cvt-6883 and Hypertension--Pulmonary

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.

Topics: Adenosine A2 Receptor Antagonists; Adenosine Deaminase; Aged; Animals; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Female; Humans; Hyaluronic Acid; Hypertension, Pulmonary; Lung; Male; Mice; Mice, Knockout; Middle Aged; Pulmonary Disease, Chronic Obstructive; Purines; Pyrazoles; Receptor, Adenosine A2B; RNA, Messenger

Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Bleomycin; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Interleukin-6; Lung Diseases, Interstitial; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Purinergic P1 Receptor Agonists; Purines; Pyrazoles; Receptor, Adenosine A2B