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Deletion of the adenosine A2A receptor increases the survival rate in a mice model of polymicrobial sepsis

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Abstract

We aim to investigate the role of A2A receptor in peritonitis-related sepsis by injection of a fecal solution (FS) as a model of polymicrobial infection. C57/black J6 wild-type (WT) and A2A-deficient mice (A2AKO) were exposed to sepsis induced by intraperitoneal injection of a FS (FS-induced peritonitis) or instead was injected with saline buffer (Sham). Survival rate and sepsis score were measured up to 48 h. The presence of bacteria in tissue homogenates was analyzed. Telemetry and speckle laser Doppler were used for systemic blood pressure and peripheral blood perfusion analysis, respectively. Histological analysis and identification of active caspase 3 were performed in selected organs, including the liver. The survival rate of A2AKO mice exposed to FS-induced peritonitis was significantly higher, and the sepsis score was lower than their respective WT counterpart. Injection of FS increases (50 to 150 folds) the number of colonies forming units in the liver, kidney, blood, and lung in WT mice, while these effects were significantly attenuated in A2AKO mice exposed to FS-induced peritonitis. A significant reduction in both systolic and diastolic blood pressure, as well as in the peripheral perfusion was observed in WT and A2AKO mice exposed to FS-induced peritonitis. Although, these last effects were significantly attenuated in A2AKO mice. Histological analysis showed a large perivascular infiltration of polymorphonuclear in the liver of WT and A2AKO mice exposed to FS-induced peritonitis, but again, this effect was attenuated in A2AKO mice. Finally, high expression of active caspase 3 was found only in the liver of WT mice exposed to FS-induced peritonitis. The absence of the A2A receptor increases the survival rate in mice exposed to polymicrobial sepsis. This outcome was associated with both hemodynamic compensation and enhanced anti-bacterial response.

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Data availability

All data is available upon author request.

Abbreviations

A2A :

A2A adenosine receptor

ADO:

Adenosine

eNOS:

Endothelial nitric oxide synthase

IL:

Interleukins

iNOS:

Nitric oxide inducible synthase

NF- κB:

Nuclear factor κB

NO:

Nitric oxide

TNFα:

Tumor necrosis factor α

VEGF:

Endothelial growth factor

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Acknowledgments

We would like to thank the research staff of the Vascular Physiology Laboratory from the Universidad del Bío-Bío for their technical support. We also thank the researchers from the GRIVAS Health group for the outstanding discussion of the ideas presented in this manuscript.

Funding

This study was supported by Fondequip EQM140104, DIUBB 184309 4/R, and GI 171709/VC. CE is currently supported by Fondecyt Regular 1200250.

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Author notes

  1. Miguel Meriño

    Present address: Facultad de Ciencias de la Salud, Universidad Adventista de Chile, Chillan, Chile

Authors and Affiliations

  1. Vascular Physiology Laboratory, Group of Investigation in Tumor Angiogenesis (GIANT), Department of Basic Sciences, Faculty of Sciences, University of Bío-Bío, 3780000, Chillán, Chile

    Miguel Meriño, Kurt Herlitz, Felipe Troncoso, Jesenia Acurio & Carlos Escudero

  2. Biomedical Research Centre, School of Medicine, Universidad de Valparaíso, Valparaíso, Chile

    Sebastián San Martín

  3. Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillán, Chile

    Sebastián San Martín, Claudio Aguayo, Alejandro Godoy, Pablo Torres-Vergara, Marcelo Gonzalez, Jesenia Acurio & Carlos Escudero

  4. Anatomo-pathology Service, Clinical Hospital Herminda Martín, Chillán, Chile

    Pedro Sandaña

  5. Universidad Católica de la Santísima Concepción, Concepción, Chile

    Pedro Sandaña

  6. Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile

    Claudio Aguayo

  7. Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Alejandro Godoy

  8. Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago, Chile

    Alejandro Godoy

  9. Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile

    Pablo Torres-Vergara

  10. Laboratorio de Investigación Materno-Fetal (LIMaf), Department of Obstetrics and Gynecology, Faculty of Medicine, University of Concepción, Concepción, Chile

    Marcelo Gonzalez

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  1. Miguel Meriño
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Contributions

This work was carried out as collaboration among all authors. CE defined the research topic. MM and JA performed most of the experiments. SSM and PS performed immunohistochemistry and tissue analysis. KH and FT helped in the animal care and in vivo analysis. MM and CE co-wrote the manuscript. CA, MG, AG, and PT-V critically monitored experimental work and review the manuscript. All authors edited and approved the final version of the manuscript.

Corresponding author

Correspondence to Carlos Escudero.

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Conflicts of interest

Miguel Meriño declares that he has not conflict of interest.

Sebastián San Martín declares that he has not conflict of interest.

Pedro Sandaña declares that he has not conflict of interest.

Kurt Herlitz declares that he has not conflict of interest.

Claudio Aguayo declares that he has not conflict of interest.

Alejandro Godoy declares that he has not conflict of interest.

Pablo Torres-Vergara declares that he has not conflict of interest.

Marcelo Gonzalez declares that he has not conflict of interest.

Felipe Troncoso declares that he has not conflict of interest.

Jesenia Acurio declares that she has not conflict of interest.

Carlos Escudero declares that he has not conflict of interest.

Ethical approval

All the experiments were performed following the recommendations of the guidelines for the Care and Use of Laboratory Animals published by the US National Institute of Health. The Ethical Committee from the Universidad del Bio Bio (UBB) and FONDECYT (FONDECYT 1140586, Chile) approved the protocol.

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Meriño, M., Martín, S.S., Sandaña, P. et al. Deletion of the adenosine A2A receptor increases the survival rate in a mice model of polymicrobial sepsis. Purinergic Signalling 16, 427–437 (2020). https://doi.org/10.1007/s11302-020-09719-w

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