MECHANISMS OF AIR POLLUTANT INDUCED AIRWAY PERMEABILITY

空气污染物改变了气道上皮细胞的通透性 例如臭氧和烟草烟雾。 尽管这种 渗透率的变化可能是有害的， 这种现象背后的机制并不完善， 明白 在我们以前的机理研究中，臭氧诱导的 渗透性、转运途径和细胞骨架的变化 类似于应用微丝引起的变化 去稳定剂细胞松弛素D。 我们现在建议扩大这项研究，包括分析 炎症细胞，炎症细胞的产物，或 上皮细胞，以及细胞产物的各种抑制剂， 涉及空气污染物对气道渗透性的影响， 细胞骨架、紧密连接和转运途径。 炎症细胞在激活后可在气管内聚集， 和肺泡粘膜并释放调节气道的产物 和血管通透性，并改变细胞的细胞骨架， 肺内皮或上皮。 细胞骨架的研究 结合上皮细胞，中性粒细胞， 或他们的产品，因此，预计将改善我们的 了解渗透性变化的机制。 渗透性增加的时间顺序和持续时间 将研究气管和支气管肺泡区域， 渗透性变化将与炎症相关， 反应、细胞骨架变化、紧密连接改变和 气管和肺泡中示踪剂转运的结构途径 在：（1）仅暴露于空气或O3（O.6 ppm）或O3（O.6 ppm）+的大鼠中 NO2（2.5 ppm），以及（2）暴露于这些气体的大鼠， 用（a）嗜神经细胞的氧化剂产物（超氧化物， 过氧化氢，羟基自由基），（B）抗氧化剂（牛磺酸， 过氧化氢酶、超氧化物歧化酶和二甲基硫脲，（c）抗- 炎性药物（马帕林和甲基强的松龙），（d） 花生四烯酸代谢产物（白三烯和 类）或其抑制剂（FPL 55712、BW 755C和 吲哚美辛），（e）细胞骨架去稳定剂及其 联合用药（秋水仙碱、长春碱、细胞松弛素D和 秋水仙碱+细胞松弛素D）。 嗜中性粒细胞在气道通透性中的作用也将被 通过研究渗透性和炎症来评估， 将分离的中性粒细胞注射到粒细胞减少的未暴露者中 或03只暴露的近交系大鼠。 涉及离体肺泡上皮细胞摄取示踪剂的其他研究 II型细胞，嗜中性粒细胞对II型细胞的粘附， 在体内改变条件下的细胞骨架变化 上述渗透性，也将做添加到我们的 了解示踪剂运输的机制。

Airway epithelial permeability is altered by airborne pollutants such as ozone and tobacco smoke. Despite the fact that such changes in permeability may be detrimental, the basic mechanisms that underlie this phenomenon are not well understood. In our previous mechanistic studies, ozone-induced changes in permeability, transport pathway and cytoskeleton were similar to changes induced by application of the microfilament destabilizing agent cytochalasin D. We now proposed to broaden this study by including an analysis of inflammatory cells, the products of inflammatory cells or epithelial cells, and various inhibitors of cell products as they relate to air pollutant effects on airway permeability, cytoskeleton, tight junctions and transport pathway. Inflammatory cells, upon activation, may aggregate in tracheal and alveolar mucosa and release products that modulate airway and vascular permeability and modify the cytoskeleton of cells in pulmonary endothelia or epithelia. A study of the cytoskeleton in combination with an investigation of epithelial cells, neutrophils, or their products, is therefore expected to improve our understanding of the mechanisms of permeability changes. The time sequence of increased permeability and duration in the tracheal and bronchoalveolar region will be studied, and permeability changes will be correlated with inflammatory response, cytoskeletal changes, tight junction alterations and structural pathways of tracer transport in the trachea and alveoli in: (1) rats exposed to air only or O3(O.6 ppm) or O3 (O.6 ppm) + NO2 (2.5 ppm), and (2) rats exposed to these gases and also treated with (a) oxidant products of neurotrophils (superoxide, hydrogen peroxide, hydroxyl radicals), (b) antioxidants (taurine, catalase, superoxide dismutase and dimethylthiourea, (c) anti- inflammatory drugs (mapacrine and methyl prednisolone), (d) products of arachidonic acid metabolism (leukotrienes and prostaglandins) or their inhibitors (FPL 55712, BW 755C and indomethacin), (e) cytoskeleton destabilizers and their combinations (colchicine, vinblastine ,cytochalasin D and colchicine + cytochalasin D). The role of neutrophils in airway permeability will also be assessed by studying permeability and inflammation following injection of isolated neutrophils into granulocytopenic unexposed or 03 expsoed inbred rats. Additional studies involving uptake of tracers by isolated alveolar type II cells, adherence of neutrophils to type II cells and cytoskeletal changes under conditions that alter in vivo permeability described above, will also be done to add to our understanding of the mechanisms of tracer transport.