GENETIC REGULATION OF 03-INDUCED INFLAMMATION

03 引起的炎症的基因调控

• 批准号: 6413558
• 负责人: W Michael Foster
• 金额: $ 46.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413558
• 关键词: biomarker; clinical research; environmental exposure; gene mutation; genetic polymorphism; genetic susceptibility; human subject; inflammation; ozone; pollution related respiratory disorder

Laboratory studies have demonstrated that short-term single exposure of adult humans to ambient levels of O3 leads to inflammation of the airway. Lung inflammation is observable 3-18 hr after exposure, and is not correlated to the functional changes that arise during exposures or slowly dissipate during recovery, 1-2 hr post-exposure. The inflammation is characterized by an influx of polymorphonuclear leukocytes and increases in total protein, albumin, pro-inflammatory cytokines, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid. Significant inter-individual variation in the inflammatory response is found among otherwise homogeneous subjects suggesting that intrinsic host factors contribute to the magnitude of beta3-induced lung injury. Further, although ambient exposure to beta3 is frequently intermittent, whether the severity of inflammation increases upon re-exposure remains controversial. Thus, basic questions remain: 1) is the inter-individual nature of the inflammatory response to O3 explained by host factors, i.e., genetic background, and 2) do inflammatory airway responses in sensitive subjects adapt upon re-exposure to O3? Understanding the mechanisms intrinsic to O3-induced airway inflammation is essential for predicting host susceptibility and risk of lung and epithelial injury from exposure to O3. Our HYPOTHESIS is that specific gene polymorphisms/mutations contribute to differential susceptibility to O3-induced lung injury in healthy subjects and are host factors that regulate risk of exposure to O3. We will use a multi-disciplinary approach that applies physiologic and genetic techniques to a controlled human exposure system. Specific aims will determine: 1) the range in susceptibility of humans to develop airway inflammation and hyperpermeability after a single exposure to O3, and 2) if subjects differentially susceptible to ozone maintain their sensitivity during intermittent exposure to O3, and 3) the association of selected genetic markers with O3-induced lung injury and airway inflammatory responses. These investigations will help to establish genetic background as a host factor in the susceptibility of humans to O3 exposure and utility of genetic factors as biomarkers of lung injury induced by inhalable oxidants and environmental pollutants.

实验室研究表明，成年人的短期单一暴露于环境水平的O3水平会导致气道发炎。 暴露后可观察到3-18小时的肺部炎症，并且与暴露期间发生的功能变化无关，或在恢复期间缓慢消失，1-2 hr暴露后1-2小时。 炎症的特征是多形核白细胞流入，总蛋白质，白蛋白，促炎细胞因子和肉芽肿巨噬细胞刺激因子刺激性因子在支气管腔液间流体中的增加。在其他均质受试者中，发现炎症反应的显着个体间差异表明，内在宿主因子有助于β3诱导的肺损伤的大小。 此外，尽管环境暴露于beta3通常是间歇性的，但是在重新暴露时炎症的严重程度是否会增加。因此，仍然存在基本问题：1）炎症反应对O3的个体性质是由宿主因素解释的，即遗传背景和2）敏感受试者的炎症气道反应是否适应了对O3的重新暴露？了解O3诱导的气道炎症固有的机制对于预测宿主易感性以及暴露于O3的肺部和上皮损伤的风险至关重要。我们的假设是，特定的基因多态性/突变有助于健康受试者对O3诱导的肺损伤的敏感性差异，并且是调节暴露于O3的风险的宿主因素。 我们将使用一种多学科方法，该方法将生理和遗传技术应用于受控的人类暴露系统。 具体目的将确定：1）单一暴露于O3后，人类易感性的易感性范围以及2）如果受试者在间歇性接触O3期间保持敏感性的敏感性，以及3）3）与O3诱导的肺部炎症和炎症的关联时，则保持其敏感性。 这些研究将有助于建立遗传背景，作为人类对O3暴露和遗传因素敏感性的宿主因素，因为遗传因素是由不可耐氧化剂和环境污染物引起的肺损伤的生物标志物。