Functional implications of the TNF

描述(申请人提供)：对于成人和幼儿来说，急性和反复的呼吸道暴露于空气毒素已导致暂时性和可逆性的呼吸道损伤，但也导致呼吸道重塑，损害肺生长和肺功能。在完全正常/健康的呼吸道中，暴露于臭氧(一种普遍存在的城市空气污染物)会引发炎症反应，其特征是上皮通透性增加、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)会导致几乎相同的反应：支气管气道高反应性(AHR)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：在年轻的健康受试者(n=135)的单一实验室暴露中，肿瘤坏死因子基因(-308)的常见单核苷酸多态(SNP)赋予了对环境浓度臭氧的易感性。我们的初步结果非常显著，与野生型TNFa(-308)(G/G)单倍型相比，TNFa(-308)多态突变等位基因纯合子(A/A)或杂合子(G/A)的受试者在臭氧作用下对乙酰甲胆碱的敏感性是野生型的2倍。以往的报道表明，TNFa(-308)基因多态性导致肿瘤坏死因子基因转录增加和细胞因子产生增加。然而，这种常见的肿瘤坏死因子基因多态性的功能意义仍然存在争议；此外，肺组织中TNFa(-308)基因多态性的功能意义仍未开发。我们假设受试者--TNFa(-308)启动子多态突变等位基因的纯合子(AA)或杂合子(GA)--将表现出对臭氧的表型反应增强，包括：增加细胞炎症和促炎细胞因子的分泌，增强常驻肺泡巨噬细胞的激活，以及改变支气管敏感性，导致AHR。这项拟议的研究侧重于了解宿主因素与暴露于典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一种常见的TNFa基因多态性在引发炎症性呼吸道疾病中的功能贡献，并分配和验证赋予臭氧易感性的遗传因素。与公共卫生相关。该研究计划建议在人类身上开展转译研究，以确定宿主对原型空气污染物臭氧的易感性因素。这些结果将对了解暴露在呼吸性空气传播刺激物中和之后的促氧化性肺损伤、呼吸道高反应性和不良健康影响的机制有重大影响和帮助。

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.