Functional implications of the TNF

描述（由申请人提供）：对于成人和幼儿，急性和反复暴露于空气毒素的气道已导致短暂和可逆的气道损伤，但也导致气道重塑，肺生长和肺功能受损。在完全正常/健康的气道中，暴露于O3（一种普遍存在的城市空气污染物）会诱导炎症反应，其特征在于上皮通透性增加、中性粒细胞浸润和支气管高反应性。吸入多效性促炎细胞因子肿瘤坏死因子（TNF）导致几乎相同的反应：支气管气道（AHR）的高反应性和中性粒细胞流入。我们最近发现了这两个挑战之间的联系：在年轻健康受试者（n=135）的单次实验室暴露中，TNF基因（-308）中常见的单核苷酸多态性（SNP）赋予对环境浓度O3的易感性。我们的初步结果是高度显著的，并且与具有野生型TNFa（-308）（G/G）单倍型的受试者相比，对于TNFa（-308）多态性的突变等位基因纯合（A/A）或杂合（G/A）的受试者在O3后对乙酰甲胆碱产生敏感性的可能性是2倍。先前的报道表明TNF α（-308）多态性导致TNF基因转录增加和TNF α细胞因子产生增加。然而，这种常见的TNF多态性的功能意义仍然存在争议;此外，TNF α（-308）多态性在肺中的功能意义仍然未开发。我们假设受试者--TNFa（-308）启动子多态性突变等位基因的纯合性（AA）或杂合性（GA），将表现出对O3的表型反应增强，包括：细胞炎症和促炎细胞因子分泌增加，增强常驻肺泡巨噬细胞的激活，以及支气管敏感性改变，导致AHR。拟议的研究重点是了解主机因素和暴露于原型城市空气污染物之间的相互作用。研究计划的结果将有助于了解TNFa常见多态性对炎症性气道疾病的启动的功能贡献，并分配和验证赋予O3易感性的遗传因素。公共卫生相关性。该研究计划提议在人类中开展转化研究，以确定导致易受原型空气污染物臭氧影响的宿主易感性因素。结果将有显着的影响，并有助于了解机制的促氧化剂肺损伤，气道高反应性，并发生在暴露于可吸入空气中的刺激物和以下的不良健康影响。

DESCRIPTION (provided by applicant): For both adults and young children acute, and repetitive exposure of the airways to air toxins has had led to both transient, and reversible airway injury, but also to remodeling of the airway with impairment of lung growth and pulmonary function. In the completely normal/healthy airway, exposure to O3, a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophil infiltration, and bronchial hyperreactivity. Inhalation of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (TNF) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. We have recently found a link between these 2 challenges: whereby in single laboratory exposures of young healthy subjects (n=135), a common single nucleotide polymorphism (SNP) in the TNF gene (-308), confers susceptibility to an ambient concentration of O3. Our preliminary results were highly significant and subjects, homozygotic (A/A) or heterozygotic (G/A) for the mutant allele of the TNFa (-308) polymorphism, were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type TNFa (-308) (G/G) haplotype. Previous reports suggest that the TNFa (-308) polymorphism leads to increased TNF gene transcription and increased TNFa cytokine production. However, the functional significance of this common TNF polymorphism remains controversial; and moreover, the functional implications of the TNFa (-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects - homozygotic (AA) or heterozygotic (GA) for the mutant allele of the TNFa (-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pro-inflammatory cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR. The proposed research is focused on understanding the interaction between host factors and exposure to a prototypal urban air pollutant. Results from the research plan will help understand the functional contribution of a common polymorphism of TNFa to the initiation inflammatory airway disease, and assign and validate genetic factors that confer vulnerability to O3. PUBLIC HEALTH RELEVANCE. The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects that occur during and following exposure to respirable airborne irritants.