REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE

气道乳过氧化物酶宿主防御的调节

• 批准号: 6227550
• 负责人: Gregory E. Conner
• 金额: $ 25.94万
• 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/6227550
• 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 婴儿、老年人、免疫受损人群的人类发病率和死亡率 还有使用机械呼吸机的。呼吸道上皮和粘膜下层 腺体是抵御这种感染的第一道防线，它通过分泌 抗生素类物质。然而，关于这几个问题，我们知之甚少。 确定了非免疫性粘膜防御。更多关于呼吸道的知识 抗感染防御将对设计预防治疗有价值。 易患呼吸道感染的个人，例如囊性纤维化和 支气管扩张症。拟议研究的长期目标是获得 乳酸过氧化物酶(LPO)介导的非免疫防御机制的研究进展 气道口。本实验的最新工作表明，大量的LPO 在呼吸道粘液中，LPO底物、硫氰酸盐(SCN-)和氢 过氧化氢(H_2O_2)，在体外也存在于呼吸道中，LPO是主要的 粘液中的过氧化氢清除活性，在体内，LPO的催化活性是 对清除吸入细菌很重要。基于上述观察， 拟议中的实验将检验关于调节 呼吸道LPO系统。这项研究将使用两种分化的呼吸道上皮细胞 深层培养中的气液界面和粘膜下腺细胞。 在特定目标1中概述的研究将检验LPO合成 或分泌受感染相关的炎性刺激和意志调节 研究LPO的生物合成途径。《特定目标2》将检验这一假设 SCN-被基侧活性转运体带入气道腔 连接到顶端阴离子通道，并测试这种阴离子传输是否可以 囊性纤维化有缺陷。具体目标3将检验这一假设 LPO底物H_2O_2的水平也受感染相关因素的调节 发炎刺激，并将确定过氧化氢的酶来源。 了解LPO制度的监管机制将提供 新的预防和治疗抗感染药物的发展机遇 探员们。此外，这些研究可能为我们提供对 以慢性呼吸道感染为特征的呼吸道疾病的病理生理学 如囊性纤维化和支气管扩张症。