Amelioration of pathology by ELR-CXC chemokine antagonism in a swine model of airway endotoxin exposure.
Airborne organic dusts in swine confinement facilities have detrimental effects on workers health. Bacterial endotoxins (i.e., lipopolysaccharides [LPS]) that contaminate these dusts have been implicated in their pro-inflammatory effects in the airways. Exposure to such dusts induces expression of ELR-CXC chemokines (e.g., interleukin [IL]-8), prototypical neutrophil chemoattractants and activators, and neutrophilic pathology. To confirm the roles of the ELR-CXC chemokines in LPS-driven airway pathology, the authors exposed swine to bacterial LPS and tested whether blocking ELR-CXC chemokines would have beneficial effects. Delivery of the ELR-CXC chemokine antagonist CXCL8(3-74)K11R/G31P (G31P) blocked reactive oxygen intermediate production and chemotactic responses by IL-8-challenged neutrophils in vitro. In vivo, one treatment with G31P (100 microg/kg) blocked neutrophil inflammatory responses to intradermal LPS challenge for > or =2 days. It also ameliorated pathology in piglets challenged via the airway with 1 mg of Eschericia coli LPS. On physical examination the saline-treated endotoxemic animals were depressed, pyrexic, and displayed labored breathing, whereas the G31P-treated animals were bright, active, and alert and had a low-grade fever and occasional cough. The lungs of the saline-treated animals displayed evidence of pleural surface hemorrhagic consolidation, and their airways contained large numbers of neutrophils (>80%) as well as substantial amounts of tumor necrosis factor (TNF) and IL-1. The G31P treatments of the LPS-challenged piglets reduced their airway neutrophilic inflammatory responses by approximately 86% and reduced the airway TNF (approximately 70%) and IL-1 (approximately 83%) levels. These data implicates the ELR-CXC chemokines in the neutrophilic inflammation observed after airways exposure to bacterial LPS.
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada. john.gordon@usask.ca
John R
JR
Gordon
Xiaobei
X
Zhang
Fang
F
Li
Aarti
A
Nayyar
Jennifer
J
Town
Xixing
X
Zhao
D000818:Animals; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004391:Dust / Q000276:immunology; D004731:Endotoxins / Q000633:toxicity; D004781:Environmental Exposure / Q000009:adverse effects*; D007249:Inflammation / Q000276:immunology*; D016209:Interleukin-8; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000473:pathology*; D010446:Peptide Fragments; D012965:Sodium Chloride / Q000008:administration & dosage; D013552:Swine
C457773:CXCL8(3-73)K11R,G31P, bovine; D019743:Chemokines, CXC; D004391:Dust; D004731:Endotoxins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012965:Sodium Chloride