PATHOPHYSIOLOGY OF BRONCHIAL ASTHMA

支气管哮喘以呼吸道通畅三联征为特征 肌肉收缩、粘液纤毛功能障碍和水肿。其中两个 这些表现累及粘膜。在上一次和 在目前的资助期内，我们在一个 绵羊呼吸道黏液纤毛功能的实验研究 过敏性支气管收缩模型。这些研究已经 证明了抗原挑战会导致脑细胞受损 粘液纤毛清除与化学介质有关 过敏反应，是由呼吸道分泌功能异常引起的， 并持续了几天。当前的总目标 提案的目的是将这些意见扩展到其他方面 并评估炎症在慢性阻塞性肺疾病中的作用 已证明存在缺陷。具体地说，我们将确定在 相同的绵羊模型，1)持续的粘液纤毛功能障碍 抗原挑战与炎症有因果关系，2)深度 而呼吸道粘液的分布会影响支气管 对吸入的支气管收缩气雾剂的反应性，3) 过敏性呼吸道的特征是不适当的适应 上皮水向渗透压刺激的转运及其异常 是由炎症细胞产物引起的，以及4)热应激 在过敏和非过敏患者中产生不同的血管反应 变态反应性呼吸道由介质代谢物的差异引起 自主反应能力。试管技术将包括 气管粘液流速、呼吸速度的测量 力学，气溶胶沉积，气管粘膜血流量和 组织体积。体外技术将包括测量 粘液糖蛋白、离子、水通量和水力 在气管组织中的电导率，和测定 纤毛搏动频率、粘液深度、粘液相互作用 流变学和粘液传输率。这些生理参数 将与组织病理学和体液指数(RIA)相关 和高效液相色谱(HPLC)。大多数建议的体内和体内 体外方法之前已经在这项研究中使用并验证过 其他实验室。我们希望证明，在过敏的呼吸道中， 粘膜缺陷与呼吸道异常反应有关 物理和药物刺激，并与 发炎。这一结果可能为新的治疗方法奠定基础 哮喘患者的治疗策略。

Bronchial asthma is characterized by the triad of airway smooth muscle contraction, mucociliary dysfunction and edema. Two of these manifestations involve the mucosa. During the previous and current grant periods, we conducted a series of experiments in an attempt to characterized airway mucociliary function in a sheep model of allergic bronchoconstriction. Those studies have demonstrated that antigen challenge leads to an impairment of mucociliary clearance which is related to chemical mediators of anaphylaxis, is caused by abnormal airway secretory functions, and persists for several days. The overall objective of the present proposal is to extend those observations to other aspects of mucosal function and to assess the role of inflammation in the demonstrated defects. Specifically, we will determine if, in the same sheep model, 1) the sustained mucociliary dysfunction after antigen challenge is causally related to inflammation, 2) the depth and distribution of airway mucus influences the bronchial responsiveness to inhaled bronchoconstrictor aerosols, 3) the allergic airway is characterized by an inappropriate adaptation in epithelial water transport to osmotic stimuli and this abnormality is caused by inflammatory cell products, and 4) thermal stress produces differential vascular responses in allergic and non- allergic airways due to differences in mediator generation of autonomic responsiveness. The in vitro techniques will include the measurement of tracheal mucus velocity, respiratory mechanics, aerosol deposition, tracheal mucosal blood flow and tissue volume. In vitro techniques will include the measurement of mucus glycoprotein, ion, water fluxes and hydraulic conductivity in tracheal tissue, and determination of the interaction among ciliary beat frequency, mucus depth, mucus rheology and mucus transport rate. These physiologic parameters will be correlated with histopathologic and humoral indices (RIA and HPLC) of inflammation. Most of the proposed in vivo and in vitro methods have been previously used and validated in this and other laboratories. We expect to show that in the allergic airway, mucosal defects re involved in the abnormal airway responses to physical and pharmacologic stimuli and are related to inflammation. The results may form the basis for new treatment strategies in patients with bronchial asthma.