Role of the SDF-1/CXCR4 Axis in the Pathogenesis of Lung Injury and Fibrosis

Am J Respir Cell Mol Biol. 2007 Sep;37(3):291-9. doi: 10.1165/rcmb.2006-0187OC. Epub 2007 Apr 26.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Movement / physiology
  • Chemokine CXCL12 / metabolism*
  • Female
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • In Vitro Techniques
  • Lung / drug effects
  • Lung / metabolism
  • Lung Injury*
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / pharmacology
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*

Substances

  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Peptides
  • Receptors, CXCR4
  • TN14003
  • Bleomycin
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse