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298 ROLE OF THE SDF-1/CXCR4 AXIS IN THE PATHOGENESIS OF LUNG INJURY AND PULMONARY FIBROSIS.
  1. J. Xu1,2,
  2. A. L. Mora1,2,3,
  3. H. Shim5,
  4. A. Stecenko1,2,3,4,
  5. K. L. Brigham1,2,3,
  6. M. Rojas1,2
  1. 1Division of Pulmonary, Allergy and Critical Care Medicine
  2. 2Center for Translational Research in the Lung
  3. 3McKelvey Center for Lung Transplantation
  4. 4Pulmonary, Allergy, Cystic Fibrosis, and Sleep, Department of Pediatrics
  5. 5Department of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA

Abstract

Recent studies demonstrated that stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 participate in recruiting stem cells from bone marrow (BM). Lung fibrogenesis may result from stem cells that home to the lung and assume a fibroblast phenotype. To determine the involvement of the SDF-1/CXCR4 axis in pulmonary fibrosis, we employed a mouse pulmonary fibrosis model resulting from intratracheal instillation of bleomycin. After bleomycin treatment, SDF-1 expression in the lung and serum SDF-1 levels increased significantly with a maximum peak at day 3 (p < .05). Immunohistochemical studies revealed that macrophages and neutrophils in the lung contributed to SDF-1 production. Bleomycin treatment also elevated BM MMP-9 activity with a peak from days 3-7, which is in parallel with serum SDF-1 levels, while CXCR4 elevation occurred at delayed time points. After treatment with bleomycin, approximately 40% of total BM stem cells were revealed as CXCR4 positive. Both SDF-1 and lung lysates from bleomycin-treated mice induced BM stem cell migration in vitro, which was blocked by CXCR4 antagonist TN14003. Treatment of bleomycin-exposed mice with TN14003 significantly attenuated lung fibrosis. SDF-1 and CXCR4 positive cells were also abundant in lungs from patients with idiopathic pulmonary fibrosis.

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