Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltration
Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltration
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DOI：
10.2353/ajpath.2007.051213
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发表时间：
2007-03-01
影响因子：
6
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Ishida, Yuko;Kimura, Akihiko;Mukaida, Naofumi
我们研究了CC趋化因子配体（CCL）3及其受体CC趋化因子受体（CCR）1和CCR5在博来霉素（BLM）诱导的肺纤维化（PF）中的致病作用。野生型（WT）小鼠气管内注射BLM可引起大量粒细胞和巨噬细胞浸润，随后发展为弥漫性PF并伴有纤维细胞积聚。肺内CCL3表达迅速增强，并保持在高水平，直到PF发展。CCL3蛋白主要在浸润性粒细胞和巨噬细胞中检测到，而转化生长因子- β 1蛋白在巨噬细胞和肌成纤维细胞中检测到。与WT小鼠相比，ccr3（-/-）和CCR5（-/-）小鼠的胶原积累减少，但CCR1（-/-）小鼠的胶原积累没有减少。此外，BLM诱导的CCL3（-/-）和CCR5（-/-）小鼠肺内巨噬细胞和纤维细胞数量的增加在ccr3（-/-）和CCR5（-/-）小鼠中减弱，但在CCR1（-/-）小鼠中没有减弱，尽管BLM在这些菌株BM从CCR5（-/-）移植到WT中增加骨髓（BM）纤维细胞数量的程度相似，但从NW到CCR5（-/-）小鼠没有重现CCR5-/-小鼠的表型。此外，CCR5（-/-）小鼠在blm诱导的纤维化变化中表现出显著减少。这些结果表明，局部产生的CCL3主要通过与CCR5相互作用，参与了blm诱导的bm来源的巨噬细胞和纤维细胞（转化生长因子- β 1的主要产生者）的募集，以及随后的PF的发展。
we investigated the pathogenic roles of CC chemokine ligand (CCL)3 and its receptors, CC chemokine receptor (CCR)1 and CCR5, in bleomycin (BLM)-induced pulmonary fibrosis (PF). An intratracheal injection of BLM into wild-type (WT) mice caused a massive infiltration of granulocytes and macrophages, followed by the development of diffuse PF with fibrocyte accumulation. Intrapulmonary CCL3 expression was enhanced rapidly and remained at elevated levels until PF developed. Moreover, CCL3 protein was detected mainly in infiltrating granulocytes and macrophages, whereas transforming growth factor-beta 1 protein was detected in macrophages and myofibroblasts. Compared with WT mice, collagen accumulation was reduced in CCL3(-/-) and CCR5(-/-) but not CCR1(-/-) mice. Moreover, the BLM-induced increases in intrapulmonary macrophage and fibrocyte numbers were attenuated in CCL3(-/-) and CCR5(-/-) but not CCR1(-/-) mice, although BLM increased bone marrow (BM) fibrocyte number to a similar extent in these strains BM transplantation from CCR5(-/-) to WT, but not that from NW to CCR5(-/-) mice recapitulated the phenotypes in CCR5-/- mice. Furthermore, CCR5(-/-) mice exhibited a significant reduction in BLM-induced fibrotic changes. These results demonstrated that locally produced CCL3 was involved in BLM-induced recruitment of BM-derived macropharges and fibrocytes, main producers of transforming growth factor-beta 1, and subsequent development of PF by interacting mainly with CCR5.