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

Division of Pulmonary, Allergy and Critical Care Medicine; Center for Translational Research in the Lung, McKelvey Center for Lung Transplantation, Department of Medicine; Department of Hematology/Oncology, Winship Cancer Institute; and Division of Pulmonary, Allergy, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Mauricio Rojas, Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Research of the Lung, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. E-mail: mrojas{at}emory.edu

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.

Key Words: bone marrow–derived stem cells • pulmonary fibrosis • SDF-1 • CXCR4

CLINICAL RELEVANCE In patients with idiopathic pulmonary fibrosis, there is an increase of stromal cell–derived factor-1 expression and an elevated number of CXCR4 cells, suggesting that chronic injury induces the recruitment of CXCR4+ cells that may be a perpetual source for new fibroblasts.

 

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