Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A2BR signaling

Taha Kelestemur; Zoltán H Németh; Pal Pacher; Jennet Beesley; Simon C Robson; Holger K Eltzschig; György Haskó

doi:10.1186/s12931-023-02486-3

Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A_2BR signaling

Respir Res. 2023 Jul 13;24(1):186. doi: 10.1186/s12931-023-02486-3.

Authors

Taha Kelestemur^{1

2}, Zoltán H Németh^{1

3}, Pal Pacher⁴, Jennet Beesley⁵, Simon C Robson⁶, Holger K Eltzschig⁷, György Haskó⁸

Affiliations

¹ Department of Anesthesiology, Columbia University, 630 W 168th Street, New York City, NY, 10032, USA.
² Department of Physiology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey.
³ Department of Surgery, Morristown Medical Center, Morristown, NJ, 07960, USA.
⁴ Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
⁵ Daresbury Proteins Ltd, Sci-Tech Daresbury, Warrington, UK.
⁶ Department of Anesthesia, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷ Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸ Department of Anesthesiology, Columbia University, 630 W 168th Street, New York City, NY, 10032, USA. gh2503@cumc.columbia.edu.

Abstract

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_2BR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A_2BRs 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_2BR) and conditional knockout (intestinal epithelial cell-specific deficient Villin^Cre-A_2BR^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_2BR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A_2BR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A_2BR 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_2BR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient Villin^Cre-A_2BR^fl/fl mice showed increased intestinal injury compared to their wild-type Villin^Cre controls.

Conclusion: In conclusion, the CD39-CD73-A_2BR axis protects against T/HS-induced multiple organ failure.

Keywords: A2BR; Acute lung injury; Adenosine; CD39; CD73; Trauma hemorrhagic shock.

MeSH terms

Adenosine Triphosphate
Adenosine*
Animals
Bronchoalveolar Lavage Fluid
Mice
Multiple Organ Failure*
Signal Transduction

Substances

Adenosine
Adenosine Triphosphate

Abstract

MeSH terms

Substances

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