Our previous work has shown that polymorphonuclear neutrophils (PMNs) require cellular adenosine triphosphate (ATP) release and autocrine purinergic signaling for their activation. Here we studied in a mouse model of cecal ligation and puncture (CLP) whether sepsis affects this purinergic signaling process and thereby alters PMN responses after sepsis. Using high-performance liquid chromatography, we found that plasma ATP, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) concentrations increased up to 6-fold during the first 8 h after CLP, reaching top levels that were significantly higher than those in sham control animals without CLP. Although leukocyte and PMN counts in sham animals increased significantly after 4 h, these blood cell counts decreased in sepsis animals. CD11b expression on the cell surface of PMNs of septic animals was significantly higher compared with sham and untreated control animals. These findings suggest increased PMN activation and sequestration of PMN from the circulation after sepsis. Plasma ATP levels correlated with CD11b expression, suggesting that increased ATP concentrations in plasma contribute to PMN activation. We found that treatment of septic mice with the ATP receptor antagonist suramin diminished CD11b expression, indicating that plasma ATP contributes to PMN activation by stimulating P2 receptors of PMNs. Increased PMN activation can protect the host from invading microorganisms. However, increased PMN activation can also be detrimental by promoting secondary organ damage. We conclude that pharmacological targeting of P2 receptors may allow modulation of PMN responses in sepsis.
*Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; †Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, Chiba, Japan; ‡Department of Anesthesiology, Ludwig Maximilian University, Munich, Germany; and §Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
Received 24 Jan 2014; first review completed 10 Feb 2014; accepted in final form 18 Mar 2014
Address reprint requests to Yuka Sumi MD, PhD, Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, Chiba, Japan. E-mail: firstname.lastname@example.org.
Co-correspondence: Wolfgang Junger, PhD, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. E-mail: email@example.com.
This study was supported by the Japan Society for the Promotion of Science (grant no. 23792086 to Y.S.) and by the National Institutes of Health (grant nos. GM-51477, GM-60475, AI-072287, and AI-080582 to W.G.J.).
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