REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE

气道乳过氧化物酶宿主防御的调节

• 批准号: 6530753
• 负责人: Gregory E. Conner
• 金额: $ 26.51万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530753
• 关键词: cystic fibrosis; enzyme biosynthesis; host organism interaction; human tissue; hydrogen peroxide; lactoperoxidase; membrane transport proteins; mucins; mucus; respiratory epithelium; respiratory infections; secretion; sheep; thiocyanates; tissue /cell culture

DESCRIPTION (Applicant's Abstract): Respiratory infection is a major cause of human morbidity and mortality in infants, the elderly, the immune-compromised and those on mechanical ventilators. The airway epithelium and submucosal glands provide the first defense against such infection by secreting several antibiotic substances. However, little is known regarding the several identified non-immunologic mucosal defenses. More knowledge of airway anti-infection defense will be valuable for designing prophylactic therapy for individuals predisposed to airway infection, e.g., in cystic fibrosis and bronchiectasis. The long-term goal of the proposed studies is to gain information about lactoperoxidase (LPO)-mediated non-immunologic defense in the airway. Recent work in this lab has shown that a significant amount of LPO is present in airway mucus, that LPO's substrates, thiocyanate (SCN-) and hydrogen peroxide (H2O2), are also present in the airway, that LPO is the major in vitro H2O2 scavenging activity in mucus, and that, in vivo, LPO catalytic activity is important for clearance of inhaled bacteria. Based on the above observations, the proposed experiments will test hypotheses regarding the regulation of the airway LPO system. The studies will use both differentiated airway epithelia at an air-liquid interface and submucosal gland cells in submerged cultures. Studies outlined in Specific Aim 1 will test the hypothesis that LPO synthesis or secretion is regulated by infection-related inflammatory stimuli and will study LPO's biosynthetic pathway. Specific Aim 2 will test the hypothesis that SCN- is carried into the airway lumen by a basolateral active transporter coupled to an apical anion channel and test whether this anion transport may be defective in cystic fibrosis. Specific Aim 3 will test the hypothesis that levels of the LPO substrate, H2O2, are also regulated by infection-related inflammatory stimuli and will identify the enzymatic source of H2O2. Understanding the regulatory mechanism of the LPO system will provide an opportunity for development of new prophylactic and therapeutic anti-infective agents. In addition, the studies may provide important insight into the pathophysiology of airway diseases characterized by chronic airway infection such as cystic fibrosis and bronchiectasis.

描述（申请人摘要）：呼吸道感染是导致流感的主要原因 婴儿、老年人、免疫功能低下者的人类发病率和死亡率 以及那些使用机械呼吸机的人。气道上皮和粘膜下层 腺体通过分泌几种物质来提供针对此类感染的第一道防御 抗生素物质。然而，关于这几个方面，人们知之甚少 确定了非免疫粘膜防御。更多气道知识 抗感染防御对于设计预防性治疗很有价值 易患气道感染的个体，例如囊性纤维化和 支气管扩张。拟议研究的长期目标是获得 有关乳过氧化物酶 (LPO) 介导的非免疫防御的信息 呼吸道。该实验室最近的工作表明，大量的 LPO 存在于气道粘液中，LPO 的底物是硫氰酸盐 (SCN-) 和氢 过氧化物（H2O2）也存在于气道中，体外实验中LPO是主要的 粘液中 H2O2 清除活性，并且在体内，LPO 催化活性为 对于清除吸入细菌很重要。根据上述观察， 拟议的实验将检验有关调节的假设 气道 LPO 系统。这些研究将使用两种分化的气道上皮细胞 深层培养物中的气液界面和粘膜下腺细胞。 具体目标 1 中概述的研究将检验 LPO 合成的假设 或分泌受到感染相关炎症刺激的调节，并且会 研究LPO的生物合成途径。具体目标 2 将检验以下假设： SCN-由基底外侧主动转运蛋白带入气道腔 耦合到顶端阴离子通道并测试该阴离子传输是否可以 囊性纤维化缺陷。具体目标 3 将检验以下假设： LPO 底物 H2O2 的水平也受到感染相关的调节 炎症刺激，并将识别 H2O2 的酶源。 了解LPO制度的监管机制将提供 开发新型预防性和治疗性抗感染药物的机会 代理。此外，这些研究可能会提供重要的见解 以慢性气道感染为特征的气道疾病的病理生理学 例如囊性纤维化和支气管扩张。