Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Abstract

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 A 2B 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.Keywords: adenosine; extracellular matrix; hyaluronic acid; remodeling; vascular Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death worldwide, and the World Health Organization predicts that it will become the third leading cause of death by 2030 (1). COPD is a heterogeneous disease characterized by airflow obstruction that is not fully reversible. Pathophysiological hallmarks of the disease include remodeling of the smallairway compartment, the loss of elastic recoil by emphysematous destruction of the parenchyma, inflammatory cell infiltration (2), and increased extracellular matrix (ECM) turnover (3). COPD is associated with a wide range of comorbidities, including ischemic heart disease, diabetes, skeletal muscle wasting, osteoporosis, and lung cancer (4). The development of pulmonary hypertension (PH) is a common and fatal complication in patients with COPD (5-7), and is strongly associated with decreased life expectancy (8).PH is a disorder of the pulmonary vasculature diagnosed by cardiac catheterization. PH is characterized by a mean pulmonary arterial pressure greater than or equal to 25 mm Hg that leads to right ventricular (RV) hypertrophy, followed by right-sided heart failure and death (9). Currently, treatment options are very limited for patients suffering from PH secondary to COPD (10, 11). Thus, to understand the mechanisms that lead to remodeling of the vasculature in COPD is important, with the hope of developing new treatment options for this fatal disorder.The pathogenesis of PH in COPD is a complex phenomenon characterized by extensive remodeling of the vasculature that results from an increased proliferation of pulmonary artery endothelial and smooth muscle cells, the muscularization of previously nonmuscular arteries, increased vascular tone, and the formation of complex vascular lesions (12). Factors involved in the development of PH in patients with COPD include ...

Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension

“…The reductions in markers for AAM were linked to reduced fibrotic deposition and improved lung function, consistent with studies in mice lacking arginase‐1 in hematopoietic cells where improved lung function following allergen challenge was reported (42). We also demonstrate that mice lacking the ADORA2B in the myeloid cell lineage were protected from the development of PH secondary to lung fibrosis (12), implicating further the role of AAM in the development of lung fibrosis and PH.…”

“…Heightened levels of adenosine have been observed in several chronic lung diseases (11) and in experimental models of PH secondary to chronic lung disease (12, 13, 32). In line with this, we describe accumulation of adenosine in BALF during the progression of fibrosis, reaching a peak on day 33 that is attenuated in BLM‐exposed Adora2B f/f ‐LysM Cre mice.…”

“…ADORA2B levels are elevated in patients with IPF (10, 11). Moreover, genetic removal of ADORA2B or treatment with an ADORA2B antagonist has been shown to improve fibrosis and PH in vivo (12, 13). Based on these observations, we aim to determine the role of conditional deletion of the ADORA2B from myeloid cells in an experimental model of lung fibrosis and PH.…”

Hyaluronan as a therapeutic target in human diseases

“…HA levels were significantly higher in patients with COPD than in those from controls [187–189]. Some reports showed that HA levels were decreased in COPD [190] and in COPD with alpha-1 antiprotease deficiency [191].…”

Protective Effects of Oxymatrine on Vascular Endothelial Cells from High-Glucose-Induced Cytotoxicity by Inhibiting the Expression of A2B Receptor

“…Studies in A 2B receptor knockout mice showed inhibition of the infiltration of neutrophils into tissues under hypoxic conditions [26,27]. Pro-inflammatory effects of A 2B receptors have been seen in murine lung inflammation models and in patients with asthma or chronic obstructive pulmonary disease, suggesting the potential therapeutic value of targeting A 2B receptors as an anti-inflammation measure to prevent the progression of these diseases [28,29]. It has been reported that the A 2B receptor may promote the expression and release of the inflammatory factor IL-6 by vascular endothelial cells in diabetes [12].…”