Role of Elastolytic Cathepsins in Emphysema

超出空间 但前提是。 越来越多的证据表明，木瓜蛋白酶家族的半胱氨酸蛋白酶参与了乳癌的病理生物学过程。 肺气肿。其中一种酶，组织蛋白酶S，是一种有效的胞外弹性蛋白酶，在中性pH和 也是MHC II类抗原呈递过程中的关键内体酸性蛋白水解酶。组织蛋白酶S的表达水平较高 在吸烟者的肺中，并由干扰素-v(干扰素-γ)诱导多种细胞类型。期间的发现 目前的资助期表明，吸烟诱导的小鼠肺气肿和组织蛋白酶S是必需的。 对干扰素-γ诱导的肺气肿有重要作用。这些研究还表明，之前 组织蛋白酶S在肺气肿中的意外作用：促进干扰素-γ诱导的免疫 免疫应答(可能是自身免疫)导致补体激活的免疫球蛋白在小鼠肺中沉积。 鉴于最近有强有力的证据表明，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，以及有证据表明在COPD患者的肺中存在显著的干扰素-γ信号。 主要提出以下假说：组织蛋白酶S凭借其胞外蛋白水解性不强 不仅有助于细胞外基质的降解，而且还会产生潜在的抗原，并通过其 在抗原提呈中的关键细胞内作用促进局部抗体对组织抗原的反应和 肺损伤的进展。这两种途径可能协同促进进行性肺气肿，后者 干扰素-γ在小鼠体内的作用途径和人类间歇性感染的假说。这项研究 策略是寻找小鼠组织蛋白酶S活性过高的生化“标志” 肺的2D凝胶电泳和质谱学，部分由候选基因的识别指导 通过与早发性波士顿COPD项目合作，对人类肺气肿进行研究，并确定 实验性肺气肿局部抗体反应的性质和重要性。届时，实验将被 在储存的血清和肺组织中寻找组织蛋白酶S蛋白裂解和肺抗体的特征 慢性阻塞性肺疾病患者的组织。慢性阻塞性肺疾病患者组织蛋白酶S活性生物标志物的鉴定 ：在药物试验期间，ERVE作为疾病进展的替代品和体内疗效的衡量标准。

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.