Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome
Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome
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DOI：
10.4049/jimmunol.169.2.1037
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发表时间：
2002-07-15
影响因子：
4.4
通讯作者：
Strieter, RM
中科院分区：
文献类型：
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作者：
Belperio, JA;Keane, MP;Strieter, RM
闭塞性细支气管炎综合征（BOS）是肺移植后生存的主要限制因素，其特征在于持续的细支气管周围炎症，最终导致气道纤维化/闭塞。急性排斥反应是BOS发生的主要危险因素，其特征是血管周围/细支气管白细胞浸润。这些白细胞募集的具体机制尚未阐明。CXC趋化因子（由IFN-γ（IFN-γ）/CXC趋化因子配体（CXCL）9、IP-10/CXCL 10和IFN-诱导型T细胞a化学引诱物（ITAC）/CXCL 11诱导的单核细胞因子）通过其共享受体CXCR 3发挥作用。因为它们是有效的白细胞化学引诱物，并参与其他炎症/纤维增生性疾病，我们假设这些趋化因子在同种异体反应期间的表达促进单核细胞的持续募集，导致慢性肺排斥。我们发现，人支气管肺泡灌洗液中IFN-γ/CXCL 9、IFN-诱导蛋白10（IP-10）/CXCL 10和ITAC/CXCL 11水平升高与从急性到慢性排斥反应的连续性相关。在鼠模型中的转化研究表明，与CXCR 3表达单核细胞的募集平行，CXCR 9、IP-10/CXCL 10和ITAC/CXCL 11的表达增加。CXCR 3或其配体MIG/CXCL 9和IP-10/CXCL 10的体内中和减少了表达CXCR 3的单核细胞的移植物内募集并减弱了BOS。这支持了配体/CXCR 3生物学在单核细胞的募集中起重要作用的观点，这是BOS发病机制中的关键事件。
Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival post-lung transplantation and is characterized by a persistent peribronchiolar inflammation that eventually gives way to airway fibrosis/obliteration. Acute rejection is the main risk factor for the development of BOS and is characterized by a perivascular/bronchiolar leukocyte infiltration. The specific mechanism(s) by which these leukocytes are recruited have not been elucidated. The CXC chemokines (monokine induced by IFN-gamma (MIG)/CXC chemokine ligand (CXCL)9, IP-10/CXCL10, and IFN-inducible T cell a chemoattractant (ITAC)/CXCL11) act through their shared receptor, CXCR3. Because they are potent leukocyte chemoattractants and are involved in other inflammation/fibroproliferative diseases, we hypothesized that the expression of these chemokines during an allogeneic response promotes the persistent recruitment of mononuclear cells, leading to chronic lung, rejection. We found that elevated levels of MIG/CXCL9, IFN-inducible protein 10 (IP-10)/CXCL10, and ITAC/CXCL11 in human bronchoalveolar lavage fluid were associated with the continuum from acute to chronic rejection. Translational studies in a murine model demonstrated increased expression of MIG/CXCL9, IP-10/CXCL10, and ITAC/CXCL11 paralleling the recruitment of CXCR3-expressing mononuclear cells. In vivo neutralization of CXCR3 or its ligands MIG/CXCL9 and IP-10/CXCL10 decreased intragraft recruitment of CXCR3-expressing mononuclear cells and attenuated BOS. This supports the notion that ligand/CXCR3 biology plays an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of BOS.