The Adenosine A2a Receptor Inhibits Matrix-Induced Inflammation in a Novel Fashion

Scheibner, Kara; Boodoo, Sada; Collins, Samuel; Black, Katharine E.; Chan‐Li, Yee; Zarek, Paul E.; Powell, Jonathan D.; Horton, Maureen R.

doi:10.1165/rcmb.2008-0168oc

Cited by 50 publications

(67 citation statements)

References 53 publications

(88 reference statements)

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“…Using human arterial smooth muscle cells, we confirmed these observations in vitro by showing that the activation of ADORA2B promotes the expression of HAS-1. The results of these studies are in line with previous observations, where adenosine was shown to regulate HA levels (20,21). However, contrary to these previous observations, we show that ADORA2B but not ADORA2A is responsible for the upregulation of HA.…”

Section: Discussionsupporting

confidence: 90%

“…Furthermore, increased HA has been observed in the monocrotaline model of PH (43), further implicating its role in vascular remodeling. Adenosine via ADORA2A was recently demonstrated to modulate the expression of HA in bleomycin-induced lung injury (20,21). In our model of chronic PH associated with chronic lung injury, we demonstrate increased levels of HAS-1 and HAS-2, as well as increased HA-staining adjacent to small pulmonary vessels.…”

Section: Discussionsupporting

confidence: 61%

“…In our Ada 2/2 mice, the activation of ADORA2B was associated with disease progression (19). It is also important to consider that although the blockade of ADORA2B prevents increased HA in our model, Collins and colleagues (21) and Scheibner and colleagues (20) showed that the activation of ADORA2A down-regulated HA. This phenomenon is consistent with the anti-inflammatory and proinflammatory dualities of adenosine action in the context of acute and chronic injury (25), and point out the need to further dissect the acute and chronic functions of adenosine and its signaling system during various stages of disease progression.…”

Section: Discussionmentioning

confidence: 73%

“…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).…”

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confidence: 99%

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

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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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 ...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

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

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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“…We have previously demonstrated that adenosine modulates LMW HA-induced gene expression via the A2aR (18). A2aR stimulation inhibits LMW HA fragment-induced profibrotic genes TNF-a, KC, MIP-2, and MIP-1a, while simultaneously synergizing with HA fragments to up-regulate the TH1 cytokine IL-12 (18).…”

mentioning

confidence: 99%

Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor.

Collins¹,

Black²,

Chan‐Li³

et al. 2009

D30. The Role of Inflammation in Chronic Interstitial Lung Disease

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Inhibition of the hyaluronan oligosaccharides inflammatory response: reduction of adenosine 2A receptor activation by EPAC and PKA

Campo

Avenoso

D’Ascola

et al. 2014

Cell Biochemistry & Function

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The aim of this study was to investigate the involvement of exchange proteins directly activated by cyclic adenosine (ADO) monophosphate (EPAC) in 4-mer hyaluronan (HA) oligosaccharide-induced inflammatory response in mouse normal synovial fibroblasts (NSF). Treatment of NSF with 4-mer HA increased Toll-like receptor-4, TNF-alpha and IL-1beta mRNA expression and of the related proteins, as well as nuclear factor kappaB (NF-kB) activation. Addition to NSF, previously stimulated with 4-mer HA oligosaccharides, of ADO significantly reduced NF-kB activation, TNF-alpha and IL-1beta expression. The pre-treatment of NSF with cyclic ADO monophosphate and/or PKA and/or EPAC-specific inhibitors significantly inhibited the anti-inflammatory effect exerted by ADO. In particular, the EPAC inhibitor reduced the ADO effect to a major extent than the PKA inhibitor. These results mean that both PKA and EPAC pathways are involved in ADO-induced NF-kB inhibition although EPAC seems to be more involved than PKA.

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The Adenosine A2a Receptor Inhibits Matrix-Induced Inflammation in a Novel Fashion

Cited by 50 publications

References 53 publications

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

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

Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor.

Inhibition of the hyaluronan oligosaccharides inflammatory response: reduction of adenosine 2A receptor activation by EPAC and PKA

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