Effects of pharmacological inactivation of adenosine 2A receptors in a murine model of polymicrobial sepsis
Helbig, Brian John
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Sepsis is a worldwide health problem with an enormous economic burden and devastatingly high mortality rate. The pathophysiology and immune dysfunctions that occur during sepsis remain largely unknown, severely limiting current treatment options for sepsis. Both the innate and adaptive parts of the immune system are known to be involved in the dysfunctions that occur during sepsis. Over the last few years adenosine has been recognized as an endogenous mediator that alters both innate and adaptive immune responses. Adenosine receptors are largely expressed on many different immune cells and may serve to limit excess collateral damage in the setting of inflammation. In this study, the pharmacological effects of an A2A receptor antagonist on septic mice were examined using the CLP model of sepsis that results in a polymicrobial infection. Pharmacological inactivation of the A2A receptor significantly increased mortality in septic mice predicted to live in comparison to those given only vehicle. Treatment with the A2A receptor antagonist also increased expression of CD40, part of a pathway well known for its roles in inflammation. Our data also showed increased monocyte MHCII expression after treatment with an adenosine antagonist. Our data support the role that A2A receptors are involved in the immune response to sepsis, and that these receptors may serve to damage excess collateral damage ensuing from the host immune response, and that additional studies on adenosine and its related purine nucleosides would be of use for better understanding of the immune dysfunctions that occur during sepsis and other diseases.