Protection from ischemic liver injury by activation of A_2Aadenosine receptors during reperfusion: inhibition of chemokine induction

Abstract

Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 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 (ATL146e), a selective agonist of the A2A adenosine receptor (A2AAR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A2AAR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1α, IL-1β, IL-1Ra, IL-6, IL-10, IL-18, INF-β, INF-γ, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1α, MIP-2, IFN-γ-inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A2AAR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A2AAR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A2AAR agonist ATL146e.

Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

“…The decreased neutrophil migration in the lung is believed to be related to the anti-inflammatory properties of CGS-21680 in the treated groups (41,42). Furthermore, the transient higher MAP values observed in the CGS-21680-treated animals may be due to preserved vascular integrity for a given amount of fluids infused in all animals.…”

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

“…56 Indeed, a serious of previous investigations from the laboratory of Dr. Okusa had shown that activation of Adora2a receptors on T cells provides protection during acute ischemic kidney disease. 2,3,21,22,57,58 As such, it is conceivable that Adora2a receptors expressed on inflammatory cells and vascular Adora2b receptors function together to protect the kidneys during diabetic nephropathy.…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]). A 2A R agonists were even named Bthe most potent anti-inflammatory drug known to mankind.^Ac-cordingly, activation of A 2A Rs has been shown to confer a robust protection against tissue damage from ischemiaYreperfusion injury in different organ such as heart [297Y299], blood vessels [300], kidney [301,302], liver [303,304], lung [305,306], joints [307], skin [308,309], and even in the spinal cord [310,311] and in the brain following hemorrhage [312] or acute infection [313]. Thus, it is the activation (rather the blockade) of A 2A Rs that confers protection against damage triggered by inflammation in peripheral tissues, precisely the opposite of what is observed in the damaged adult brain.…”