BACKGROUND & AIMS:
: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.
背景与目标:
:肺移植仍然是终末期肺部疾病患者的唯一有效疗法,但存活率因闭塞性细支气管炎(OB)的发展而受到限制。趋化因子受体CXCR3及其两个配体CXCL9和CXCL10被确定为OB的重要介体。但是,CXCL9和CXCL10对OB发育的相对贡献以及这些趋化因子的调节机制尚未明确。在这项研究中,我们证明小鼠气管移植后,CXCL9和CXCL10以独特的模式上调。在这些实验中,CXCL9表达在移植后7天达到峰值,而CXCL10表达在移植后1天达到峰值,然后在移植后7天再次达到峰值。 CXCL10的表达在新型小鼠肺缺血模型中以及在肺移植后24小时取自人肺的支气管肺泡灌洗液中也上调。在进一步的分析中,我们发现移植后3小时CXCL10是来自供体组织,而不依赖于IFN-γ或STAT1,而移植后24小时CXCL10来自受体组织,并受IFN-γ和STAT1调节。移植后7天CXCL9和CXCL10的表达均受IFN-γ和STAT1的调节。最后,我们证明了受体中CXCR3的缺失减少了气道闭塞。但是,删除CXCL9或CXCL10不会影响气道闭塞。这些数据表明,在这种小鼠的闭塞性细支气管炎模型中,这些趋化因子在移植后受到不同的调节,并且单独删除任一趋化因子均不会影响气道闭塞的发展。