The A _2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

Abstract

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.

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…Endothelin-1, in turn, promotes mesangial cell proliferation and collagen production in the kidney [52]. Notably, adenosine, signaling via A 2B R, also modulates the release of IL-6 and ET-1 in interstitial lung disease leading to collagen deposition, vascular remodeling, and, over time, pulmonary hypertension; this represents a convergent signaling pathway in fibrosis of the two organs [53]. The transcription factor hypoxia inducible factor (HIF) is also overexpressed in renal hypoxia and is in part responsible for the increased expression of A 2B R in this setting [54].…”

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

“…Arterial oxygen saturation, right ventricle systolic pressure (RVSP), heart rate, and RV hypertrophy and lung function measurements were performed as described previously (18).…”

“…Elements of the adenosine signaling system have been closely linked with the production of several mediators, including IL-6 (18,19), endothelin-1 (18), HA (20,21), and mediators associated with hypoxia (22,23). Adenosine is a nucleoside that exerts its actions through G-protein-coupled receptors, including the adenosine 1, 2A, 2B, and 3 receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3, respectively) (24).…”

“…Adenosine is a nucleoside that exerts its actions through G-protein-coupled receptors, including the adenosine 1, 2A, 2B, and 3 receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3, respectively) (24). Adenosine is largely generated in response to cell injury, where it exerts both protective and detrimental effects (18,19,25). In the context of chronic lung disease, the engagement of ADORA2B via elevated adenosine levels has been implicated in disease progression and tissue remodeling (19,26).…”

“…Indeed, increased levels of ADORA2B transcript levels are observed in lung samples from patients with COPD and IPF (27). In vivo experiments also demonstrated that the genetic and pharmacological blockade of ADORA2B attenuates the development of fibrosis and PH in an experimental model of fibrosis (18,19,25). However, it remains unknown whether adenosine (and in particular, ADORA2B) plays a role in the pathogenesis of PH secondary to COPD.…”