Anales RANF

S7-01 ADENOSINE AT THE CROSS-ROADS OF LUNG FIBROSIS AND PULMONARY HYPERTENSION S.D. Collum 1 , T.C.J. Mertens 1 , T. Weng 1 , Y. Xia 1 , H.K. Eltzschig 1 , M.R. Blackburn 1 and H. Karmouty-Quintana 1* 1 University of Texas Health Science Center at Houston, Houston TX-77030, USA Group III pulmonary hypertension (PH) is a deadly lung disorder with limited treatment options. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). PH affects over 40% of patients with IPF and contributes significantly to mortality, yet the molecular mechanisms leading to PH in patients with IPF are not fully understood. Our hypothesis was that the hypoxic- adenosinergic system is enhanced in patients IPF + PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor (ADORA2B), CD73, and equilibrate nucleotide transporter-1. Increased expression of HIF-1A was observed in tissues from patients with IPF + PH. These changes were consistent with increased evidence of adenosine accumulation in IPF + PH. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in IPF + PH. Next, to demonstrate whether the hypoxic-adenosinergic axis is a therapeutic target for IPF + PH, we utilized the bleomycin model of lung fibrosis and PH. Using this model we demonstrate that pharmacological deletion of ADORA2B protects and prevents mice from the development of PH in the setting of lung fibrosis. These results were correlated with experiments using conditional knockout mice lacking ADORA2B in myeloid and vascular smooth muscle cells. Taken together, these results highlight the hypoxic-adenosinergic axis as a causative mechanism in IPF + PH that can be targeted therapeutically. (Funding: R01-HL-138510 to HKQ and P01-HL114457 to MRB, YX, HKE)