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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Cell Movement / genetics
-
Cell Movement / immunology
-
Chemokine CXCL1
-
Chemokines, CXC / biosynthesis
-
Chemokines, CXC / genetics
-
Dose-Response Relationship, Drug
-
Hyperoxia / immunology*
-
Hyperoxia / metabolism
-
Hyperoxia / mortality
-
Hyperoxia / pathology*
-
I-kappa B Proteins / metabolism
-
Intercellular Signaling Peptides and Proteins / biosynthesis
-
Intercellular Signaling Peptides and Proteins / genetics
-
Ligands
-
Lung / immunology*
-
Lung / metabolism
-
Lung / pathology*
-
Lung / 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
-
Receptors, Chemokine / genetics
-
Receptors, Interleukin-8B / biosynthesis
-
Receptors, Interleukin-8B / deficiency
-
Receptors, Interleukin-8B / genetics
-
Receptors, Interleukin-8B / physiology*
-
Signal Transduction / genetics
-
Signal Transduction / immunology
-
Up-Regulation / immunology
Substances
-
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