CXCR2 is critical to hyperoxia-induced lung injury.

Abstract

Hyperoxia-induced lung injury is characterized by infiltration of activated neutrophils in conjunction with endothelial and epithelial cell injury, followed by fibrogenesis. Specific mechanisms recruiting neutrophils to the lung during hyperoxia-induced lung injury have not been fully elucidated. Because CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil chemoattractants, we investigated their role in mediating hyperoxia-induced lung injury. Under variable concentrations of oxygen, murine survival during hyperoxia-induced lung injury was dose dependent. Eighty percent oxygen was associated with 50% mortality at 6 days, while greater oxygen concentrations were more lethal. Using 80% oxygen, we found that lungs harvested at day 6 demonstrated markedly increased neutrophil sequestration and lung injury. Expression of CXCR2 ligands paralleled neutrophil recruitment to the lung and CXCR2 mRNA expression. Inhibition of CXC chemokine ligands/CXCR2 interaction using CXCR2(-/-) mice exposed to hyperoxia significantly reduced neutrophil sequestration and lung injury, and led to a significant survival advantage as compared with CXCR2(+/+) mice. These findings demonstrate that CXC chemokine ligand/CXCR2 biological axis is critical during the pathogenesis of hyperoxia-induced lung injury.

• Authors: Richard D Sue, John A Belperio, Marie D Burdick, Lynne A Murray, Ying Ying Xue, Maria C Dy, Jeffery J Kwon, Michael P Keane, Robert M Strieter
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 172 Issue 6 Pg. 3860-8 (Mar 15 2004) ISSN: 0022-1767 [Print] United States
• PMID: 15004193 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokine CXCL1
• Chemokines, CXC
• Cxcl1 protein, mouse
• Cxcr3 protein, mouse
• I-kappa B Proteins
• Intercellular Signaling Peptides and Proteins
• Ligands
• NF-kappa B
• Nfkbia protein, mouse
• RNA, Messenger
• Receptors, CXCR3
• Receptors, Chemokine
• Receptors, Interleukin-8B
• NF-KappaB Inhibitor alpha
• Oxygen

Topics

• Animals
• Cell Movement (genetics, immunology)
• Chemokine CXCL1
• Chemokines, CXC (biosynthesis, genetics)
• Dose-Response Relationship, Drug
• Hyperoxia (immunology, metabolism, mortality, pathology)
• I-kappa B Proteins (metabolism)
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics)
• Ligands
• Lung (immunology, metabolism, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors)
• Neutrophils (pathology)
• Oxygen (toxicity)
• Phosphorylation
• RNA, Messenger (biosynthesis)
• Receptors, CXCR3
• Receptors, Chemokine (biosynthesis, genetics)
• Receptors, Interleukin-8B (biosynthesis, deficiency, genetics, physiology)
• Signal Transduction (genetics, immunology)
• Up-Regulation (immunology)