Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome
Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome
复制标题
DOI：
10.1172/jci12214
复制
发表时间：
2001-08-01
影响因子：
15.9
通讯作者：
Strieter, RM
中科院分区：
文献类型：
--
作者：
Belperio, JA;Keane, MP;Strieter, RM
闭塞性细支气管炎综合征（BOS）是肺移植术后生存的主要限制因素。急性排斥反应是其主要危险因素，其特征是血管周围/细支气管白细胞浸润。BOS的特点是持续的细支气管周围白细胞聚集导致气道纤维化和闭塞。这些白细胞募集的具体机制尚不清楚。由于MCP-1通过其受体CCR2起作用，是一种有效的单核细胞趋化剂，我们假设在异体反应中表达这种趋化因子可促进白细胞的持续募集，并最终导致排斥反应。我们发现，人支气管灌洗液（BALF）中生物活性MCP-1水平升高与急性到慢性同种异体移植排斥反应的连续性有关。小鼠BOS模型的翻译研究表明MCP-1表达增加与单核细胞募集和CCR2表达平行。在CCR2（-/-）小鼠或使用MCP-1中和抗体处理的WT小鼠中，MCP-1/CCR2信号的丢失显著减少了气管移植后单核吞噬细胞的募集，并导致BOS的衰减。淋巴细胞浸润在这些条件下没有减少。我们认为MCP-1/CCR2信号在单核吞噬细胞的募集中起重要作用，这是BOS发病的关键事件。
Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2(-/-) mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.