Effects of Tobacco Smoke on Airway Bactericidal Activity

描述(摘自调查人员摘要) 微生物和有毒化学物质等环境压力 对肺损伤和肺部疾病有深远影响。呼吸道细菌 感染与肺炎等各种肺部疾病有关， 囊性纤维化和肺结核。众所周知，烟草烟雾(TS)会导致 肺部疾病，如肺气肿和肺癌，对 寄主对病原菌的防御机制，但分子机制是通过 目前还不能完全理解这种情况的发生。这样做的长期目标是 建议研究一种新的呼吸道的功能特性 特异基因DD4及其调控及其在健康和人类中的潜在作用 与烟草烟雾有关的肺部疾病。人类的DD4基因是 在具有杀菌作用的粘膜下腺的浆液细胞中特异表达 溶菌酶和乳铁蛋白等蛋白质被分泌出来。这种新的基因具有 对粘液细胞促进剂有显著反应 分化，如UTP和维甲酸，以及几个介体。 肿瘤坏死因子-α(TNF-α)等炎症和增殖 和表皮生长因子(EGF)。潜在的意义，候选人？S 初步研究表明，DD4具有抗菌性能， 它的分泌在不同的肺部疾病之间有很大的差异。在……里面 此外，考生S实验室还观察到人DD4mRNA 在TS刺激下，表达增加，呈时间和剂量依赖性 举止。本申请的目的是阐明TS在以下方面的影响 DD4？S基因表达的调控机制及对DD4？S的检测 在体外和体内暴露TS后的功能。中心假说 待检测的是DD4是一种分泌的杀菌蛋白，它起到了 在对抗病原体的呼吸道防御机制中。这背后的理由是 研究表明，调制(如TS暴露)分泌的DD4蛋白 是直接影响宿主对人类呼吸道的防御反应的手段之一 感染。因此，DD4基因表达和蛋白分泌的调节 对病理性刺激的反应必须在动员前了解 与宿主防御和呼吸道疾病的发病机制有关的 DD4是完全可以理解的。为了实现这一目标 应用程序，他们将追求三个具体目标：(1)描述 DD4的杀菌活性；(2)阐明TS的调控机制 暴露对DD4？S杀菌功能的影响；(3)对DD4？S抗菌作用的评价 体内效应。在完成这项研究后，应聘者希望 测定了DD4的杀菌效力及TS对其的调节作用 DD4的抗菌防御机制。这位候选人希望 对DD4的监管将被证明至少在一定程度上与 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.