PATHOPHYSIOLOGY OF BRONCHIAL ASTHMA

支气管哮喘的病理生理学

• 批准号: 3336319
• 负责人: Adam Wanner
• 金额: $ 14.84万
• 依托单位: MOUNT SINAI MEDICAL CENTER (MIAMI BEACH)
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336319
• 关键词: Pasteurella; acetylcholine; airborne allergen; alveolar macrophages; anaphylaxis; antihistamines; asthma; autoradiography; bacterial pneumonia; biological models; body fluid viscosity; bronchial mucus; bronchodilators; bronchoscopy; cilium /flagellum motility; disease /disorder model; histamine; ion transport; neurotransmitters; nonblood rheology; prostaglandins; radiotracer; respiratory airflow disorder; respiratory airflow measurement; respiratory airway clearance; respiratory airway pressure; respiratory airway volume; respiratory imaging /visualization; respiratory pharmacology; scanning electron microscopy; secretion; tissue /cell culture

The important role of abnormal airway secretions in bronchial asthma is recognized by clinicians and pathologists; however, the pathophysiologic significance of this abnormality has been insufficiently examined in the past. During the previous and current grant periods, a series of experiments have been conducted in our laboratory in an attempt to characterize airway mucociliary function in a sheen model of allergic bronchoconstriction. Those studies have demonstrated that antigen-induced bronchoconstriction is associated with an impairment of mucociliary transport, that this impairment is related to chemical mediators of anaphylaxis (notably leukotriences), that antigen challenge causes ciliostimulation and mucus hypersecretion, and that allergic mucociliary dysfunction persists for several days. The objectives of the present proposal are to further clarify the mechanisms underlying abnormal mucociliary function in asthma, and to determine if this defect has physiologic consequences that might be clinically significant. In vivo measurements of mucociliary activity (mucociliary transport, mucus rheology) combined with in vitro determinations of its component functions (ciliary activity, mucus secretion and water transport) will be obtained in sheep with Ascaris suum hypersensitivity to 1) demonstrate that the airway hyperresponsiveness in bronchial asthma is associated with "mucociliary hyperresponsiveness" which includes both facilitated release of secretagogues and enhanced target tissue responsiveness to secretagogues and chemical mediators of anaphylaxis, 2) determine the mechanisms underlying prolonged allergic mucociliary dysfunction, 3) establish a relation between the accumulation of mucus in peripheral airways and minimal airway obstruction during prolonged allergic mucociliary dysfunction, and 4) determine if mucoiliary dysfunction impairs bacterial clearance from the airways. Most of the proposed methods have been previously used and validated in this and other laboratories. We expect that the information derived from these studies will contribute to the understanding of the mechanisms controlling the secretion and transport of airway mucus in allergic asthma, and demonstrate some of the detrimental consequences of asthma-associated mucociliary dysfunction. The obtained results will form the basis for pharmacologic intervention.

气道分泌物异常在支气管哮喘中的重要作用是 被临床医生和病理学家所认可;然而， 这一异常的重要性没有得到充分的研究， 过去 在上一个和当前赠款期间， 在我们的实验室里进行了一些实验， 在变应性哮喘模型中表征气道粘膜纤毛功能 支气管收缩 这些研究表明， 支气管收缩与粘膜纤毛损伤有关 运输，这种损害与化学介质有关， 过敏反应（特别是白细胞增多症），抗原激发引起 纤毛刺激和粘液分泌过多，以及过敏性粘液纤毛 功能障碍持续数天。 当前的目标 建议是进一步澄清机制的异常 哮喘中的粘膜纤毛功能，并确定这种缺陷是否 可能具有临床意义的生理后果。 体内 粘液纤毛活性（粘液纤毛运输，粘液 流变学）结合其组分功能的体外测定 （纤毛活动，粘液分泌和水运输）将在 羊与猪蛔虫过敏1）表明，气道 支气管哮喘的高反应性与“粘膜纤毛 高反应性”，包括促进释放 促分泌素和增强的靶组织对促分泌素的反应性 和过敏反应的化学介质，2）确定机制 潜在的长期过敏性粘膜纤毛功能障碍，3）建立一个 外周气道中粘液积聚与 长期过敏性粘膜纤毛炎期间的气道阻塞最小 功能障碍，和4）确定粘膜纤毛功能障碍是否损害细菌 从气道清除。 大多数提出的方法都是 以前在本实验室和其他实验室使用和验证过。 我们预计 从这些研究中获得的信息将有助于 了解控制分泌和运输的机制， 过敏性哮喘的气道粘液，并证明了一些有害的 哮喘相关的粘膜纤毛功能障碍的后果。 所获得的 结果将构成药物干预的基础。