CXC-chemokine stimulation of neutrophils correlates with plasma levels of myeloperoxidase and lactoferrin and contributes to clinical outcome after pediatric cardiac surgery

Abstract

Several CXC-chemokines, of which interleukin (IL)-8 is the prototype, are potent neutrophil chemotactic and activating cytokines, inducing the secretion of granule proteins and the generation of reactive oxygen intermediates that may cause tissue damage and amplify inflammatory responses. Here, we investigated whether chemokines play a key role in the inflammatory process following cardiac surgery with cardiopulmonary bypass (CPB) in children. We performed an observational prospective clinical study of 40 pediatric patients before, during, and after open heart surgery with CPB. Plasma levels of chemokines, myeloperoxidase (MPO), and lactoferrin were measured by immunoassays. Cell surface receptors were detected by flow cytometry. Plasma levels of IL-8 were increased after CPB, correlating strongly with a reduction of expression of the CXC-chemokine receptors (CXCR) 1 and 2 on neutrophils indicating in vivo activation of neutrophils by IL-8. Other CXC-chemokines with Glu-Leu-Arg motif showed no correlation with CXCR1 or CXCR2 expression. Two components of neutrophilic granules, MPO and lactoferrin, were strongly elevated postoperatively, and the levels of both were correlated with IL-8. Levels of monocyte chemoattractant protein (MCP)-1 were increased postoperatively, correlating with a reduction of CCR2 expression and an increase of CD11b expression on monocytes, suggesting monocyte activation by MCP-1. The early postoperative course was complicated in patients with an increase of these inflammatory parameters. Impaired cardiovascular function correlated with increased levels of IL-8 and activation of neutrophils and was most prominent in patients with a long time on CPB and in those with cyanotic heart lesions. In conclusion, MCP-1 is involved in the regulation of chemotaxis and function of monocytes during and early after the end of CPB. Activation of neutrophils and down-regulation of CXCR1 and CXCR2 were predominantly caused by IL-8. This activation implies release of components of neutrophilic granules and correlates with the need for inotropic support.