Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury

Abstract

Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair. Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses, prolonged elevations can enhance destructive tissue remodeling processes associated with chronic disease states. The generation of adenosine and the subsequent activation of the adenosine 2B receptor (A2BR) is an important processes in the regulation of both acute and chronic lung disease. The goal of this study was to examine the contribution of the A2BR in models of bleomycin-induced lung injury that exhibit varying degrees of acute and chronic injury. Intratracheal bleomycin exposure results in substantial acute lung injury followed by progressive fibrosis. In this model, genetic removal of the A2BR resulted in enhanced loss of barrier function and increased pulmonary inflammation, with few differences in indexes of pulmonary fibrosis. These results support an anti-inflammatory role for this receptor in this model of acute lung injury. In contrast, systemic exposure of mice to bleomycin resulted in modest acute lung injury together with progressive pulmonary fibrosis. In this model, the effects of A2BR removal on acute lung injury were negligible; however, there were substantial reductions in pulmonary fibrosis, supporting a profibrotic role for this receptor. A2BR-dependent regulation of IL-6 production was identified as a potential mechanism involved in the diminished pulmonary fibrosis seen in A2BR knockout mice exposed to i.p. bleomycin. These studies highlight the distinct roles of A2BR signaling during acute and chronic stages of lung injury.

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

“…The role of A 2B R in disease pathogenesis is highly complex, being determined by rates of local production and clearance of adenosine, the extent of expression of A 2B R by resident and recruited cells, and the repertoire of these cells for the other adenosine receptors, which compete with A 2B R for adenosine. A 2B R signaling has been reported to be broadly antiinflammatory in several models of acute lung injury; in particular, A 2B R deficiency is associated with increased lung inflammation after challenge with bleomycin, LPS, ischemia-reperfusion, and ventilator-associated lung injury (29,(36)(37)(38). The reported mechanisms of these effects have varied markedly between these models and have included alteration of leukocyte traffic, reduction in vascular permeability mediated by bone marrow-derived cells, and attenuation of the neutrophil oxidative burst (14,37,38); on the other hand, work has shown A 2B R expression on bone marrow-derived cells to paradoxically enhance neutrophil migration to the lung interstitium in response to LPS (39).…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…For example, extracellular adenosine generation and signaling appears to be protective during the acute phase of lung injury, but has been implicated in promoting a fibrotic response during chronic forms of lung disease. [33][34][35][36][37] Diabetic nephropathy is among the leading causes of morbidity and mortality in patients with diabetes mellitus. It belongs to the group of CKDs and is characterized by its progressive nature, eventually leading to nephrotic syndrome and diffuse glomerulosclerosis.…”

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

“…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.…”