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Peripheral Blood Neutrophil Activation Patterns Are Associated with Pulmonary Inflammatory Responses to Lipopolysaccharide in Humans¹

Edward Abraham^2,*, Jerry A. Nick^*, Tania Azam^*, Soo Hyun Kim^*, Jean-Paul Mira, Daiva Svetkauskaite^*, Qianbin He^*, Marty Zamora^*, James Murphy, Jong Sung Park^*, Katherine Overdier^* and Charles A. Dinarello^*

^* Division of Pulmonary Sciences and Critical Care Medicine and Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262; National Jewish Medical and Research Center, Denver, CO 80206; and Université René Descartes, Paris, France.

Increased nuclear accumulation of NF-B in LPS-stimulated peripheral blood neutrophils has been shown to be associated with more severe clinical course in patients with infection associated acute lung injury. Such observations suggest that differences in neutrophil response may contribute to the pulmonary inflammation induced by bacterial infection. To examine this question, we sequentially measured LPS-induced DNA binding of NF-B in neutrophils collected from healthy humans on at least three occasions, each separated by at least 2 wk, and then determined pulmonary inflammatory responses after instillation of LPS into the lungs. Consistent patterns of peripheral blood neutrophil responses, as determined by LPS-induced NF-B DNA binding, were present in volunteers, with a >80-fold difference between individuals in the mean area under the curve for NF-B activation. The number of neutrophils recovered from bronchoalveolar lavage after exposure to pulmonary LPS was significantly correlated with NF-B activation in peripheral blood neutrophils obtained over the pre-LPS exposure period (r = 0.65, p = 0.009). DNA binding of NF-B in pulmonary neutrophils also was associated with the mean NF-B area under the curve for LPS-stimulated peripheral blood neutrophils (r = 0.63, p = 0.01). Bronchoalveolar lavage levels of IL-6 and TNFRII were significantly correlated with peripheral blood neutrophil activation patterns (r = 0.75, p = 0.001 for IL-6; and r = 0.48, p = 0.049 for TNFRII. These results demonstrate that stable patterns in the response of peripheral blood neutrophils to LPS exist in the human population and correlate with inflammatory response following direct exposure to LPS in the lung.

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