Role of Elastolytic Cathepsins in Emphysema

弹性组织蛋白酶在肺气肿中的作用

• 批准号: 6752914
• 负责人: Harold A Chapman
• 金额: $ 32.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752914
• 关键词: chronic obstructive pulmonary disease; clinical research; collagen; connective tissue; cysteine endopeptidases; elastases; elastin; emphysema; enzyme activity; gamma globulin; genetic polymorphism; genetic susceptibility; human tissue; interferon gamma; interleukin 13; laboratory mouse; pathologic process; protease inhibitor; smoking; tobacco abuse

DESCRIPTION (Applicant's Abstract): Although excessive proteolysis is a key element in the pathogenesis of emphysema, pathways of protease dysregulation in this disorder remain uncertain. New studies implicate lymphocyte-derived cytokines in emphysema. Interferon-y acts on macrophages as well as non-inflammatory cells such as smooth muscle cells to promote expression and secretion of the active cysteine protease cathepsin S, a potent elastase stable at neutral pH. Transgenic mice expressing either IL-13 or interferon-y on airway surfaces develop cysteine protease-dependent emphysematous changes. Further, a significant correlation was recently found between serum levels of cystatin C, the major cysteine protease inhibitor, and severe reductions in FEV1 (<20 percent predicted) in a cohort of 30 patients with early-onset emphysema compared to controls with normal FEV1 and comparable smoking history. These studies invite the hypothesis that pro-inflammatory cytokines and possibly cigarette smoke stimulate mesenchymal lung cells and macrophages to secrete elastolytic cysteine proteases and downregulate their cystatin C release. This imbalance creates an accelerated process of collagen and elastin degradation important to the development of emphysema and COPD. The research plan is centered on the question of whether dysregulation of elastolytic cathepsins is important to the pathogenesis of emphysema. Parallel tracks of animal and human experiments are proposed: Mouse cathepsin S/L and cystatin C "knockouts" are used in Aims 1 and 2 to answer the question of whether excess elastolytic cathepsin activity exacerbates the development of interferon-y-induced emphysema and whether mesenchymal cells in the lung are a source of these enzymes. Aim 3 is designed to determine if low levels of cystatin C and/or polymorphic markers in or near the major genes regulating cystatin C (and elastolytic cathepsins) are associated with increased risk of COPD. Together, these studies should determine if some patients with early-onset COPD can be grouped, based on either phenotypic (cystatin C) or genetic markers, into a functional subset defined by a common pathogenic pathway involving dysregulation of elastolytic cathepsins.

描述（申请人的摘要）：尽管过度蛋白水解是关键 肺气肿发病机制中的因素，蛋白酶失调的途径 这种疾病仍然不确定。新研究表明淋巴细胞衍生 肺气肿中的细胞因子。干扰素-y 作用于巨噬细胞以及 非炎症细胞，如平滑肌细胞，促进表达和 分泌活性半胱氨酸蛋白酶组织蛋白酶 S，一种有效的弹性蛋白酶稳定剂 在中性pH值下。表达 IL-13 或干扰素-γ 的转基因小鼠 气道表面出现半胱氨酸蛋白酶依赖性肺气肿变化。 此外，最近发现血清水平之间存在显着相关性。 半胱氨酸蛋白酶抑制剂 C（主要的半胱氨酸蛋白酶抑制剂）和严重减少 30 名早发型患者的队列中的 FEV1（< 预测值的 20%） 与具有正常 FEV1 和类似吸烟史的对照组相比，出现肺气肿。 这些研究提出了这样的假设：促炎细胞因子和 香烟烟雾可能会刺激间充质肺细胞和巨噬细胞 分泌弹性半胱氨酸蛋白酶并下调其胱抑素 C 发布。这种不平衡导致胶原蛋白和弹性蛋白的加速过程 降解对于肺气肿和慢性阻塞性肺病的发展很重要。研究 该计划的核心问题是弹力松解调节是否失调 组织蛋白酶对于肺气肿的发病机制很重要。平行轨道 提出动物和人体实验：小鼠组织蛋白酶 S/L 和胱抑素 C 目标 1 和 2 中使用“淘汰”来回答是否过量的问题 弹性组织蛋白酶活性加剧了 干扰素 y 诱发的肺气肿以及肺中的间充质细胞是否是一种 这些酶的来源。目标 3 旨在确定低水平是否 半胱氨酸蛋白酶抑制剂 C 和/或多态性标记位于或靠近主要调节基因 胱抑素 C（和弹力组织蛋白酶）与以下风险增加相关： 慢性阻塞性肺病。总之，这些研究应该确定一些患者是否患有 早发性 COPD 可根据表型（胱抑素 C）或 遗传标记，转化为由常见致病性定义的功能子集 涉及弹性组织蛋白酶失调的途径。