Roles of Peptidases in Chronic Airway Inflammation

在炎症的呼吸道中，上皮结构、基质、腺体和血管的变化促进慢性支气管炎和哮喘的阻塞和高分泌。该项目测试了肽酶控制慢性呼吸道炎症的重塑和其他方面的消退这一假设。它使用了新的方法，如用基于活性的探针瞄准活细胞中的肽酶，用实时成像探测慢性感染小鼠模型中免疫细胞的相互作用，以及探索肥大细胞肽酶基因变异对人类哮喘的贡献。目的1确定呼吸道上皮肽酶前列腺素在慢性感染中的作用。上皮的完整性和水合作用对于抵御微生物和毒素是必不可少的。屏障功能的丧失会导致慢性感染和重塑，如囊性纤维化。目的1研究证实前列腺素支持气道离子流量和完整性的假说是由膜的锚定、激活、抑制和脱落控制的。目的2确定肥大细胞多肽酶在消炎中的作用。肥大细胞产品可能会造成伤害，但小鼠研究表明，它们也可以提高感染性腹膜炎和肺炎的存活率。通过帮助消除感染，它们的总体效果可以是消炎的。目的2项研究验证了肥大细胞多肽酶促进慢性炎症消退的假设。目的3确定肥大细胞类胰蛋白酶缺乏对慢性呼吸道炎症的影响。类胰蛋白酶与呼吸道重塑、变态反应性炎症和自身免疫性炎症以及抵御细菌感染有关，因此具有产生和化解炎症的潜力。我们最近的工作表明，功能失调的人类类胰蛋白酶是常见的，而且个体和群体在继承的活性类胰蛋白酶基因的数量上存在显著差异。通过探索基因型和哮喘之间的联系，拟议中的研究检验了这样一个假设，即类胰酶基因的差异导致哮喘严重程度和易感性的遗传变异。哮喘不仅与慢性炎症有关，而且与感染加剧有关。总体而言，拟议的研究有望确定提出以前未探索的预防或逆转慢性气道炎病理的策略的机制。

In inflamed airway, changes in epithelial architecture, matrix, glands, and vessels promote obstruction and hypersecretion in chronic bronchitis and asthma. This project tests the hypothesis that peptidases control resolution of remodeling and other aspects of chronic airway inflammation. It uses novel approaches such as targeting peptidases in living cells with activity-based probes, probing immune cell interactions with real time imaging in mouse models of chronic infection, and exploring contributions of genetic variation in mast cell peptidases to human asthma. Aim 1 is to determine roles of the airway epithelial peptidase prostasin in chronic infection. Epithelial integrity and hydration is essential for defense against microbes and toxins. Failure of barrier function leads to chronic infection and remodeling, as in cystic fibrosis. Aim 1 studies test the hypothesis that prostasin support of airway ion flux and integrity is controlled by membrane anchoring, activation, inhibition and shedding. Aim 2 is to determine roles of mast cell peptidases in resolving inflammation. Mast cell products can Inflict harm, but mouse studies suggest they also promote survival from septic peritonitis and pneumonia. By helping to resolve infection, their overall effect can be anti-inflammatory. Aim 2 studies test the hypothesis that mast cell peptidases promote resolution of chronic inflammation. Aim 3 is to determine impact of mast cell tryptase deficiency on chronic airway inflammation. Tryptases are implicated in airway remodeling in allergic and autoimmune inflammation and in defense against bacterial infection and thus have the potential to produce as well as to resolve inflammation. Our recent work reveals that dysfunctional human tryptases are common and that Individuals and populations vary strikingly in number of active tryptase genes inherited. By exploring connections between genotype and asthma, a disease associated not only with chronic inflammation but with exacerbation by infection, the proposed studies test the hypothesis that differences in tryptase genotype contribute to inherited variation in asthma severity and susceptibility. Overall, the proposed studies are expected to identify mechanisms that suggest previously unexplored strategies to prevent or reverse the pathology of chronic airway inflammation.