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: 6701326
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701326
• 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（由申请人提供）：支气管组织钾化酶（TK）是一种关键