title: CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function.
abstract: 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-gamma or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN-gamma and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN-gamma 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.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
authors.forename: John C
authors.initials: JC
authors.lastname: Wain
authors.forename: Edward
authors.initials: E
authors.lastname: Seung
authors.forename: Ryan
authors.initials: R
authors.lastname: Jackobek
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Leo C
authors.initials: LC
authors.lastname: Ginns
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Farber
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D002464:Cell Migration Inhibition; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D008024:Ligands; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000502:physiology; D014132:Trachea / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma