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Published online before print October 4, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0805458

Received for publication August 16, 2005.

Accepted for publication August 17, 2005.

Article

The combined CXCR1/CXCR2 antagonist CXCL8_(3-73)K11R/G31P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals

John R. Gordon ^*@, Fang Li , Xiaobei Zhang ^*, Wenjun Wang ^*, Xixing Zhao ^*, and Aarti Nayyar ^*

*Immunology Research Group, University of Saskatchewan, Saskatoon, Canada; and Department of Immunology, Dalian Medical University, Peoples Republic of China

^@ To whom correspondence should be addressed. E-mail: john.gordon{at}usask.ca.

	Abstract

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_(3-73) [CXCL8_(3-73)]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 µg/kg) were given CXCL8_(3-73)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 6 h; strong pulmonary, neutrophilic inflammation; and marked pleural hemorrhagic consolidation, as assessed at 15 h. CXCL8_(3-73)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_(3-73)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.

Key Words: inflammation • IL-8 • chemokine

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