Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation
University of Colorado, Mucosal Inflammation Program, Department of Medicine, Denver, 12700 E 19th Avenue, Mailstop B112, Research Complex 2, Room 7124, Aurora, CO 80045, USA. Expert Opinion on Therapeutic Targets
(Impact Factor: 5.14).
09/2009; 13(11):1267-77. DOI: 10.1517/14728220903241666
Extracellular adenosine functions as an endogenous distress signal via activation of four distinct adenosine receptors (A1, A2A, A2B and A3). Conditions of limited oxygen availability or acute inflammation lead to elevated levels of extracellular adenosine and enhanced signaling events. This relates to a combination of four mechanisms: i) increased production of adenosine via extracellular phosphohydrolysis of precursor molecules (particularly ATP and ADP); ii) increased expression and signaling via hypoxia-induced adenosine receptors, particularly the A2B adenosine receptor; iii) attenuated uptake from the extracellular towards the intracellular compartment; and iv) attenuated intracellular metabolism. Due to their large surface area, mucosal organs are particularly prone to hypoxia and ischemia associated inflammation. Therefore, it is not surprising that adenosine production and signaling plays a central role in attenuating tissue inflammation and injury during intestinal ischemia or inflammation. In fact, recent studies combining pharmacological and genetic approaches demonstrated that adenosine signaling via the A2B adenosine receptor dampens mucosal inflammation and tissue injury during intestinal ischemia or experimental colitis. This review outlines basic principles of extracellular adenosine production, signaling, uptake and metabolism. In addition, we discuss the role of this pathway in dampening hypoxia-elicited inflammation, specifically in the setting of intestinal ischemia and inflammation.
Available from: Edwin K Jackson
- "Adenosine is an endogenous nucleoside that is an agonist for four G-protein coupled receptors (A1, A2A, A2B, A3) that reduce inflammation [8–11], particular in the intestines [12, 13], and inhibit fibroblast migration, proliferation and collagen formulation [14–18]. Previous studies from our laboratory demonstrate that adenosine significantly inhibits post-surgical adhesion formation in rodents  and pigs (preliminary data) following severe peritoneal abrasion. "
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ABSTRACT: Intraperitoneal adenosine reduces abdominal adhesions. However, because of the ultra-short half-life and low solubility of adenosine, optimal efficacy requires multiple dosing.
Here, we compared the ability of potential adenosine prodrugs to inhibit post-surgical abdominal adhesions after a single intraperitoneal dose.
Abdominal adhesions were induced in mice using an electric toothbrush to damage the cecum. Also, 20 μL of 95 % ethanol was applied to the cecum to cause chemically induced injury. After injury, mice received intraperitoneally either saline (n = 18) or near-solubility limit of adenosine (23 mmol/L; n = 12); 5'-adenosine monophosphate (75 mmol/L; n = 11); 3'-adenosine monophosphate (75 mmol/L; n = 12); 2'-adenosine monophosphate (75 mmol/L; n = 12); 3',5'-cyclic adenosine monophosphate (75 mmol/L; n = 19); or 2',3'-cyclic adenosine monophosphate (75 mmol/L; n = 20). After 2 weeks, adhesion formation was scored by an observer blinded to the treatments. In a second study, intraperitoneal adenosine levels were measured using tandem mass spectrometry for 3 h after instillation of 2',3'-cyclic adenosine monophosphate (75 mmol/L) into the abdomen.
The order of efficacy for attenuating adhesion formation was: 2',3'-cyclic adenosine monophosphate > 3',5'-cyclic adenosine monophosphate ≈ adenosine > 5'-adenosine monophosphate ≈ 3'-adenosine monophosphate ≈ 2'-adenosine monophosphate. The groups were compared using a one-factor analysis of variance, and the overall p value for differences between groups was p < 0.000001. Intraperitoneal administration of 2',3'-cAMP yielded pharmacologically relevant levels of adenosine in the abdominal cavity for >3 h.
Administration of 2',3'-cyclic adenosine monophosphate into the surgical field is a unique, convenient and effective method of preventing post-surgical adhesions by acting as an adenosine prodrug.
Available from: PubMed Central
- "Experiments comparing disease progression in compound/double knockout mice using P2X−/−7 mice and genetically orthologous/non-orthologous murine models of PKD are required (Hillman et al., 2005). In addition, in experimental models of cancer, the over-expression of either CD39 or CD73 promotes tumor progression due to loss of tumor-associated inflammation (Synnestvedt et al., 2002; Eltzschig et al., 2009). On the other hand, in PKD, the loss of interstitial inflammation due to the transgenic expression of CD39 or CD73, might be renoprotective, as shown in experimental renal ischaemia (Crikis et al., 2010). "
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ABSTRACT: Polycystic kidney diseases (PKD) are a group of inherited ciliopathies in which the formation and growth of multiple cysts derived from the distal nephron and collecting duct leads to the disruption of normal kidney architecture, chronic interstitial inflammation/fibrosis and hypertension. Kidney failure is the most life-threatening complication of PKD, and is the consequence of cyst expansion, renal interstitial disease and loss of normal kidney tissue. Over the last decade, accumulating evidence suggests that the autocrine and paracrine effects of ATP (through its receptor family P2X and P2Y), could be detrimental for the progression of PKD. (2009). In vitro, ATP-P2 signaling promotes cystic epithelial cell proliferation, chloride-driven fluid secretion and apoptosis. Furthermore, dysfunction of the polycystin signal transduction pathways promotes the secretagogue activity of extracellular ATP by activating a calcium-activated chloride channel via purinergic receptors. Finally, ATP is a danger signal and could potentially contribute to interstitial inflammation associated with PKD. These data suggest that ATP-P2 signaling worsens the progression of cyst enlargement and interstitial inflammation in PKD.
Available from: Aneta Gandjeva
- "While the mechanisms of how netrin-1 interacts with the A2BAR remain unclear, this study demonstrates that netrin-1 signaling events enhance adenosine-dependent tissue protection from hypoxia , , , , , . This assumption would be consistent with other studies on the role of the A2BAR in myocardial ischemia , , vascular leakage , , intestinal inflammation , , , or acute lung injury , , where hypoxia-elicited induction of the A2BAR  attenuates organ inflammation and dysfunction. In fact, hypoxia has been shown to drive a coordinated adenosine response of different tissues , , , , including increased adenosine production , , , , , , , , , induction of the A2BAR , attenuated adenosine uptake , ,  and metabolism , thereby enhancing anti-inflammatory and protective tissue responses during acute hypoxia , , . "
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ABSTRACT: The netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes beyond their functions in the brain, incluing the ochrestration of inflammatory events. Particularly netrin-1 has been implicated in dampening hypoxia-induced inflammation. Here, we hypothesized an anti-inflammatory role of endogenous netrin-1 in acute kidney injury (AKI). As homozygous deletion of netrin-1 is lethal, we studied mice with partial netrin-1 deletion (Ntn-1(+/-) mice) as a genetic model. In fact, Ntn-1(+/-) mice showed attenuated Ntn-1 levels at baseline and following ischemic AKI. Functional studies of AKI induced by 30 min of renal ischemia and reperfusion revealed enhanced kidney dysfunction in Ntn-1(+/-) mice as assessed by measurements of glomerular filtration, urine flow rate, urine electrolytes, serum creatinine and creatinine clearance. Consistent with these findings, histological studies indicated a more severe degree kidney injury. Similarly, elevations of renal and systemic inflammatory markers were enhanced in mice with partial netrin-1 deficiency. Finally, treatment of Ntn-1(+/-) mice with exogenous netrin-1 restored a normal phenotype during AKI. Taking together, these studies implicate endogenous netrin-1 in attenuating renal inflammation during AKI.
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