title: The combined CXCR1/CXCR2 antagonist CXCL8(3-74)K11R/G31P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals.
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(3-74) [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.
authors.affiliation: Immunology Research Group, Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada S7N 5B4. john.gordon@usask.ca
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.forename: Xixing
authors.initials: X
authors.lastname: Zhao
authors.forename: Aarti
authors.initials: A
authors.lastname: Nayyar
mesh_terms: D000818:Animals; D019743:Chemokines, CXC / Q000494:pharmacology* / Q000627:therapeutic use; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005334:Fever / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D006168:Guinea Pigs; D006470:Hemorrhage / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D016209:Interleukin-8; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C457773:CXCL8(3-73)K11R,G31P, bovine; D019743:Chemokines, CXC; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B