Amelioration of Pathology by ELR-CXC Chemokine Antagonism in a Swine Model of Airway Endotoxin Exposure

ABSTRACT

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 μg/kg) blocked neutrophil inflammatory responses to intradermal LPS challenge for ≥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 ≈86% and reduced the airway TNF (≈70%) and IL-1 (≈83%) levels. These data implicates the ELR-CXC chemokines in the neutrophilic inflammation observed after airways exposure to bacterial LPS.

KEYWORDS:

• Airway
• endotoxin
• neutrophil
• ELR-CXC chemokine
• antagonist
• G31P