Airway Metalloproteinases in Mucosal Immunity

描述（由申请方提供）：铜绿假单胞菌引起的肺部慢性感染是囊性纤维化患者发病和死亡的主要原因。已经提出了许多假设来解释这些患者长期被这种微生物定植的倾向，其中许多假设意味着气道上皮的防御机制有缺陷。基质溶素是一种基质金属蛋白酶（MMP），在先天免疫中起作用，并促进上皮再生和中性粒细胞流入。基质溶素在感染的肺中显著表达，并且通过暴露于细菌或细菌产物（特别是铜绿假单胞菌鞭毛蛋白）在上皮细胞中诱导。我们假设基质溶解素是呼吸道粘膜先天防御的关键参与者，通过前体蛋白的蛋白水解产生抗菌活性。事实上，R21应用的初步数据表明，来自未处理基质溶素缺失（Mmp 7-/-）小鼠的气道液中的非防御素抗菌活性明显不足，并且这种活性的大小估计表明它是一种新的因子。此外，这种活性在野生型小鼠中响应于铜绿假单胞菌感染而显著上调，但在Mmp 7-/-肺中仍然缺乏。为了研究该MMP在肺免疫中的作用，我们计划：1）分离和表征肺中的基质溶解素依赖性抗菌剂;和2）验证基质溶解素在防御铜绿假单胞菌感染中的作用。这些研究将为了解基质溶解素在粘膜防御机制中的作用提供重要的信息。 各种病原体引起的肺部感染（例如，金黄色葡萄球菌、流感嗜血杆菌、铜绿假单胞菌等）是囊性纤维化和通气患者社区获得性感染以及发病率和死亡率的主要原因。我们假设基质溶解素通过前体蛋白的蛋白水解产生抗菌活性，在呼吸道粘膜先天防御中发挥关键作用。这些研究将为了解基质溶解素在粘膜防御机制中的作用提供重要的信息。

DESCRIPTION (provided by applicant): Chronic infection of the lung by Pseudomonas aeruginosa is the major cause of morbidity and mortality in patients with cystic fibrosis. A number of hypotheses have been proposed to explain the predisposition of these patients to prolonged colonization by this microorganism, many of which imply defective defense mechanisms of the airway epithelium. Matrilysin, a matrix metalloproteinase (MMP), functions in innate immunity and facilitates re-epithelialization and neutrophil influx. Matrilysin is markedly expressed in infected lungs and is induced in epithelial cells by exposure to bacteria or bacterial products, specifically P. aeruginosa flagellin. We hypothesize that matrilysin is a key player in respiratory mucosal innate defense by generating an antibacterial activity via proteolysis of a precursor protein. Indeed, preliminary data for this R21 application demonstrates a marked deficiency in non-defensin antibacterial activity in airway fluid from na¿ve matrilysin-null (Mmp7-/-) mice, and size estimates of this activity suggest that it is a novel factor. Furthermore, this activity is markedly upregulated in wildtype mice in response to P. aeruginosa infection, yet remains deficient in Mmp7-/- lung. To investigate the role of this MMP in lung immunity, we plan to: 1) isolate and characterize the matrilysin- dependent antibacterial in lung; and 2) verify the role of matrilysin in defense against P. aeruginosa infection. These studies will provide important insight into the role of matrilysin in mucosal defense mechanisms. Infection of the lung by various pathogens (e.g., Staphylococcus aureus, haemophilus influenzae, Pseudomonas aeruginosa, and other) are a major cause of community-acquired infection and morbidity and mortality in cystic fibrosis and ventilated patients. We hypothesize that matrilysin is a key player in respiratory mucosal innate defense by generating an antibacterial activity via proteolysis of a precursor protein. These studies will provide important insight into the role of matrilysin in mucosal defense mechanisms.