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      The combined CXCR1/CXCR2 antagonist CXCL8(3-74)K11R/G31P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals.

      Journal of Leukocyte Biology

      Animals, Chemokines, CXC, pharmacology, therapeutic use, Chemotaxis, Leukocyte, drug effects, immunology, Disease Models, Animal, Dose-Response Relationship, Drug, Endotoxemia, complications, physiopathology, Female, Fever, microbiology, prevention & control, Guinea Pigs, Hemorrhage, drug therapy, Interleukin-8, Lipopolysaccharides, Lung, Neutrophil Infiltration, Neutrophils, Peptide Fragments, Pneumonia, Pulmonary Artery, Receptors, Interleukin-8A, antagonists & inhibitors, Receptors, Interleukin-8B, Time Factors, Treatment Outcome

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          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 microg/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 approximately 6 h; strong pulmonary, neutrophilic inflammation; and marked pleural hemorrhagic consolidation, as assessed at approximately 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 neutrophilia by up to 85% and 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.

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