Activation of Adenosine A2A Receptor Attenuates Inflammatory Response in a Rat Model of Small-for-Size Liver Transplantation

Tang, Liming; Zhu, Jianfei; Wang, F.; Qian, Jun; Mo, Qi; Lü, Hui; Li, G.-Q.; Wang, X.-H.

doi:10.1016/j.transproceed.2010.02.084

“…ADORA2A is an important regulator of inflammation in other models of injury, yet the actions of ADORA2A in macrophages remain largely unknown (25,29,(45)(46)(47)(48). Because CGS-21680 does express weak affinity for another adenosine receptor, ADORA2B (1/100 potency compared with ADORA2A), we used NECA as a nonselective AR agonist to assess the potential additional contribution of ADORA2B to the observed response in our model (11).…”

Section: Discussionmentioning

confidence: 99%

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Aggarwal¹,

D’Alessio²,

Eto³

et al. 2013

Am J Respir Cell Mol Biol

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Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting antiinflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A2/2 mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A 2/2 mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A2/2 mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A 2/2 mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A 2/2 bone marrow cells into irradiated ADORA2A2/2 mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway.

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“…Similar studies have demonstrated that activation of the A 2A R inhibits the secretion of pro-inflammatory cytokines, IL-12 and TNF-α [39]. In a rat model of small-for-size liver transplantation, A 2A R expression increased after transplantation, suppressing NF-κB activation and decreasing the expression of TNF-a, CXCL2 and cluster of differentiation 54 [CD54, also known as intercellular adhesion molecule-1 (ICAM-1)] [40]. …”

Section: Introductionmentioning

confidence: 99%

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

Chhabra¹,

Linden²,

Lobo³

et al. 2012

CDR

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Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted.

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“…Similar studies have demonstrated that activation of the A 2A R inhibits the secretion of pro-inflammatory cytokines, IL-12 and TNF- [39]. In a rat model of small-for-size liver transplantation, A 2A R expression increased after transplantation, suppressing NF-kB activation and decreasing the expression of TNF-a, CXCL2 and cluster of differentiation 54 [CD54, also known as intercellular adhesion molecule-1 (ICAM-1)] [40].…”

Section: Livermentioning

confidence: 79%

Review of Evidence that Epidemics of Type 1 Diabetes and Type 2 Diabetes/ Metabolic Syndrome are Polar Opposite Responses to Iatrogenic Inflammation

Classen¹

2012

CDR

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Activation of adenosine A 2A receptors (A 2A R) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A 2A R agonists, antagonists, A 2A R knockout as well as chimeric mice have suggested the therapeutic potential of A 2A R agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A 2A R agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A 2A R activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4 + CD25 + FoxP3 + T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A 2A R activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A 2A R agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A 2A R agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted. and promote repair via four general modes, namely, increasing oxygen supply/demand ratio, preconditioning/postconditioning [5], anti-inflammatory effects [5,[6][7] and stimulation of angiogenesis [5,8]. In vitro proliferation assays and mixed lymphocyte cultures demonstrate the ability of adenosine to decrease lymphocyte activation [9]. Adenosine receptor activation on monocytes, macrophages, and DCs has been documented to decrease the secretion of many of proinflammatory mediators including tumor necrosis factor-(TNF-), chemokine (C-C motif) ligand 3 and 4 (CCL3 and CCL4), interleukin (IL)-12, and nitric oxide (NO) [10]. While both A 2A and/or A 2B receptors have been implicated in the suppressive effects of adenosine on lymphocyte proliferation as well as cytokine production [5,7,11], the actual receptor sub-type involved in transducing the antiinflammatory signal is determined largely by the cell type, organism and model being studied [3,12]. Gs-coupled Adenosine A 2A ReceptorsA 2A Rs are found on most bone marrow-derived cells including, but not limited to, macrophages, monocytes, DCs, mast cells, eosinophils, T lymphocytes (CD4 + and CD8 + T cells), platelets, natural killer (NK) cells, natural killer T (NKT) cells and PMNLs [13][14][15][16]. Numerou...

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Activation of Adenosine A2A Receptor Attenuates Inflammatory Response in a Rat Model of Small-for-Size Liver Transplantation

Cited by 19 publications

References 23 publications

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

Review of Evidence that Epidemics of Type 1 Diabetes and Type 2 Diabetes/ Metabolic Syndrome are Polar Opposite Responses to Iatrogenic Inflammation

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