MECHANISMS OF AIR POLLUTANT-INDUCED AIRWAY PERMEABILITY

已知空气污染物会破坏上皮屏障， 空气波的粘膜渗透性，但细胞机制 参与产生这些影响的因素还远不清楚。 拟议 研究扩展了我们以前的工作，并代表了对 细胞骨架成分、炎性细胞因子、 事件和上皮变化引起的臭氧（O3）作为原型 氧化剂空气污染物。 由于O3暴露后的细胞反应可能是短暂的， 渗透性、炎症和结构变化的过程分析 将在急性暴露于清洁空气的大鼠中进行，0.1 ppm，0.2 ppm，0.5 ppm ppm和1.0 ppm的O3。 急性心肌梗死所产生效应的时间顺序 将暴露与亚慢性（4周）和 长期（9个月）暴露与内皮细胞的相互作用相当 和上皮细胞损伤前，多形性 将研究来自暴露于O3的大鼠的白细胞（PMN）和巨噬细胞的 (i)中性粒细胞和巨噬细胞与内皮细胞和上皮细胞的粘附 在培养中，（ii）细胞粘附分子的变化，（iii） 与PMN刺激和运动相关的细胞骨架成分， (iv)破坏紧密连接和细胞骨架成分， 上皮细胞，和（v）释放细胞介质，即，前列腺素E2 前列腺素E2（PGE2）、白三烯B4（LTB4）和细胞粘附促进剂（TNF）。 到 逆转O3的影响，细胞将被处理与抑制剂， PGE2和LTB4（吲哚美辛和FPL 55712），抗氧化剂（过氧化氢酶），和 TNF和IL 1抗体。 将体外研究扩展至体内研究 设置将涉及大鼠暴露于O3和检测（i） 肺毛细血管中的中性粒细胞，（ii）IL 1和TNF的表达， 上皮细胞和巨噬细胞和（iii）预防O3效应， TNF或IL 1的抗体，或用这些抗体处理的PMN。 该项目提供了一个连贯的毒理学和机制的方法， 了解氧化性空气污染物对 呼吸系统，并填补了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.