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Adenosine A2A receptor as a drug target for treatment of sepsis

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Abstract

Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the adenosine A2A receptor (A2AAR). The activation of this receptor, which is mediated by extracellular adenosine, manifests in almost all types of immune cells (lymphocytes, monocytes, macrophages, and dendritic cells) and results in reducing the severity of inflammation and reperfusion injury in various tissues. The activation of adenosine A2A receptor inhibits the proliferation of T cells and production of proinflammatory cytokines, which contributes to the activation of the synthesis of anti-inflammatory cytokines, thereby suppressing the systemic response. For this reason, various selective A2AAR agonists and antagonists may be considered to be drug candidates for sepsis pharmacotherapy. Nevertheless, they remain only efficient ligands and objects of pre-clinical and clinical trials. This review examines the molecular mechanisms of inflammatory response in sepsis and the structure and functions of A2AAR and its role in the pathogenesis of sepsis, as well as examples of using agonists and antagonists of this receptor for the treatment of SIRS and sepsis.

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Abbreviations

MOF:

multiple organ failure

5-LO:

5-lipoxigenase

A2AAR:

adenosine A2A receptor

AC:

adenylate cyclase

AP-1:

activator protein 1

AR:

adenosine receptor

CD:

cluster of differentiation (of lymphocytes)

CDC42:

cell division control protein 42 homolog

CEBPβ:

CCAAT-enhancer-binding protein

beta-COX-2:

cycloxygenase of type 2

CREB1:

cAMP responsive element binding protein 1

CTLA-4:

cytotoxic T-lymphocyte-associated antigen 4

CXCL:

chemokine (C-X-C motif) ligand 1

eNOS:

endothelial NO synthase

GCSF:

granulocyte colony-stimulating factor

GPCR:

G-protein-coupled receptor

ICAM-1:

intercellular adhesion molecule 1

IFN:

interferon

IL:

interleukin

iNOS:

inducible NO synthase

IP3:

inositol 3,4,5-triphosphate

MAPK:

mitogen-activated protein kinase

MCSF:

macrophage colony-stimulating factor

MOF:

multiple organ failure

NF-κB:

nuclear factor κB

NOS:

NO synthase

PAF:

platelet activating factor

PAI-1:

plasminogen activator inhibitor-1

PDZ-GEF1:

guanine nucleotide exchange factor containing PDZ-domain

PGE2:

prostaglandin E2

PI3K:

phosphoinositide 3-kinase

PIP2:

phosphatidylinositol 4,5-diphosphate

PKA:

protein kinase A

PKB (or Akt):

protein kinase B

PKC-zeta:

protein kinase С-zeta

SIRS:

systemic inflammatory response syndrome

SUMO-1:

small ubiquitin-related modifier 1

TF:

tissue factor III (thromboplastin)

TGF-β:

transforming growth factor beta

TLRs:

Toll-like receptors

TNF-α:

tumor necrosis factor α

TRAX:

translin-associated factor X

USP4:

ubiquitin specific protease 4

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Authors and Affiliations

  1. Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, 197376, Russia

    K. V. Sivak, A. V. Vasin, V. V. Egorov, V. B. Tsevtkov, N. N. Kuzmich, V. A. Savina & O. I. Kiselev

  2. St. Petersburg State Polytechnical University, St. Petersburg, 195251, Russia

    A. V. Vasin

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  1. K. V. Sivak
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  2. A. V. Vasin
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  3. V. V. Egorov
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  4. V. B. Tsevtkov
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Correspondence to K. V. Sivak.

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Original Russian Text © K.V. Sivak, A.V. Vasin, V.V. Egorov, V.B. Tsevtkov, N.N. Kuzmich, V.A. Savina, O.I. Kiselev, 2016, published in Molekulyarnaya Biologiya, 2016, Vol. 50, No. 2, pp. 231–245.

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Sivak, K.V., Vasin, A.V., Egorov, V.V. et al. Adenosine A2A receptor as a drug target for treatment of sepsis. Mol Biol 50, 200–212 (2016). https://doi.org/10.1134/S0026893316020230

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