Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with Chronic obstructive pulmonary disease

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 extracellularmatrix(ECM)havebeenimplicatedinthepathogenesis 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 A_2B receptor (ADORA2B) and aheightened depositionofhyaluronan (HA; acomponentof 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 ADORA2Bisabletoattenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involvedin the synthesis of HA.