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: 6620887
• 负责人: Rosanna C Malbran Forteza
• 金额: $ 25.95万
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620887
• 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（由申请方提供）：支气管组织激肽释放酶（TK）是 支气管哮喘的病理生理学。它在一个 以高选择性方式产生赖氨酰-缓激肽（胰激肽）。胰激肽导致 血管舒张，增加血管通透性，导致 支气管收缩和气道高反应性（AHR），所有的标志， 哮喘尽管事实上支气管TK是肺组织中主要的激肽原酶， 航空公司，很少有人知道它的规则。我们发现支气管TK 由粘膜下腺体的浆液细胞与透明质酸一起分泌， 结合并由此抑制气道腔中的TK。我们还发现 透明质酸与气道上皮细胞的顶膜结合 将灭活的TK固定在上皮表面。这些发现挑战 分泌到气道腔中的蛋白质（如TK）迅速被 由粘膜纤毛器清除，粘膜上的酶可用性 表面完全依赖于分泌。我们的研究结果表明， 依赖于“即用型”顶端酶池的监管控制， 防止纤毛清除。这可能对以下方面产生重要影响： 哮喘病理生理学，因为呼吸道中的透明质酸分解可以释放 大量的活性TK。因此，本提案将检验这一假设 在炎症过程中， 反应和已知的切割透明质酸，将导致释放活性TK 由于透明质酸降解和活性TK，反过来， 随后引起AHR。为了验证这一假设，我们将确定 透明质酸在粘膜下腺体中合成，研究其性质， 透明质酸和支气管TK之间相互作用，并检查活性氧 种属诱导透明质酸体内降解及其与支气管TK的关系 活动和AHR。这些研究的结果将提供新的，重要的， 令人兴奋的机制的见解，我们的理解气道生物学，因为它 涉及哮喘中透明质酸、支气管TK和激肽的相互作用。 此外，在粘膜表面酶固定化的原理可能 适用于许多上皮细胞，这些上皮细胞是通过机械清除分泌物的， 行动上因此，这项建议的结果不仅将大大促进 我们对气道生物学和哮喘的了解，但可能有重要的意义， 其他粘膜表面也是如此。