Effects of Distension on the Airway Vasculature

扩张对气道脉管系统的影响

• 批准号: 7312429
• 负责人: Elizabeth Wagner
• 金额: $ 37.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312429
• 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研究。肺内的这种体循环从传导气道延伸到末端细支气管，并且在解剖学上定位成有助于气道稳态。然而，嵌入气道壁内的该脉管系统也暴露于施加在气道上的通气的机械应力。内皮细胞单层在受到机械应力时会释放血管活性介质， 分子表达和改变的单层渗透性。尚未确定这些效应中的每一种是否发生在相关体内模型中的气道脉管系统内。我们假设深吸气或机械通气时应用呼气末正压时出现的短暂性大扩张导致rive气道内皮细胞活化。此外，由于固有的内皮细胞异质性，我们认为动脉内皮的激活将主要导致调节灌注的介质的释放，而过度扩张将影响毛细血管后微静脉内皮主要改变屏障功能和粘附分子的表达。初步数据支持气道扩张的血管舒张和促炎作用。在所提出的实验中，我们将应用独特的动物模型，专注于这些异质性反应的内皮细胞气道扩张。因此，本项目中描述的方案将确定气道扩张对局部气道灌注和气道反应性、气道壁炎症细胞募集和血管渗漏的影响，所有这些都有助于气道过度活跃疾病的病理学。这些过程中的每一个都被证明是由内皮型一氧化氮合酶（eNOS）的活性，这反过来，是严格的机械应力施加在内皮细胞调节。虽然eNOS活性增加与血管舒张有关，但也显示其对白细胞减少具有屏障保护和抗炎作用。 招聘为了研究过度气道扩张对气道血管系统的总体影响的潜在机制，我们将重点关注动脉内皮与静脉内皮相比的独特变化，特别是在相关的绵羊和小鼠体内模型以及体外气道血管内皮细胞单层中的eNOS表达。