MECHANISMS OF AIR POLLUTANT-INDUCED AIRWAY PERMEABILITY

众所周知，空气污染物会破坏上皮屏障，增加 电波的粘膜通透性，但细胞机制 参与产生这些效应的人还远不清楚。建议数 研究扩展了我们以前的工作，并代表了对 细胞骨架成分与炎症的相互关系 以臭氧(O3)为原型的事件和上皮变化 氧化性空气污染物。 由于臭氧后的细胞反应可能是短暂的，一段时间 通透性、炎性和结构变化的病程分析 将在暴露在清洁空气中的大鼠身上进行，0.1ppm，0.2ppm，0.5ppm Ppm和1.0ppm 03。急性发作所产生的TIM效应序列 暴露将与亚慢性(4周)和 慢性(9个月)暴露与内皮细胞有类似的相互作用 和细胞损伤前的上皮细胞，中性粒细胞 将研究03暴露大鼠的白细胞(PMN)和巨噬细胞 (I)中性粒细胞和巨噬细胞与内皮细胞和上皮细胞的黏附 在培养中，(Ii)细胞黏附分子的变化，(Iii) 与PMN刺激和运动相关的细胞骨架成分， (4)细胞紧密连接和细胞骨架成分的破坏 和(V)释放细胞介质，即前列腺素E2 (PGE2)、白三烯B4(LTB4)和细胞黏附促进剂(TNF)。至 逆转了臭氧的影响，细胞将被处理的抑制剂 PGE2和LTB4(吲哚美辛和FPL55712)，抗氧化剂(过氧化氢酶)，以及 抗肿瘤坏死因子和白介素1抗体。将体外研究扩展到体内研究 设置将包括将大鼠暴露在臭氧中并检测(I) 肺毛细血管内中性粒细胞边际化；(Ii)IL-1、TNF在肺毛细血管内的表达 上皮细胞和巨噬细胞以及(III)对臭氧效应的预防 抗肿瘤坏死因子或白介素1的抗体，或用这些抗体处理的中性粒细胞。 该项目提供了一种连贯的毒理学和机械学方法 了解氧化性空气污染物对环境的影响 呼吸系统，并用于填补现有的一些关键空白 文学。

Air pollutants are known to disrupt the epithelial barrier and increase the mucosal permeability of the airwaves, but the cellular mechanisms involved in producing these effects are far from clear. The proposed studies extend our previous work and represent an in-depth analysis of the interrelationships among cytoskeletal components, inflammatory events, and epithelial changes elicited by ozone (O3) as the prototypical oxidant air pollutant. Since the cellular responses after O3, exposure may be transient, a time course analysis of permeability, inflammatory, and structural changes will be done in rats exposed acutely to clean air, 0.1 ppm, 0.2 ppm, 0.5 ppm, and 1.0 ppm 03. The tim sequence of effects produced by acute exposure will be compared to the effects of subchronic (4 week) and chronic (9 months) exposures st comparable interactions with endothelial and epithelial cells prior to cellular injury, polymorphonuclear leukocytes (PMNs) and macrophage from 03-exposed rats will be studied for (i) adhesion of PMNs and macrophage to endothelial and epithelial cells in culture, (ii) changes in cell adhesion molecules, (iii) changes in cytoskeletal components associated with PMN stimulation and motility, (iv) disruption of tight junctions and cytoskeletal components of epithelia, and (v) release cellular mediators, i.e., prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and a cell adherence promoter (TNF). To reverse the O3 effects, the cells will be treated with the inhibitors of PGE2 and LTB4 (indomethacin and FPL55712), antioxidant (catalase), and antibodies to TNF and IL1. Extension of in vitro studies to an in vivo setting will involve exposure of rats to O3 and detection of (i) marginating PMNs in lung capillaries, (ii) expression of IL1 and TNF in epithelial cells and macrophage and (iii) prevention of O3 effect by antibodies to TNF or IL1, or by PMNs treated with these antibodies. This project offers a coherent toxicologic and mechanistic approach for an understanding of the impact of oxidant air pollutants on the respiratory system and serves to fill some critical gaps in the existing literature.