REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE

描述（申请人摘要）：呼吸道感染是导致呼吸道感染的主要原因。 婴儿、老年人、免疫功能低下者 和那些在机械制冷机上。气道上皮和粘膜下层 腺体通过分泌几种 抗生素物质。然而，对这几个人知之甚少。 确定了非免疫粘膜防御。了解更多气道知识 抗感染防御将是有价值的设计预防性治疗， 易受气道感染的个体，例如，囊性纤维化， 支气管扩张拟议研究的长期目标是获得 关于乳过氧化物酶（LPO）介导的非免疫防御的信息， 气道。该实验室最近的工作表明，大量的LPO是 存在于气道粘液中，即LPO的底物，硫氰酸盐（SCN-）和氢 过氧化氢（H2 O2）也存在于气道中，LPO是体外主要的 H2 O2清除活性，在粘液中，和，在体内，LPO催化活性， 对清除吸入的细菌很重要。根据上述观察， 拟议的实验将测试有关调节的假设， 气道LPO系统。这些研究将使用分化的气道上皮细胞， 空气-液体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 或分泌受感染相关的炎症刺激调节， 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携带进入气道腔 偶联到顶端阴离子通道，并测试这种阴离子转运是否可以 囊性纤维化的缺陷。具体目标3将检验以下假设： LPO底物H2 O2的水平也受感染相关的 炎症刺激，并将确定H2 O2的酶源。 了解LPO系统的监管机制将提供 新的预防和治疗性抗感染药物的发展机遇 剂.此外，这些研究可能会提供重要的洞察力， 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。

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.