Attenuation of Obliterative Bronchiolitis by a CXCR4 Antagonist in the Murine Heterotopic Tracheal Transplant Model
Received 13 March 2008; received in revised form 14 May 2008; accepted 26 August 2008.
Background
Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB), yet the mechanism for this disease is not well understood. Chemokine SDF-1 and its receptor, CXCR4, have been reported to be involved in several fibrogenic processes by recruiting inflammatory and fibroblast progenitor cells into injured tissues. We hypothesized that the SDF-1/CXCR4 axis also plays a role in the pathogenesis of OB.
Methods
Using the mouse heterotopic allogeneic airway transplant model, we transplanted mouse tracheas from BALB/c donors into C57BL/6 recipients. At Day 10 after transplant, we found high expression of SDF-1 in cells in the sub-epithelial layers of the allograft. Approximately 26% of cells infiltrating the allograft were CD45+CXCR4+, as determined by flow cytometry analysis.
Results
Treatment of the recipients with a CXCR4 antagonist, TN14003, decreased cell infiltration into the grafts at Day 10 post-implantation. At Day 42, a significant reduction in luminal occlusion was found in the TN14003-treated animals compared with controls (57.40% vs 98.21%, p < 0.01). To demonstrate the relevance of the SDF-1/CXCR4 axis in OB, sections of lung tissue obtained from lung transplant patients with OB were examined for SDF-1 and CXCR4 expression. We found a higher number of CXCR4- and SDF-1–positive cells in samples from patients with OB as compared with normal lungs.
Conclusions
These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new intervention tools for the treatment of OB.
aDivision of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia
bCenter for Translational Research in the Lung, Emory University School of Medicine, Atlanta, Georgia
cMcKelvey Center for Lung Transplantation, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
dDepartment of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
Reprint requests: Mauricio Rojas, MD, Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Research of the Lung, Emory University School of Medicine, Atlanta, GA 30322. Telephone: 404-712-2169. Fax: 404-712-2974
ABSTRACT