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议，关于粘液分泌过多是否在气道疾病的病因学中至关重要的观点正在形成。对于患有哮喘、慢性阻塞性肺疾病（COPD）和囊性纤维化的患者，粘液分泌过多现在被认为是发病率增加的风险因素。O3的刺激性和上皮细胞膜的影响，城市烟雾的主要成分，对气道，特别是粘蛋白型分泌细胞和/或与上皮生理的相互作用，还没有被大力调查，最好的只是表面上，在体内。我们最近在遗传多样的近交系小鼠中证明，O3诱导的肺部炎症和肺粘蛋白分泌和气道粘膜纤毛清除的上调是宿主因子依赖性的。这些结果与我们在人体中的评价结果一致，其中O3暴露导致粘膜纤毛清除的改变，并释放能够增加体外粘蛋白合成和分泌的介质。重要的是，我们在一个健康的非吸烟人群（n=135）中的额外观察表明，醌氧化还原酶NQO 1的单核苷酸多态性的纯合子基因型可以保护暴露于环境水平的O3时发生的对气流的急性刺激作用。我们还发现，NQO 1可以调节体外气道上皮细胞的粘蛋白的合成;与宿主因子依赖性有关，NQO 1在对O3敏感和耐药的小鼠模型中差异表达。作为一个工作的全球性假设，我们提出，暴露于O3的易感人群激活NQO 1，产生活性氧代谢产物，并导致增加MUC 5AC mRNA的表达和气道上皮细胞的粘蛋白的生产。当O3-诱导的气道嗜中性粒细胞导致NQO 1被中性粒细胞弹性蛋白酶重新激活，导致粘蛋白的表达和分泌，粘膜纤毛清除障碍和肺功能降低时，该循环重新启动。提出了以O3敏感株、肺粘蛋白高分泌模型和NQO 1缺陷模型为代表的小鼠模型的研究，并同时进行了在野生型（NQO 1充足）和与NQO 1缺陷相关的单核苷酸多态性之间遗传隔离的人类翻译研究。该研究计划是迈向普遍存在的城市空气污染物与调节氧化剂诱导的气道粘液分泌过多的遗传因素之间明确联系的第一步。项目叙述：该研究计划提议在相关动物模型和人类受试者中进行转化研究，以确定导致易受原型空气污染物臭氧影响的宿主（遗传）易感性因素。结果将有显着的影响，并有助于了解机制调节促氧化剂肺损伤，气道粘蛋白的生产和分泌，呼吸道粘液的清除，以及不良健康影响，发生在暴露于空气中的呼吸道刺激物。

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.