Role of Lysozyme in Airways Host Defense

溶菌酶是一种阳离子蛋白，含有146个氨基酸残基（Mr约为14k），在体外对多种革兰氏阳性细菌具有杀菌作用。虽然溶菌酶是气道表面液（ASL）中最丰富的抗菌蛋白，但其在体内保护气道免受感染、慢性定植和炎症的作用尚未得到证实。本应用程序中报告的初步研究结果表明，在过度表达溶菌酶的急性感染转基因小鼠中，支气管肺泡灌洗液中溶菌酶活性水平与革兰氏阳性和阴性生物的细菌杀灭率之间存在剂量依赖关系。本应用中提出的研究将验证溶菌酶是气道宿主体内防御的关键组成部分的中心假设。在急性和慢性肺部感染后，将评估溶菌酶（-/-）小鼠和溶菌酶过表达小鼠的病原体杀灭情况。还将评估外源性给药重组溶菌酶蛋白的抗菌谱和效力。这些研究将深入了解溶菌酶在气道宿主防御中的作用，并对外源性溶菌酶的治疗潜力进行初步评估。

Lysozyme is a cationic protein of 146 amino acid residues (Mr approximately 14k) that is bactericidal against multiple gram-positive bacteria in vitro. Although lysozyme is the most abundant antimicrobial protein in airway surface fluid (ASL), its role in protecting the airways against infection, chronic colonization, and inflammation in vivo remains unproven. The results of preliminary studies reported in this application demonstrate a dose-dependent relationship between the level of lysozyme activity in bronchoalveolar lavage fluid and the rate of bacterial killing, of both gram positive and negative organisms, in acutely infected transgenic mice that overexpress lysozyme. Studies proposed in this application will test the central hypothesis that lysozyme is a critical component of airway host defense in vivo. Pathogen killing will be assessed in lysozyme (-/-) mice and lysozyme overexpressing mice following acute and chronic lung infection. The antimicrobial spectrum and potency of exogenously-administered recombinant lysozyme protein will also be assessed. These studies will provide insight into the role of lysozyme in airway host defense and provide a preliminary assessment of the therapeutic potential of exogenously administered lysozyme.