Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis
Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis
复制标题
巨噬细胞分泌的 TSLP 和 MMP9 促进博莱霉素诱导的肺纤维化
DOI：
10.1016/j.taap.2019.01.011
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发表时间：
2019-03-01
影响因子：
3.8
通讯作者：
Luo, Peihua
中科院分区：
文献类型：
--
作者：
Li, Guanqun;Jin, Fuquan;Luo, Peihua
特发性肺纤维化是组织损伤修复功能障碍的病理结果，导致慢性气体交换障碍和死亡。巨噬细胞被认为在这种疾病的发病机制中起关键作用；然而，确切的机制仍然是个谜。在小鼠和大鼠实验性肺纤维化模型中，巨噬细胞的聚集早于上皮-间充质转化和纤维化，因此，我们证明巨噬细胞可能在早期参与肺纤维化的形成。在巨噬细胞与肺泡上皮细胞/成纤维细胞共培养模型中，已发现巨噬细胞可促进肺泡上皮细胞向间充质转化和成纤维细胞迁移。重要的是，我们使用蛋白质微阵列分析了博莱霉素治疗后细胞因子的变化。仅胸腺间质淋巴生成素和基质金属蛋白酶9显著升高。我们利用TSLP重组蛋白进一步证实了TSLP参与了巨噬细胞诱导的肺泡上皮细胞上皮-间充质转化。MMP9还参与巨噬细胞诱导的成纤维细胞迁移，这种迁移可以被MMP9的抑制剂逆转。总而言之，这些发现解释了巨噬细胞促进肺纤维化的潜在机制。
Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis.