PATHOPHYSIOLOGY OF BRONCHIAL ASTHMA

描述：(根据申请者的抽象和具体目标改编。) 哮喘患者的呼吸道粘液纤毛清除功能受损， 损伤似乎是由呼吸道炎症引起的。更改后的 粘液纤毛功能会损害呼吸道对细菌的防御。 因为炎症细胞产物对呼吸道的直接作用 上皮细胞不能完全解释这种缺陷，可能是 呼吸道微血管的内皮细胞，它形成一个 广泛的上皮下网络，可能在 炎性细胞和上皮细胞。应用假设 人参皂苷可溶性产物对呼吸道内皮细胞的刺激作用 炎症细胞导致内皮素-1(ET-1)和 可能是其他引起纤毛活动改变的多肽 以及呼吸道上皮及其分泌物的糖偶联谱。 这可能会抑制纤毛作用和细菌的清除 促进细菌与上皮性糖萼的结合。为了测试 这一假设的具体目的是：1)确定粒细胞 介体(主要是脂类)改变转录和/或分泌 内皮衍生因子，如ET-1，2)测量对 这种内皮多肽和粒细胞脂在呼吸道纤毛上的作用 活性，表征它们的受体并描绘信号 调节其作用的转导通路，以及3)决定是否 内皮肽和粒细胞介体有能力改变 呼吸道分泌物或上皮细胞的糖偶联谱 糖萼。这样的信息，通过提高对 纤毛和分泌物对细菌的防御，可能提供基础 对于呼吸道炎症的新治疗策略，一个重要的 支气管哮喘的特点。

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.