THE ROLE OF HYALURONAN IN AIRWAY HYPERREACTIVITY

透明质酸在气道高反应性中的作用

• 批准号: 6845321
• 负责人: Rosanna C Malbran Forteza
• 金额: $ 25.59万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845321
• 关键词: asthma; bradykinin; bronchomotion; free radical oxygen; human tissue; hyaluronate; kallikreins; kininogens; kinins; respiratory airway clearance; respiratory epithelium; respiratory hypersensitivity; secretion; sheep

DESCRIPTION (provided by applicant): Bronchial tissue kallikrein (TK) is a key enzyme in the pathophysiology of bronchial asthma. It cleaves kininogen in a highly selective fashion to yield lysyl-bradykinin (kallidin). Kallidin causes vasodilatation, increases vascular permeability and leads to bronchoconstriction and airway hyperresponsiveness (AHR), all hallmarks of asthma. Despite the fact that bronchial TK is the major kininogenase in the airways, little is known about its regulation. We have found that bronchial TK is secreted by serous cells of submucosal glands together with hyaluronan that binds to and thereby inhibits TK in the airway lumen. We have also found that hyaluronan binds to the apical membrane of airway epithelial cells thereby immobilizing inactivated TK at the epithelial surface. These findings challenge the notion that proteins (such as TK) secreted into the airway lumen is rapidly cleared by the mucociliary apparatus and that enzyme availability on mucosal surfaces is solely dependent on secretion. Our results suggest another level of regulatory control that relies on an apical enzyme pool "ready for use" and protected from ciliary clearance. This may have important implications for asthma pathophysiology since hyaluronan breakdown in the airways could release large amounts of active TK. This proposal will therefore test the hypothesis that reactive oxygen species, generated in the airway lumen during inflammatory reactions and known to cleave hyaluronan, will cause the release of active TK due to hyaluronan degradation and active TK, in turn, will generate kinins subsequently causing AHR. To test this hypothesis we will identify how hyaluronan is synthesized in submucosal glands, study the nature of the interaction between hyaluronan and bronchial TK, and examine reactive oxygen species-induced hyaluronan degradation in vivo and its relation to bronchial TK activity and AHR. The results of these studies will provide new, important, and exciting mechanistic insights into our understanding of airway biology as it pertains to hyaluronan, bronchial TK and kinin interactions in asthma. Moreover, the principle of enzyme immobilization at mucosal surfaces maybe applicable to many epithelia that are cleared from secretions by mechanical action. Thus, the results of this proposal will not only significantly advance our knowledge of airway biology and asthma, but may have important implications to other mucosal surfaces as well.

描述(申请人提供)：支气管组织激肽释放酶(TK)是关键 酶在哮喘病理生理学中的作用。它将激肽原分解在 高度选择性的方式，以产生赖氨酰缓激肽(Kallidin)。卡利丁起因 血管扩张，增加血管通透性，导致 支气管收缩和呼吸道高反应性(AHR)，所有特征 哮喘。尽管事实是，支气管TK是主要的激肽原酶 航空公司，人们对其监管知之甚少。我们发现，支气管TK 是由粘膜下腺的浆液细胞和透明质酸共同分泌的 与气道腔中的TK结合，从而抑制TK。我们还发现， 透明质酸与呼吸道上皮细胞的顶膜结合 将灭活的TK固定在上皮表面。这些发现对我们提出了挑战 蛋白质(如TK)分泌到气道腔的概念是迅速的 被粘膜纤毛器清除和粘膜上的酶可利用性 表面完全依赖于分泌物。我们的研究结果表明， 调节控制依赖于顶端酵素池“随时可用”，以及 保护不受纤毛清除。这可能对以下方面有重要影响 哮喘的病理生理机制，因为透明质酸在呼吸道中的破坏可能会释放 大量活跃的TK。因此，这一提议将检验这一假设 炎症过程中在气道腔中产生的活性氧类 已知的反应和裂解透明质酸，会导致活性TK的释放 由于透明质酸的降解和活性的TK，进而会产生激动素 随后导致AHR。为了检验这一假设，我们将确定 透明质酸是在粘膜下腺中合成的，研究 透明质酸与支气管TK的相互作用及活性氧的检测 物种诱导的透明质酸体内降解及其与支气管TK的关系 活动度和AHR。这些研究的结果将提供新的、重要的和 令人兴奋的机械洞察到我们对呼吸道生物学的理解 与哮喘中透明质酸、支气管TK和激动素的相互作用有关。 此外，在粘膜表面固定酶的原理可能是 适用于许多通过机械方法从分泌物中清除的上皮 行动。因此，这项提议的结果不仅将显著推进 我们对呼吸道生物学和哮喘的了解，但可能会有重要的启示 对其他粘膜表面也是如此。