Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis

Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis, PMN ex press two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2, W e investigated the expression and function Of these receptors in patients w ith severe sepsis, Compared with normal donors, CXCR2 surface expression wa s down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR 1 expression persisted, In vitro migratory responses to the CXCR1 ligand, I L-8, were similar in PMN from septic patients and normal donors, By contras t, the migratory response to the CXCR2 ligands, epithelial cell-derived neu trophil activator (ENA-78) and the growth-related oncogene proteins, was ma rkedly suppressed in PMN from septic patients (p < 0.05), Ab specific for C XCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0. 05), but not to FMLP, Thus, functionally significant down-regulation of CXC R2 occurs on PMN in septic patients, We conclude that in a complex milieu o f multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemo kine receptor in patients with sepsis, These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving h ost defenses mediated by bacteria-derived peptides such as FMLP.