GENETIC REGULATION OF 03-INDUCED INFLAMMATION

实验室研究表明，成年人短期单次暴露于环境水平的O3会导致气道炎症。 在暴露后3-18小时可观察到肺部炎症，与暴露期间出现的功能变化或暴露后1-2小时恢复期间缓慢消失的功能变化无关。 炎症的特征是多形核白细胞的流入和支气管肺泡灌洗液中总蛋白、白蛋白、促炎细胞因子和粒细胞-巨噬细胞集落刺激因子的增加。在其他同质受试者中发现炎症反应的显著个体间差异，表明内在宿主因素有助于β 3诱导的肺损伤的程度。 此外，尽管环境暴露于β 3通常是间歇性的，但再次暴露后炎症的严重程度是否会增加仍然存在争议。因此，基本问题仍然存在：1）对O3的炎症反应的个体间性质是否由宿主因素解释，即，遗传背景，和2）是否炎症气道反应在敏感的科目适应后重新暴露于O3？了解O3诱导的气道炎症的内在机制对于预测宿主易感性以及暴露于O3引起的肺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/突变导致健康受试者对O3诱导的肺损伤的不同易感性，并且是调节O3暴露风险的宿主因素。 我们将采用多学科方法，将生理学和遗传学技术应用于受控的人体暴露系统。 具体目标将决定：1）人类在单次暴露于O3后发生气道炎症和高通透性的易感性范围，2）如果受试者对臭氧的敏感性差异在间歇暴露于O3期间保持其敏感性，3）选定的遗传标记与O3诱导的肺损伤和气道炎症反应的关联。 这些调查将有助于建立遗传背景作为一个主机因素的易感性，人类O3暴露和效用的遗传因素作为生物标志物的肺损伤引起的可吸入氧化剂和环境污染物。

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.