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(American Journal of Pathology. 2004;165:2187-2196.)
© 2004 American Society for Investigative Pathology

Novel Chemokine Responsiveness and Mobilization of Neutrophils during Sepsis

Cecilia L. Speyer^*, Hongwei Gao^*, Nicholas J. Rancilio^*, Thomas A. Neff^*, Gary B. Huffnagle, J. Vidya Sarma^* and Peter A. Ward^*

From the Department of Pathology^* and the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Blood neutrophils (PMN) are usually unresponsive to CC chemokines such as monacyte chemotactic protein-1 and macrophage inflammatory protein-1. In rodents, the lung buildup of PMN as determined by myeloperoxidase (MPO) activity after airway instillation of bacterial lipopolysaccharide (LPS) was independent of MCP-1 and MIP-1. In striking contrast, during sepsis following cecal ligation and puncture (CLP), blood PMN demonstrated mRNA for CC chemokine receptors. Furthermore, PMN from CLP, but not from sham rodents, bound MCP-1 and MIP-1 and responded chemotactically in vitro to both MCP-1 and MIP-1. In CCR2^–/– mice or WT mice treated in vivo with antibodies to either MCP-1 or MIP-1, MPO activity was greatly attenuated in CLP animals. In CLP mice, increased serum IL-6 levels were found to be dependent on CCR2, MCP-1, and MIP-1. When PMN from CLP rodents were incubated in vitro with either MCP-1 or MIP-1, release of IL-6 was also shown. These findings suggest that sepsis fundamentally alters the trafficking of PMN into the lung in a manner that now engages functional responses to CC chemokines.

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