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ADORA2B 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 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 heightened deposition of hyaluronan (a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that expression of hyaluronan synthase 2 (HAS2) 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 pulmonary hypertension we show that blockade of ADORA2B is able to attenuate the development of a pulmonary hypertension phenotype that correlates with reduced levels of hyaluronan deposition in the vessels and down regulation of genes involved in the synthesis of hyaluronan.

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