A2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury

Abstract

Activation of the A2A adenosine receptor (A2AR) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A2AR on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester (ATL313; 3 μg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-γ-inducible protein-10, IL-1α, IL-1-β, IL-1Rα, IL-18, IL-6, and IFN-γ), or histological criteria. ATL313, which is highly selective for the A2AR, produces more liver protection of chimeric BMT mice than 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid, which has similar affinity for the A2AR and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A2AR on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.

Therapeutic Anti-Inflammatory Effects of Myeloid Cell Adenosine Receptor A2a Stimulation in Lipopolysaccharide-Induced Lung Injury

“…LPS-induced PMN accumulation in the BAL was highest when A2a was selectively removed from leukocytes. This is consistent with the known anti-inflammatory effect of A2a on leukocytes (38). Inhalation with the selective A2a agonist ATL202 reduced LPS-induced PMN migration, microvascular permeability, and chemokine release.…”

“…In addition, activation of A2a has been implicated in mediating anti-inflammatory effects and tissue protection (19). Consistent with this, A2a gene-deficient mice exhibit enhanced ischemia reperfusion-induced tissue damage in kidney and liver (20,21). Activation of A2a by selective receptor agonists has been shown to reduce tissue damage and maintain organ function in models of cardiac (22), renal (23), and pulmonary (24) ischemia reperfusion injury.…”

“…Detrimental effects have been described in a model of cerebral ischemia where A2a activation on BM-derived cells led to increased brain tissue damage (47). However, in most other models, anti-inflammatory effects of A2a agonists predominate (38,48).…”

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

“…Accumulating data suggest that hepatic reperfusion injury can be triggered by lymphocyte activation and that the activation of the adenosine A2A-receptor (A2AR) on bone marrow-derived cells mediates liver protection [33,34]. In our model, the Cd39-null mice died rapidly after hepatic injury, most within 4 h, which suggests that a conventional CD4 + T lymphocyte pathway is unlikely given the rapid temporal relationship to the reperfusion injury.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Adenosine is an endogenous mediator that generally serves as a cytoprotective modulator in response to various stress stimuli, and the protective effects of adenosine in the setting of organ IR injury have been shown in various studies (Day, et al, 2005(Day, et al, , 2006Reece, et al, 2008;Rork, et al, 2008). Adenosine signals through 4 subtypes of the G protein-coupled receptors, A 1 R, A 2A R, A 2B R, and A 3 R, all of which are expressed in the lung.…”