Role of Elastolytic Cathepsins in Emphysema

描述（申请人的摘要）：虽然过度的蛋白水解是一个关键 肺气肿发病机制中的元素，蛋白酶失调的途径， 这种疾病仍然不确定。新的研究表明， 肺气肿中的细胞因子干扰素-γ作用于巨噬细胞以及 非炎性细胞如平滑肌细胞以促进表达， 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 在中性pH下表达IL-13或干扰素-γ的转基因小鼠 气道表面产生半胱氨酸蛋白酶依赖性肺气肿性变化。 此外，最近发现血清中的 半胱氨酸蛋白酶抑制剂C，主要的半胱氨酸蛋白酶抑制剂， 30例早发性心力衰竭患者的FEV 1（<20%预测值） 肺气肿与正常FEV 1和类似吸烟史的对照组相比。 这些研究提出了一种假设，即促炎细胞因子和 香烟烟雾可能刺激间充质肺细胞和巨噬细胞， 分泌弹性蛋白溶解性半胱氨酸蛋白酶并下调其半胱氨酸蛋白酶抑制剂C release.这种不平衡造成了胶原蛋白和弹性蛋白的加速过程 这种降解对肺气肿和COPD的发展很重要。研究 该计划的核心问题是， 组织蛋白酶在肺气肿的发病机制中是重要的。平行轨道 提出了动物和人体实验：小鼠组织蛋白酶S/L和胱抑素C 目标1和目标2中使用“敲除”来回答是否过量 弹性蛋白溶解组织蛋白酶活性加剧了 干扰素-γ诱导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旨在确定低水平的 胱抑素C和/或多态性标记在或附近的主要基因调节 半胱氨酸蛋白酶抑制剂C（和弹性蛋白溶解性组织蛋白酶）与以下风险增加相关： 慢性阻塞性肺病总之，这些研究应该确定是否有些患者 早发性COPD可根据表型（胱抑素C）或 遗传标记，分为一个功能子集定义的共同致病 涉及弹性蛋白分解组织蛋白酶调节异常的途径。

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.