Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice
Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice
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DOI：
10.1074/jbc.m802400200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Hollingsworth, John W.
中科院分区：
文献类型：
--
作者：
Garantziotis, Stavros;Li, Zhuowei;Hollingsworth, John W.
臭氧是一种常见的城市环境空气污染物，对呼吸系统疾病的住院治疗有重要影响。调节臭氧引起的支气管收缩的机制仍然知之甚少。最近的研究表明，海帕洛南在非感染性肺损伤的反应中起着重要作用。因此，我们假设，透明质酸有助于气道高反应性（AHR）后，暴露于环境臭氧。使用一个已建立的臭氧诱导的气道疾病模型，我们的特点是透明质酸在气道高反应性的作用。透明质酸在臭氧反应中的作用通过使用治疗性阻断、转基因动物和直接激发透明质酸来确定。臭氧暴露的小鼠表现出与灌洗液中透明质酸水平升高相关的增强的AHR。缺乏CD 44（透明质酸的主要受体）或间α-胰蛋白酶抑制剂（促进透明质酸结合的分子）的小鼠显示类似的透明质酸升高，但免受臭氧诱导的AHR。用透明质酸结合肽预处理的小鼠免受臭氧诱导的AHR的发展。透明质酸的过度表达增强了呼吸道对臭氧的反应。腔内滴注无内毒素的低分子量透明质酸可诱导依赖于CD 44的AHR，而滴注高分子量透明质酸可防止臭氧诱导的AHR。总之，我们证明，透明质酸介导臭氧诱导的AHR，这是依赖于片段的大小和CD 44和间α-胰蛋白酶抑制剂。这些数据支持了肺基质可以促进气道高反应性的发展的结论。
Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced broncho-constriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-alpha-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-alpha-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.