The combined CXCR1/CXCR2 antagonist CXCL8(3-74)K11R/G31 P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals

CXC chemokine receptor 2 (CXCR2) antagonism alone can reduce neutrophil infiltration of some inflammatory sites, but the CXCR1 and CXCR2 critically regulate neutrophil responses to Glu-Leu-Arg-CXC chemokines. Herein, we assessed a combined CXCR1/CXCR2 antagonist, CXC chemokine ligand 8((3-74)) [CXCL8((3-74))]K11R/G31P, for its ability to blunt neutrophil-influx and ancillary pathology in severe endotoxemia. Guinea pigs challenged via the airways with Escherichia coli lipopolysaccharide (LPS; 5 mu g/kg) were given CXCL8(3-74)K11R/G31P (subcutaneously) before or after the onset of symptoms. The airways of the LPS-challenged animals contained high levels of endogenous pyrogens interleukin (IL)-1 and tumor necrosis factor (TNF) at 2-4 h, and the animals developed pyrexia, which peaked at approximate to 6 h; strong pulmonary, neutrophilic inflammation; and marked pleural hemorrhagic consolidation, as assessed at approximate to 15 h. CXCL8((3-74))K11R/ G31P treatment before LPS challenge reduced lung pleural hemorrhagic consolidation and airway neutrophilia by >90% and essentially abrogated the IL-1, TNF, and fever responses. When given 3 or 6 h after LPS, CXCL8((3-74))K11R/G31P reduced pulmonary nentrophifia by up to 85% anti Pleural hemorrhagic consolidation by 50-85%. The 3-h treatment reduced the 6- to 24-h fever response to background. Delays of 6 or 9 h in beginning treatment had significant effects on the fever decay curve, but only the 6-h treatment had a significant effect on the 24-h fever. These results indicate that combined CXCR1/CXCR2 antagonism can have significant therapeutic effects on Pulmonary inflammation and hemorrhage, as well as pyrexia in endotoxemic animals.