Dependency of O-3 Induced Lung Mucus Hypersecretion on NQ01

描述（由申请人提供）：最近的流行病学研究重新点燃了一个古老的争论，关于粘液分泌过多是否在气道疾病的病因中至关重要的观点正在形成。对于哮喘、慢性阻塞性肺疾病（COPD）和囊性纤维化患者，粘液分泌过多现在被认为是发病率增加的一个危险因素。臭氧（城市烟雾的主要成分）对气道的刺激性和上皮膜效应，特别是对黏液型分泌细胞和/或与上皮生理学的相互作用，尚未进行深入研究，充其量只是表面上的活体研究。我们最近在遗传多样性的近交系小鼠中证明，臭氧诱导的肺部炎症和肺黏液分泌上调以及气道黏液纤毛清除依赖于宿主因子。这些结果与我们在人体中的评估结果相吻合，在人体中，O3暴露会导致粘膜纤毛清除的改变，并释放一种能够增加黏液蛋白合成和分泌的介质。重要的是，我们在一组不吸烟的健康人群中（n=135）进行的额外观察表明，醌氧化还原酶（NQO1）的单核苷酸多态性的纯合子基因型可以防止暴露于环境水平的O3对空气流动的急性刺激作用。我们还发现NQO1可以在体外调节气道上皮细胞黏液蛋白的合成；并且与宿主因子依赖性有关，NQO1在对O3易感和耐药的小鼠模型中存在差异表达。作为一个有效的全球假设，我们提出易感人群暴露于O3可激活NQO1，产生活性氧代谢物，并导致气道上皮细胞MUC5AC mRNA表达增加和黏素产生。当o3诱导的气道嗜中性粒细胞增多，导致中性粒细胞弹性酶重新激活NQO1，导致粘蛋白的表达和分泌，粘膜纤毛清除紊乱，肺功能降低时，该循环重新启动。研究人员提出了以O3易感菌株、肺粘蛋白高分泌模型和NQO1缺陷模型为代表的小鼠模型，并同时进行了在野生型（NQO1充足）和与NQO1缺陷相关的单核苷酸多态性之间进行遗传分离的人类翻译研究。这项研究计划是研究无处不在的城市空气污染物与调节氧化诱导的气道粘液高分泌的遗传因素之间明确联系的第一步。项目描述：该研究计划提出在相关动物模型和人类受试者中进行转化研究，以确定宿主（遗传）易感性因素，这些因素赋予了对原型空气污染物臭氧的脆弱性。这些结果将对理解在暴露于空气传播的呼吸道刺激物期间和之后发生的促氧化性肺损伤、气道粘蛋白的产生和分泌、呼吸道粘液的清除以及不良健康影响的调节机制产生重大影响和帮助。

DESCRIPTION (provided by applicant): Recent epidemiologic studies have re-ignited an old controversy and opinions are forming as to whether mucus hypersecretion is crucial in the etiology of airway disease. For patients with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, mucus hypersecretion is now being considered as a risk factor for increased morbidity. The irritant and epithelial membrane effects of O3, a main component of urban smog, upon the airway, and in particular on mucin-type secretory cells and/or interaction with epithelial physiology, have not been investigated vigorously, and at best only superficially, in vivo. We have recently demonstrated in genetically diverse inbred mice that O3-induced pulmonary inflammation and up-regulation of lung mucin secretion and airway mucociliary clearance are host factor dependent. These results match translationally with our evaluations in humans where O3 exposure leads to alterations in mucociliary clearance, and release of a mediator(s) capable of increasing mucin protein synthesis and secretion in vitro. Importantly additional observations by us in a healthy cohort of non-smoking human subjects (n=135) demonstrates that a homozygotic genotype for a single nucleotide polymorphism of the quinone oxido-reductase enzyme, NQO1, protects from the acute irritant effects on air flow that occur with exposure to ambient levels of O3. We have also found that NQO1 can modulate synthesis of mucin proteins by airway epithelial cells in vitro; and in connection with host-factor dependency, that NQO1 is differentially expressed in mouse models susceptible and resistant to O3. As a working global hypothesis we propose that exposure to O3 by susceptible humans activates NQO1, generates reactive oxygen metabolites and leads to an increase in MUC5AC mRNA expression and production of mucins by airway epithelial cells. This cycle is re-initiated when O3-induced airway neutrophilia, leads to re-activation of NQO1 by neutrophil elastase, leading to expression and secretion of mucins, disordered mucociliary clearance, and reduced pulmonary function. Investigations are proposed for mouse models represented by an O3 susceptible strain, a lung mucin hypersecretion model, and a NQO1 deficient model and simultaneous with translational studies in humans that are segregated genetically between wild-type (NQO1 sufficient) and a single nucleotide polymorphism associated with NQO1 deficiency. The research plan is the initial step towards a definitive link between an ubiquitous urban air pollutant, and genetic factors that regulate oxidant-induced airway hypersecretion of mucus. PROJECT NARRATIVE: The research plan proposes translational studies in relevant animal models and human subjects in order to identify host (genetic) susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon, and aid in, understanding mechanisms regulating pro-oxidant lung injury, production and secretion of airway mucins, and clearance of respiratory mucus, and adverse health effects, that occur during and following exposure to airborne respiratory irritants.