Bronchial Vascular Proliferation and Function

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

Under conditions of chronic pulmonary artery ischemia, the systemic bronchial circulation undergoes massive proliferation. However, the functional consequences of this rapidly constructed new circulation remain largely unexplored. Systemic angiogenic beds in general have been shown to demonstrate a proinflammatory phenotype. Our laboratory has studied systemic angiogenesis in mice after chronic left pulmonary artery ligation where ELR+ CXC chemokines appear to play a role in intercostal artery angiogenesis. However, since mice lack an intraparenchymal bronchial circulation and therefore are unlike humans, a larger animal model is required to determine the physiology of the angiogenic bronchial vasculature within the lung. In this application, we propose to study the process and consequences of bronchial vascular growth and proliferation after left pulmonary artery obstruction in rats, a species known to display a bronchial vascular anatomy similar to humans. An underlying question in this model is how growth factors released within the perfusion-starved lung, communicate with distant, upstream bronchial vessels. We propose a conduit role for lung lymphatic vessels, which drain unidirectionally and in proximity to major bronchial arteries. We hypothesize that bronchial angiogenesis is dependent on growth factors (CXC chemokines) released by trapped inflammatory cells, that drain and diffuse through lung lymphatics and mediastinal lymph nodes, causing bronchial vascular proliferation and enlargement. Furthermore, we hypothesize that the neovasculature is like other systemic beds and is proinflammatory (vasodilated, hyperpermeable, leukocyte recruiting) within the lung. In a rat model of left pulmonary artery obstruction, we will determine the importance of proangiogenic ELR+ CXC chemokines for the growth of new bronchial blood vessels, determine whether mediastinal lymph drainage provides a mechanism whereby parenchymal growth factors transit upstream to promote bronchial angiogenesis, and measure bronchial vascular function (permeability, inflammation, vasoreactivity) at time points before and after a new vasculature is established. Results will provide new information concerning the mechanisms of bronchial vascular angiogenesis, function and impact on ischemic parenchyma. Furthermore, results may explain properties of bronchial vessels that contribute to hemoptysis and loss of pulmonary function.