CXCR2 is critical to hyperoxia-induced lung injury.
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.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Richard D
RD
Sue
John A
JA
Belperio
Marie D
MD
Burdick
Lynne A
LA
Murray
Ying Ying
YY
Xue
Maria C
MC
Dy
Jeffery J
JJ
Kwon
Michael P
MP
Keane
Robert M
RM
Strieter
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018496:Hyperoxia / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D020672:I-kappa B Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000473:pathology; D010100:Oxygen / Q000633:toxicity; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C515188:Cxcr3 protein, mouse; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; D000072000:NF-KappaB Inhibitor alpha; D010100:Oxygen