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Molecular Biology

, Volume 50, Issue 2, pp 200–212 | Cite as

Adenosine A2A receptor as a drug target for treatment of sepsis

  • K. V. SivakEmail author
  • A. V. Vasin
  • V. V. Egorov
  • V. B. Tsevtkov
  • N. N. Kuzmich
  • V. A. Savina
  • O. I. Kiselev
Reviews

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.

Keywords

sepsis systemic inflammatory response syndrome adenosine adenosine A2A receptors agonists and antagonists of adenosine receptors 

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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Copyright information

© Pleiades Publishing, Inc. 2016

Authors and Affiliations

  • K. V. Sivak
    • 1
    Email author
  • A. V. Vasin
    • 1
    • 2
  • V. V. Egorov
    • 1
  • V. B. Tsevtkov
    • 1
  • N. N. Kuzmich
    • 1
  • V. A. Savina
    • 1
  • O. I. Kiselev
    • 1
  1. 1.Research Institute of InfluenzaMinistry of Health of the Russian FederationSt. PetersburgRussia
  2. 2.St. Petersburg State Polytechnical UniversitySt. PetersburgRussia

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