Role of Elastolytic Cathepsins in Emphysema

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 肺气肿这些酶之一，组织蛋白酶S，是一种有效的细胞外弹性蛋白酶，在中性pH下稳定， 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 在吸烟者的肺中，并且在许多细胞类型中由干扰素-V（IFN-γ）诱导。期间的结果 目前的资助期表明，吸烟诱导的鼠肺气肿需要组织蛋白酶S， 对IFN-γ诱导的肺气肿有重要作用。这些研究也暗示了以前 组织蛋白酶S在肺气肿中的作用：促进IFN-γ驱动的免疫 免疫应答（可能是自身免疫）导致小鼠肺中补体激活IgG的沉积。 鉴于最近有强有力的证据将气道壁中人类B细胞的数量与进行性丧失联系起来 COPD患者肺功能的变化以及IFN-γ信号传导在COPD患者肺中显著的证据， 提出了以下主要假设：组织蛋白酶S由于其细胞外蛋白水解活性， 不仅有助于细胞外基质降解，而且还产生潜在的抗原， 在抗原呈递中的关键细胞内作用促进对组织抗原的局部抗体应答， 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 在小鼠中由IFN-γ驱动的途径，我们假设在人类中由间歇性感染驱动。研究 策略是继续鉴定小鼠中过量组织蛋白酶S活性的生化“特征”， 肺使用2D凝胶电泳和质谱，部分由候选基因的鉴定指导 通过与早发性波士顿COPD项目的合作， 实验性肺气肿局部抗体反应的性质和重要性。实验将在 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活性的生物标志物可以 ：在药物试验期间，用作疾病进展的替代物和体内疗效的测量。

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.