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CXCR3 and Its Ligands in a Murine Model of Obliterative Bronchiolitis: Regulation and Function¹

Benjamin D. Medoff^*,, John C. Wain^*,, Edward Seung^*, Ryan Jackobek^*, Terry K. Means^*, Leo C. Ginns, Joshua M. Farber and Andrew D. Luster^2,*

^* Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Pulmonary and Critical Care Unit, and Division of Thoracic Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; and Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Lung transplantation remains the only effective therapy for patients with end-stage lung disease, but survival is limited by the development of obliterative bronchiolitis (OB). The chemokine receptor CXCR3 and two of its ligands, CXCL9 and CXCL10, have been identified as important mediators of OB. However, the relative contribution of CXCL9 and CXCL10 to the development of OB and the mechanism of regulation of these chemokines has not been well defined. In this study, we demonstrate that CXCL9 and CXCL10 are up-regulated in unique patterns following tracheal transplantation in mice. In these experiments, CXCL9 expression peaked 7 days posttransplant, while CXCL10 expression peaked at 1 day and then again 7 days posttransplant. Expression of CXCL10 was also up-regulated in a novel murine model of lung ischemia, and in bronchoalveolar lavage fluid taken from human lungs 24 h after lung transplantation. In further analysis, we found that 3 h after transplantation CXCL10 is donor tissue derived and not dependent on IFN- or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN- and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN- and STAT1. Finally, we demonstrate that deletion of CXCR3 in recipients reduces airway obliteration. However, deletion of either CXCL9 or CXCL10 did not affect airway obliteration. These data show that in this murine model of obliterative bronchiolitis, these chemokines are differentially regulated following transplantation, and that deletion of either chemokine alone does not affect the development of airway obliteration.

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