Farah OR, Li D, McIntyre BA, Pan J, Belik J. Airway epithelialderived factor relaxes pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 296: L115-L120, 2009. First published October 24, 2008 doi:10.1152/ajplung.90391.2008.-The factors controlling the pulmonary vascular resistance under physiological conditions are poorly understood. We have previously reported on an apparent cross talk between the airway and adjacent pulmonary arterial bed where a factor likely derived from the bronchial epithelial cells reduced the magnitude of agonist-stimulated force in the vascular smooth muscle. The main purpose of this investigation was to evaluate whether bronchial epithelial cells release a pulmonary arterial smooth muscle relaxant factor. Conditioned media from SPOC-1 or BEAS-2B, a rat-and a human-derived bronchial epithelial cell line, respectively, were utilized. This media significantly relaxed precontracted adult but not fetal pulmonary arterial muscle in an oxygen tension-dependent manner. This response was mediated via soluble guanylate cyclase, involving AKT/PI3-kinase and neuronal nitric oxide synthase. Airway epithelial cell-conditioned media increased AKT phosphorylation in pulmonary smooth muscle cells (SMC) and reduced intracellular calcium change following ATP stimulation to a significantly greater extent than observed for bronchial SMC. The present data strongly support the evidence for bronchial epithelial cells releasing a stable and soluble factor capable of inducing pulmonary arterial SMC relaxation. We speculate that under physiological conditions, the maintenance of a low pulmonary vascular resistance, postnatally, is in part modulated by the airway epithelium. pulmonary hypertension; pulmonary vascular resistance; fetal; hypoxic pulmonary vasoconstriction response WE HAVE SHOWN THAT THE PRESENCE of an attached bronchus significantly reduces the rat pulmonary arterial smooth muscle contraction via a mechanism that appeared to be airway epithelium dependent (3). We reasoned that the bronchial epithelium releases a factor capable of relaxing the adjacent pulmonary arterial smooth muscle and coined the term bronchial epithelium-derived relaxing factor (BrEpRF). The fact that BrEpRF activity/expression was absent in fetal pulmonary arteries and under low oxygen concentration (4) led us to suggest that this factor is released under physiological conditions and may have an important role in the regulation of the pulmonary vascular resistance.Our previous data demonstrated that the adjacent airway tissue modulated the pulmonary arterial smooth muscle, but the cells responsible for the release of this relaxing factor and its signaling pathway was not known. The purpose of the present study was to determine whether isolated bronchial epithelial cells are capable of releasing a pulmonary arterial muscle relaxing factor in vitro and to examine its downstream targets. Based on our previous studies (3, 4), we hypothesized that these cells secrete BrEpRF, which in turn relaxes pulmonary smooth mu...
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