Effects of Tobacco Smoke on Airway Bactericidal Activity

描述（摘自研究者摘要） 环境压力，如微生物和有毒化学品， 对肺损伤和肺部疾病的深远影响。气道细菌 感染与各种肺部疾病如肺炎有关， 囊性纤维化和肺结核。已知烟草烟雾（TS）诱导 肺气肿和肺癌等肺部疾病， 宿主对病原体的防御机制，但分子机制 这种情况的发生并不完全清楚。长期目标是 一个建议是调查一种新型气道的功能特性 特异基因DD 4调控及其在健康和人类中的潜在作用 与吸烟有关的肺部疾病。人类DD 4基因是 在粘膜下腺体的浆液细胞中特异性表达， 分泌蛋白质如溶菌酶和乳铁蛋白。这种新基因具有 对粘液细胞促进剂有明显反应 分化，如UTP和类维生素A，以及几种介质， 炎症和增殖，如肿瘤坏死因子-α（TNF-α） 表皮生长因子（EGF）有潜在的重要性，候选人？S 初步研究表明，DD 4具有抗菌特性， 它的分泌在不同的肺部疾病之间变化很大。在 此外，候选人？实验室还观察到人类DD 4 mRNA TS刺激后表达升高，呈时间和剂量依赖性 方式本申请的目的是阐明TS对 DD 4的调节机制？的基因表达，并检查DD 4？S 在体外和体内TS暴露后的功能。核心假设 DD 4是一种分泌的杀菌蛋白， 呼吸道防御病原体的机制。这背后的基本原理 研究是调节（如TS暴露）分泌DD 4蛋白 是直接影响宿主对人体气道防御反应的一种手段 感染因此，DD 4基因表达和蛋白分泌的调节 对病理刺激的反应必须在动员之前被理解 宿主防御和气道疾病的发病机制， DD 4可以完全理解。为了实现这一目标， 应用，他们将追求三个具体目标：（1）表征 DD 4杀菌活性的研究;（2）阐明TS的调控机制 在DD 4上暴露？的杀菌功能;（3）评价DD 4？S抗菌 体内效应在这项研究完成后，候选人希望 测定了DD 4的杀菌效力和TS对 DD 4的抗菌防御机制候选人预计， DD 4的监管将被证明是相关的，至少部分， 炎症反应和烟草烟雾暴露。最后，候选人可以 更好地了解细菌感染的发病机制， 烟草烟雾影响下的某些肺部疾病，以及 新的治疗策略。

DESCRIPTION (Taken from the Investigator's Abstract) Environmental stresses such as microorganisms and toxic chemicals have profound effects on lung injury and pulmonary disease. Airway bacterial infection has been associated with various lung diseases such as pneumonia, cystic fibrosis, and tuberculosis. Tobacco smoke (TS) is known to induce pulmonary diseases such as emphysema and lung cancer and has effects on the host defense mechanism against pathogens, but the molecular mechanisms by which this occurs is not completely understood. The long-term goal of this proposal is to investigate the functional characteristics of a novel airway specific gene, DD4, its regulation and its potential role in health and human lung diseases that relate to tobacco smoke. The human DD4 gene is specifically expressed in serous cells of submucosal glands where bactericidal proteins such as lysozyme and lactoferrin are secreted. This novel gene has exhibited significant response to promoting agents of mucous cell differentiation such as UTP and retinoids, as well as to several mediators of inflammation and proliferation such as tumor necrosis factor-alpha (TNF-alpha) and epidermal growth factor (EGF). Of potential significance, the candidate?s preliminary studies revealed that DD4 has antibacterial properties and that its secretion varied dramatically between different lung diseases. In addition, the candidate?s laboratory also observed that human DD4 MRNA expression is elevated upon TS stimulations in both time and dose dependent manner. The objective of this application is to elucidate effects of TS on the regulatory mechanism of DD4?s gene expression and to examine DD4?s function after TS exposure both in vitro and in vivo. The central hypothesis to be tested is that DD4 is a secreted bactericidal protein that plays a role in airway defense mechanisms against pathogens. The rationale behind this research is that modulation (such as TS exposure) of the secretary DD4 protein is one means of directly affecting host defense response against human airway infection. Therefore, regulation of DD4 gene expression and protein secretion in response to pathological stimuli must be understood before the mobilization of host defenses and the pathogenesis of airway diseases that are related to DD4 can be fully appreciated. To accomplish the objectives of this application, they will pursue three specific aims: (1) to characterize the bactericidal activity of DD4; (2) to elucidate the regulatory mechanism of TS exposure on DD4?s bactericidal function; (3) to evaluate DD4?s antibacterial effect in vivo. At the completion of this research, the candidate expects to have determined the bactericidal potency of DD4 and the regulation by TS of the antibacterial defense mechanism of DD4. The candidate expects that regulation of DD4 will prove to be related, at least in part, to the inflammatory response and tobacco smoke exposure. Finally, the candidate may obtain a better understanding of the pathogenesis of bacterial infections in certain lung diseases under effects of tobacco smoke, and the development of new therapeutic strategies.