Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis.
Stromal cell-derived factor-1 (SDF-1) participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4. We studied the role of the SDF-1/CXCR4 axis in a rodent model of bleomycin-induced lung injury in C57BL/6 wild-type and matrix metalloproteinase (MMP)-9 knockout mice. After intratracheal instillation of bleomycin, SDF-1 levels in serum and bronchial alveolar lavage fluid increased. These changes were accompanied by increased numbers of CXCR4(+) cells in the lung and a decrease in a population of CXCR4(+) cells in the bone marrow that did not occur in MMP-9(-)/(-) mice. Both SDF-1 and lung lysates from bleomycin-treated mice induced migration of bone marrow-derived stem cells in vitro that was blocked by a CXCR4 antagonist, TN14003. Treatment of mice with TN14003 with bleomycin-induced lung injury significantly attenuated lung fibrosis. Lung tissue from patients with idiopathic pulmonary fibrosis had higher numbers of cells expressing both SDF-1 and CXCR4 than did normal lungs. Our data suggest that the SDF-1/CXCR4 axis is important in the complex sequence of events triggered by bleomycin exposure that eventuates in lung repair. SDF-1 participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4.
Xu
Jianguo
J
Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Mora
Ana
A
Shim
Hyunsuk
H
Stecenko
Arlene
A
Brigham
Kenneth L
KL
Rojas
Mauricio
M
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D010455:Peptides; D019718:Receptors, CXCR4; C488289:TN14003; D001761:Bleomycin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse