Role of Elastolytic Cathepsins in Emphysema

描述(申请人摘要)：尽管过度的蛋白质分解是关键 肺气肿发病机制中的因素，蛋白水解酶失调的途径 这种混乱仍然不确定。新研究表明淋巴细胞来源 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，促进表达和 分泌活性半胱氨酸蛋白酶的组织蛋白酶S，一种稳定的强效弹性蛋白酶 在中性pH条件下。表达IL-13或干扰素-γ的转基因小鼠 呼吸道表面发生半胱氨酸蛋白酶依赖的肺气肿改变。 此外，最近发现血清中的胆碱能激素水平与 胱抑素C，主要的半胱氨酸蛋白酶抑制剂，并严重减少 30例早发性患者队列中的FEV1(预测为20%) 肺气肿与FEV1正常和吸烟史相似的对照组比较。 这些研究提出了一种假设，即促炎细胞因子和 香烟烟雾可能刺激肺间充质细胞和巨噬细胞 分泌弹性半胱氨酸蛋白酶并下调其半胱氨酸蛋白酶C的表达 放手。这种失衡会加速胶原蛋白和弹性蛋白的合成。 降解对肺气肿和慢性阻塞性肺病的发展很重要。这项研究 计划的中心问题是弹性溶解的失调 组织蛋白酶在肺气肿的发病机制中起重要作用。平行的轨道 拟进行动物和人体实验：小鼠组织蛋白酶S/L和胱抑素C 在目标1和目标2中使用了“击倒”来回答这样一个问题： 弹性组织蛋白酶活性加剧了糖尿病的发展。 干扰素诱导的肺气肿和肺内间充质细胞是否是 这些酶的来源。AIM 3的设计目的是确定低水平的 胱抑素C和/或调控主基因或其附近的多态标记 胱抑素C(和弹性组织蛋白)与高血压的风险增加有关 慢性阻塞性肺疾病（慢阻肺）。总之，这些研究应该确定一些患者是否患有 早发性COPD可以根据表型(胱抑素C)或 遗传标记，转化为由共同致病基因定义的功能子集 涉及弹性组织蛋白调节失调的途径。

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.