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Functional Significance of CXCR2 Downregulation on Neutrophils From Patients With Severe Sepsis* FREE TO VIEW

R. Goodman, MD; C. Cummings; C. Frevert; J. Quan, MD; T. Martin, MD, FCCP
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*From the Seattle Veterans Affairs Medical Center, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA

Correspondence to Richard Goodman, MD, VA Medical Center, Pulmonary 111B, 1660 S. Columbian Way, Seattle, WA 98108

Chest. 1999;116(suppl_1):111S-112S. doi:10.1378/chest.116.suppl_1.111S-a
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Sepsis remains a common risk factor for the development of ARDS. Neutrophils are important participants in the acute lung injury process. However, multiple CXC chemokines are present in the lung fluids of patients with ARDS, including interleukin-8 (IL-8), epithelial neutrophil activating protein-78, and growth-related oncogene-α, all of which are potent and specific chemoattractants for polymorphonuclear leukocytes (PMNs). Thus, the predominant mechanisms for PMN recruitment in ARDS remain unclear. PMNs express two cell surface receptors for the CXC chemokines. IL-8 binds both CXCR1 and CXCR2 with high affinity, whereas the other CXC chemokines bind with high affinity to only CXCR2. In vitro, stimulation of normal PMNs with IL-8 results in internalization of both receptors. However, CXCR1 is rapidly reexpressed, whereas CXCR2 reexpression is considerably slower. We sought to investigate the effect of these mechanisms in vivo, with PMNs from patients with severe sepsis. By flow cytometry, CXCR2 expression was downregulated by 50% in patients with sepsis (n = 14) relative to normal donors (n = 8) (p < 0.003), while CXCR1 expression was not significantly reduced. In vitro, the migratory response toward IL-8 was similar in PMNs from patients with sepsis and normal donors. By contrast, the migratory response to the other CXC chemokines, epithelial neutrophil activating protein-78, growth-related gene-α, -β, -γ, which bind only CXCR2, was markedly suppressed in PMNs from patients with sepsis compared with normal PMNs (p < 0.05). Polyclonal antibody specific for CXCR1 substantially inhibited in vitro migration of PMNs from patients with sepsis compared with normal donors (p < 0.05). As expected, antibody inhibition of CXCR1 did not affect PMN migration to the bacterial-derived chemoattractant, formyl-methionyl-leucyl-phenylalanine, whose signal is mediated by a distinct receptor. Thus, we demonstrate that CXCR2 is downregulated to a functionally significant degree in PMNs from patients with sepsis. We speculate that despite a redundant system of CXC chemokines and receptors, IL-8 and CXCR1 function as the dominant ligand/receptor pair in patients with sepsis. These observations are relevant to therapeutic strategies aimed at attenuating host-mediated acute inflammation, while potentially preserving host defenses mediated by bacterial-derived peptides such as formyl-methionyl-leucyl-phenylalanine.




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