Effects of Distension on the Airway Vasculature

扩张对气道脉管系统的影响

• 批准号: 6967834
• 负责人: Elizabeth Wagner
• 金额: $ 36.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967834
• 关键词: artery; bronchus circulation; enzyme activity; inflammation; laboratory mouse; mechanical stress; nitric oxide synthase; respiratory airway pressure; respiratory airway volume; respiratory hypersensitivity; sheep; vascular cell adhesion molecule; vascular endothelium; vascular endothelium permeability; vasoactive agent; vasomotion; veins

The importance of the bronchial circulation in modulating airway function is largely unstudied. This systemic circulation within the lung extends from the conducting airways to the terminal bronchioles and is anatomically positioned to contribute to airway homeostasis. However, this vasculature, embedded within the airway wall, is also exposed to the mechanical stresses of ventilation that are imposed on airways. Endothelial cell monolayers subjected to mechanical stress have been shown to release vasoactive mediators, display increased adhesion molecule expression, and altered monolayer permeability. Whether each of these effects occur within the airway vasculature in a relevant in vivo model has not been determined. We hypothesize that large transient distensions that occur with deep inspirations or the application of positive end-expiratory pressures during mechanical ventilation lead to airway endothelial cell activation in rive. Furthermore, because of inherent endothelial cell heterogeneity, we propose that activation of arterial endothelium will result primarily in release of mediators that modulate perfusion, whereas excessive distension will affect post-capillary venular endothelium primarily to alter barrier function and adhesion molecule expression. Preliminary data supports both vasodilatory and proinflammatory effects of airway distension. In the proposed experiments, we will apply unique animal models to focus on these heterogeneous responses of endothelium to airway distension. Thus, protocols described in this project will determine the effects of airway distension on local airway perfusion and airways reactivity, inflammatory cell recruitment to the airway wall, and vascular leak, all of which contribute to the pathology of hyperactive airways diseases. Each of these processes has been shown to be regulated by endothelial nitric oxide synthase (eNOS) activity, which in turn, is tightly regulated by mechanical stresses imposed on endothelial cells. Although increased eNOS activity has been associated with vasodilation, it has also been shown to be barrier protective and anti-inflammatory with regard to leukocyte recruitment. To investigate a potential mechanism responsible for the overall effects of excessive airway distension on the airway vasculature, we will focus on the unique alterations in arterial endothelium compared to venous endothelium with specific regard to eNOS expression, in relevant in vivo sheep and mouse models as well as in vitro airway vascular endothelial cell monolayers.

支气管循环在调节气道功能中的重要性在很大程度上尚未得到研究。肺内的体循环从导气管延伸到末端细支气管，解剖定位有助于气道稳态。然而，这种嵌入气道壁内的血管系统也暴露于施加在气道上的通气机械应力下。内皮细胞单层受到机械应力已被证明释放血管活性介质，显示增加的粘附