A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation.
Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein-coupled receptors and can regulate the host's response to sepsis. In this study, we studied the role of A(2B) adenosine receptors in regulating the mortality and inflammatory response of mice following polymicrobial sepsis. Genetic deficiency of A(2B) receptors increased the mortality of mice suffering from cecal ligation and puncture-induced sepsis. The increased mortality of A(2B) knockout mice was associated with increased levels of inflammatory cytokines and chemokines and augmented NF-kappaB and p38 activation in the spleen, heart, and plasma in comparison with wild-type animals. In addition, A(2B) receptor knockout mice showed increased splenic apoptosis and phosphatase and tensin homolog activation and decreased Akt activation. Experiments using bone-marrow chimeras revealed that it is the lack of A(2B) receptors on nonhematopoietic cells that is primarily responsible for the increased inflammation of septic A(2B) receptor-deficient mice. These results indicate that A(2B) receptor activation may offer a new therapeutic approach for the management of sepsis.
Csóka
Balázs
B
Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
Németh
Zoltán H
ZH
Rosenberger
Peter
P
Eltzschig
Holger K
HK
Spolarics
Zoltán
Z
Pacher
Pál
P
Selmeczy
Zsolt
Z
Koscsó
Balázs
B
Himer
Leonóra
L
Vizi
E Sylvester
ES
Blackburn
Michael R
MR
Deitch
Edwin A
EA
Haskó
György
G
D055371:Acute Lung Injury / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002432:Cecum; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D011677:Punctures / Q000009:adverse effects; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000502:physiology*; D018805:Sepsis / Q000382:microbiology / Q000401:mortality* / Q000517:prevention & control*; D015996:Survival Rate
D058917:Adenosine A2 Receptor Antagonists; D018836:Inflammation Mediators; D043704:Receptor, Adenosine A2B