Airway Metalloproteinases in Mucosal Immunity

粘膜免疫中的气道金属蛋白酶

• 批准号: 7701521
• 负责人: WILLIAM C PARKS
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701521
• 关键词: Air; Alveolar; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biochemical; Cells; Chronic; Community-Acquired Infections; Coughing; Cystic Fibrosis; Data; Defense Mechanisms; Defensins; Development; Disease model; Elevator; Epithelial; Epithelial Cells; Excision; Exposure to; Flagellin; Foundations; Future; Gases; Gene Family; Generations; Goals; Haemophilus influenzae; Health; Host Defense; Immunity; Infection; Inflammation; Influenza; Injury; Liquid substance; Lung; Matrilysin; Matrix Metalloproteinases; Mediating; Metalloproteases; Metalloproteinase Gene; Modeling; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Muramidase; Mus; Natural Immunity; Nature; Organ; Patients; Play; Predisposition; Production; Protein Precursors; Proteins; Proteolysis; Pseudomonas aeruginosa; Publishing; Research Project Grants; Respiration; Role; Staphylococcus aureus; Structure of parenchyma of lung; Surface; Ventilator; airway epithelium; antimicrobial drug; base; cystic fibrosis patients; in vivo; insight; member; microorganism; mortality; mouse model; neutrophil; novel; pathogen; repaired; respiratory; response

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.

描述(申请人提供)：铜绿假单胞菌慢性肺部感染是囊性纤维化患者发病和死亡的主要原因。已经提出了许多假说来解释这些患者对这种微生物长期定植的易感性，其中许多假说暗示了呼吸道上皮防御机制的缺陷。基质溶素是一种基质金属蛋白酶，在先天免疫中发挥作用，并促进再上皮化和中性粒细胞的流入。基质溶素在感染的肺中显著表达，并在接触细菌或细菌产物，特别是铜绿假单胞菌鞭毛蛋白的情况下在上皮细胞中诱导表达。我们推测，母溶素通过前体蛋白的蛋白分解产生抗菌活性，从而在呼吸道粘膜的先天防御中发挥关键作用。事实上，R21应用的初步数据显示，在母溶素缺失(Mmp7-/-)小鼠的气道液中，非防御素抗菌活性明显不足，对这一活动的大小估计表明，这是一个新的因素。此外，这种活性在野生型小鼠对铜绿假单胞菌感染的反应中显著上调，但在Mmp7-/-肺中仍然缺乏。为了研究基质溶素在肺免疫中的作用，我们计划：1)分离和鉴定肺中依赖基质溶素的抗菌素；2)验证基质溶素在抵抗铜绿假单胞菌感染中的作用。这些研究将对基质溶素在粘膜防御机制中的作用提供重要的见解。 各种病原体(如金黄色葡萄球菌、流感嗜血杆菌、铜绿假单胞菌等)对肺部的感染是囊性纤维化和呼吸机患者社区获得性感染、发病率和死亡率的主要原因。我们推测，母溶素通过前体蛋白的蛋白分解产生抗菌活性，从而在呼吸道粘膜的先天防御中发挥关键作用。这些研究将对基质溶素在粘膜防御机制中的作用提供重要的见解。