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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL010342-39
Application #
7312429
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
39
Fiscal Year
2006
Total Cost
$376,274
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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