Role of Elastolytic Cathepsins in Emphysema

弹性组织蛋白酶在肺气肿中的作用

• 批准号: 7009143
• 负责人: Harold A Chapman
• 金额: $ 42.17万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009143
• 关键词: Role; Elastolytic; Cathepsins; Emphysema

EXCEED THE SPACE PROVIDED. Accumulating evidence indicates papain-family cysteine proteases are involved in the pathobiology of emphysema. One of these enzymes, cathepsin S, is a potent extracellular elastase stable at neutral pH and also a key endosomal acidic protease in MHC class II antigen presentation. Cathepsin S expression is higher in lungs of cigarette smokers and is induced in numerous cell types by interferon-v (IFN-y). Findings during the current funding period indicate that cathepsin S is required for smoking-induced murine emphysema and contributes significantly to IFN-y induced emphysema. These studies also implicate a previously unsuspected role for cathepsin S in emphysema: promotion of an interferon-y (IFN-y) driven immune response (possibly autoimmune) leading to the deposition of complement-activating IgG in the mouse lungs. Given the recent strong evidence linking the number of human B cells in airway walls with progressive loss of lung function in COPD patients and evidence IFN-y signaling is prominent in lungs of COPD patients, the following main hypothesis is advanced: Cathepsin S by virtue of its extracellular proteolytic activity not only contributes to extracellular matrix degradation but also generates potential antigens and by virtue of its critical intracellular role in antigen presentation promotes local antibody responses to tissue antigens and progression of lung injury. Both pathways may synergize to promote progressive emphysema, the latter pathway driven in mice by IFN-Y an^ we hypothesize in humans by intermittent infection. The research strategy is to pursue the identification of the biochemical "signature" of excess cathepsin S activity in mouse lung using 2D gel electrophoresis and mass spectroscopy , guided in part by identification of candidate genes in human emphysema through collaborationwith the early-onset Boston COPD Project, and to define the nature and importance of local antibody responses in experimental emphysema. Experiments will then be undertaken to search for characteristic cathepsin S protein cleavages and lung antibodies in stored sera and tissues of patients with COPD. Identification of biomarkers of cathepsin S activity in COPD patients could :erve as a surrogate for disease progression and an in vivo measure of efficacy during drug trials.

超越空间 假如。 越来越多的证据表明木瓜蛋白酶家族半胱氨酸蛋白酶参与了以下疾病的病理生物学： 气肿。其中一种酶组织蛋白酶 S 是一种有效的细胞外弹性蛋白酶，在中性 pH 值和 也是 MHC II 类抗原呈递中的关键内体酸性蛋白酶。组织蛋白酶S表达较高 它存在于吸烟者的肺部，并由干扰素 v (IFN-y) 在多种细胞类型中诱导。期间的调查结果 目前的资助期限表明组织蛋白酶 S 是吸烟引起的小鼠肺气肿所必需的，并且 显着促进 IFN-γ 诱导的肺气肿。这些研究还暗示了先前 组织蛋白酶 S 在肺气肿中的意想不到的作用：促进干扰素 y (IFN-y) 驱动的免疫 反应（可能是自身免疫）导致补体激活 IgG 在小鼠肺部沉积。 鉴于最近强有力的证据表明气道壁中人类 B 细胞的数量与进行性损失有关 COPD 患者肺功能的变化以及 IFN-γ 信号传导在 COPD 患者肺部显着的证据 提出了以下主要假设：组织蛋白酶 S 凭借其细胞外蛋白水解活性不 不仅有助于细胞外基质降解，而且还产生潜在的抗原，并且凭借其 在抗原呈递中的关键细胞内作用促进局部抗体对组织抗原的反应 肺损伤的进展。两种途径可能协同促进进行性肺气肿，后者 在小鼠中，该途径是由 IFN-Y 驱动的，我们假设在人类中是由间歇性感染驱动的。研究 策略是寻求鉴定小鼠组织蛋白酶 S 活性过剩的生化“特征” 使用二维凝胶电泳和质谱法对肺进行检测，部分通过候选基因的鉴定来指导 通过与早发波士顿慢性阻塞性肺病项目合作，研究人类肺气肿，并定义 实验性肺气肿中局部抗体反应的性质和重要性。接下来将进行实验 致力于在储存的血清中寻找特征性组织蛋白酶 S 蛋白裂解和肺抗体 COPD 患者的组织。鉴定 COPD 患者组织蛋白酶 S 活性的生物标志物 ：作为疾病进展的替代指标和药物试验期间体内疗效的衡量标准。