A2B Adenosine Receptors Protect against Sepsis-Induced Mortality by Dampening Excessive Inflammation

被引:119
作者
Csoka, Balazs [1 ]
Nemeth, Zoltan H. [1 ,2 ]
Rosenberger, Peter [3 ]
Eltzschig, Holger K. [4 ]
Spolarics, Zoltan [1 ]
Pacher, Pal [5 ]
Selmeczy, Zsolt [1 ]
Koscso, Balazs [1 ]
Himer, Leonora [1 ,6 ]
Vizi, E. Sylvester [6 ]
Blackburn, Michael R. [8 ]
Deitch, Edwin A. [1 ]
Hasko, Gyoergy [1 ,7 ]
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA
[2] Morristown Mem Hosp, Dept Surg, Morristown, NJ 07960 USA
[3] Goethe Univ Frankfurt, Dept Anesthesiol & Intens Care Med, Univ Hosp Frankfurt Main, Frankfurt, Germany
[4] Univ Colorado, Mucosal Inflammat Program, Dept Anesthesiol, Denver, CO 80045 USA
[5] NIAAA, Bethesda, MD 20892 USA
[6] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, Budapest, Hungary
[7] Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, Debrecen, Hungary
[8] Univ Texas Houston Med Sch, Dept Biochem & Mol Biol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
MURINE SEPTIC PERITONITIS; KAPPA-B; IMMUNE-RESPONSE; HEPATIC-INJURY; TISSUE-DAMAGE; KNOCKOUT MICE; MACROPHAGES; DYSFUNCTION; ACTIVATION; SURVIVAL;
D O I
10.4049/jimmunol.0901295
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B 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. The Journal of Immunology, 2010, 185: 542-550.
引用
收藏
页码:542 / 550
页数:9
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