Role of Lysozyme in Airways Host Defense

溶菌酶是一种由146个氨基酸残基（Mr约14 k）组成的阳离子蛋白质，其在体外对多种革兰氏阳性菌具有杀菌作用。 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。本申请中报道的初步研究结果证明，在急性感染的过表达溶菌酶的转基因小鼠中，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体的细菌杀灭率之间存在剂量依赖性关系。本申请中提出的研究将检验中心假设，即溶菌酶是体内气道宿主防御的关键组分。 在急性和慢性肺部感染后，将在溶菌酶（-/-）小鼠和溶菌酶过表达小鼠中评估病原体杀灭。 还将评估外源施用的重组溶菌酶蛋白的抗微生物谱和效力。 这些研究将提供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.