PATHOPHYSIOLOGY OF BRONCHIAL ASTHMA

描述：（改编自申请人的摘要和具体目标。） 支气管哮喘患者气道黏膜纤毛清除功能受损， 损伤似乎是由气道炎症引起的。 改变 粘膜纤毛功能可损害气道对细菌的防御。 由于炎症细胞产物对气道的直接影响 上皮不能完全解释这种缺陷，这可能是因为 气道微血管的内皮细胞， 广泛的上皮下网络，可能在 本申请假设， 通过可溶性产物刺激气道内皮， 炎症细胞导致内皮素-1（ET-1）的释放， 可能是引起纤毛活性改变的其它肽 和气道上皮及其分泌物的糖缀合物谱。 这可以抑制通过纤毛作用去除细菌， 促进细菌与上皮糖萼的结合。测试 该假设的具体目的是：1）确定粒细胞 介质（主要是脂质）改变转录和/或分泌 内皮衍生因子如ET-1的影响，2）测量 这些内皮肽和粒细胞脂质对气道纤毛的影响 活性，表征其受体并描绘信号 介导其作用的转导途径，以及3）确定 内皮肽和粒细胞介质能够改变 气道分泌物或上皮细胞的糖缀合物谱 糖萼这些信息，通过提高对 纤毛和分泌防御细菌，可能提供了基础 对于气道炎症的新治疗策略， 支气管哮喘的症状

DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) Airway mucociliary clearance is impaired in bronchial asthma, and the impairment appears to be caused by airway inflammation. Altered mucociliary function can compromise airway defenses against bacteria. Since a direct effect of inflammatory cell products on the airway epithelium does not fully explain this defect, it may be that the endothelial cells of the airway microvasculature which forms an extensive subepithelial network, could have an intermediary role between inflammatory cells and the epithelium.The application hypothesizes that the stimulation of the airway endothelium by soluble products of inflammatory cells leads to the release of endothelin-1 (ET-1) and possibly other peptides which cause alterations in the ciliary activity and glycoconjugate profiles of the airway epithelium and its secretions. This could inhibit the removal of bacteria by ciliary action and facilitate the binding of bacteria to the epithelial glycocalyx. To test this hypothesis, the Specific Aims are to: 1) determine if granulocyte mediators (primarily lipids) change the transcription and/or secretion of endothelium derived factors like ET-1, 2) measure the influence of such endothelial peptides and of granulocyte lipids on airway ciliary activity, characterize their receptors and delineate the signal transduction pathways that mediate their action, and 3) determine if endothelial peptides and granulocyte mediators have the ability to alter either the glycoconjugate profile of airway secretions or the epithelial glycocalyx. Such information, by improving the understanding of the ciliary and secretory defense against bacteria, may provide the basis for new treatment strategies of airway inflammation, an important feature of bronchial asthma.