Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A(2B)R signaling

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5’ triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A(2B)R. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A(2B)Rs in regulating the host’s response to T/HS. METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A(2B)R) and conditional knockout (intestinal epithelial cell-specific deficient Villin(Cre)-A(2B)R(fl/fl)) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury. RESULTS: T/HS upregulated the expression of CD39, CD73, and the A(2B)R in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A(2B)R mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A(2B)R knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and A(2B)R KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient Villin(Cre)-A(2B)R(fl/fl) mice showed increased intestinal injury compared to their wild-type Villin(Cre) controls. CONCLUSION: In conclusion, the CD39-CD73-A(2B)R axis protects against T/HS-induced multiple organ failure. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02486-3.