Dependency of O-3 Induced Lung Mucus Hypersecretion on NQ01

描述(申请人提供)：最近的流行病学研究重新点燃了一场古老的争论，关于粘液高分泌是否在呼吸道疾病的病因中起关键作用的观点正在形成。对于哮喘、慢性阻塞性肺疾病(COPD)和囊性纤维化患者，粘液高分泌现在被认为是发病率增加的危险因素。臭氧是城市烟雾的主要成分，其对呼吸道的刺激性和上皮膜的影响，特别是对粘液型分泌细胞和/或与上皮生理学的相互作用，还没有深入的研究，充其量只是在体内进行了肤浅的研究。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以及肺粘蛋白分泌和呼吸道粘液纤毛清除的上调是宿主因素依赖的。这些结果与我们在人体中的评估结果相一致，在人体中，臭氧暴露会导致粘液纤毛清除的改变，并释放一种能够增加粘蛋白蛋白质合成和分泌的介体(S)。重要的是，我们在一组不吸烟的健康受试者(n=135)中的其他观察结果表明，苯醌氧化还原酶NQO1的单核苷酸多态的纯合子基因型可以保护人体免受暴露在环境臭氧水平下对空气流动的急性刺激影响。我们还发现，NQO1在体外可以调节呼吸道上皮细胞粘蛋白的合成；在与宿主因素依赖有关的问题上，NQO1在对臭氧敏感和耐药的小鼠模型中差异表达。作为一个有效的全球假说，我们提出，易感人群暴露在臭氧中会激活NQO1，产生活性氧代谢产物，并导致呼吸道上皮细胞MUC5AC mRNA表达和粘蛋白产生增加。当臭氧引起中性粒细胞增多时，这个循环被重新启动，导致中性粒细胞弹性蛋白酶重新激活NQO1，导致粘蛋白的表达和分泌，粘液纤毛清除紊乱，肺功能下降。建议对以臭氧敏感菌株、肺粘蛋白高分泌模型和NQO1缺陷模型为代表的小鼠模型进行研究，同时在人类中进行翻译研究，这些研究在基因上分离于野生型(NQO1充足)和与NQO1缺乏相关的单核苷酸多态。这项研究计划是朝着确定无处不在的城市空气污染物与调节氧化剂诱导的呼吸道粘液过度分泌的遗传因素之间的明确联系迈出的第一步。项目简介：该研究计划建议在相关动物模型和人类受试者中进行转译研究，以确定宿主(遗传)易感因素，这些因素使人容易受到原型空气污染物臭氧的影响。这些结果将对了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、呼吸道粘蛋白的产生和分泌、呼吸道粘液的清除以及对健康的不利影响的调节机制具有重大影响和帮助。

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.