI) and proepithelin (PEPI) were originally discovered as two unrelated secreted products of epithelial cells. SLPI is a small 12-kDa leukocyte protease inhibitor, while PEPI is best known as the precursor for epithelins (EPIs), a group of 6-kDa peptides with unknown functions that are found in diverse tissues and body fluids. Leukocytes, especially macrophages, are also rich sources of SLPI and PEPI. Expression of both proteins is upregulated in macrophages by microbial products such as lipopolysaccharide (LPS). We have identified PEPI as a SLPI interacting protein. We also discovered that PEPI and EPIs exert opposing biological activities. EPIs promote whereas PEPI downregulates inflammatory reactions. Binding of PEPI by SLPI prevents its conversion to EPIs. Both SLPI and PEPI block TNF-triggered neutrophil activation. SLPI also suppresses the macrophage response to LPS. Thus, SLPI and PEPI appear to be a pair of host-derived anti-inflammatory mediators that serve to prevent excess innate immune responses. The underlying mechanisms for the anti-inflammatory actions of SLPI and PEPI are poorly understood. The goal of this project is to further explore the mechanisms of the novel anti-inflammatory actions of SLPI and PEPI. We will focus on: (1) characterizing the role of PEPI/EPIs in the inflammatory responses of leukocytes; (2) understanding the molecular basis by which SLPI and PEPI affect macrophage function; and (3) testing the role of SLPI and PEPI in three in vivo inflammation models (cutaneous wounding, smoke-induced emphysema and septic shock induced by cecal-ligation and puncture) using PEPI and SLPI knock out mice and SLPI transgenic mice. Elucidating how SLPI and PEPI interfere with specific steps in LPS signaling may contribute important insights to the pathophysiology of inflammation-related diseases including septic shock and to the development of novel therapeutic strategies.

描述（由申请人提供）： 分泌性白细胞蛋白酶抑制剂（SLPI）和上皮素原（PEPI）最初被发现是两种无关的上皮细胞分泌产物。SLPI是一种小的12-kDa白细胞蛋白酶抑制剂，而PEPI最为人所知的是上皮蛋白（EPI）的前体，这是一组在不同组织和体液中发现的功能未知的6-kDa肽。白细胞，特别是巨噬细胞，也是SLPI和PEPI的丰富来源。这两种蛋白质的表达在巨噬细胞中被微生物产物如脂多糖（LPS）上调。我们已经确定PEPI作为SLPI相互作用蛋白。我们还发现，PEPI和EPI发挥相反的生物活性。EPI促进而PEPI下调炎症反应。SLPI与PEPI的结合阻止其转化为EPI。SLPI和PEPI均阻断TNF触发的中性粒细胞活化。SLPI还抑制巨噬细胞对LPS的反应。因此，SLPI和PEPI似乎是一对宿主来源的抗炎介质，其用于防止过度的先天免疫应答。SLPI和PEPI的抗炎作用的潜在机制知之甚少。本课题的目的是进一步探讨SLPI和PEPI新的抗炎作用机制。我们将重点关注：（1）表征PEPI/EPI在白细胞炎症反应中的作用;（2）理解SLPI和PEPI影响巨噬细胞功能的分子基础;和（3）使用PEPI和SLPI敲除小鼠和SLPI转基因小鼠测试SLPI和PEPI在三种体内炎症模型（皮肤创伤、烟雾诱导的肺气肿和盲肠结扎和穿刺诱导的败血性休克）中的作用。阐明SLPI和PEPI如何干扰LPS信号传导中的特定步骤，可能有助于对炎症相关疾病（包括感染性休克）的病理生理学以及新治疗策略的开发的重要见解。