Inhibition of Cell Apoptosis and Amelioration of Pulmonary Fibrosis by Thrombomodulin
Inhibition of Cell Apoptosis and Amelioration of Pulmonary Fibrosis by Thrombomodulin
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DOI：
10.1016/j.ajpath.2017.06.013
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发表时间：
2017-10-01
影响因子：
6
通讯作者：
Gabazza, Esteban C.
中科院分区：
文献类型：
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作者：
Fujiwara, Kentaro;Kobayashi, Tetsu;Gabazza, Esteban C.
肺纤维化是一组特发性间质性肺炎的末期，其中特发性肺纤维化是最常见和致命的形式。最近的研究表明，重组人血栓调节蛋白（rhTM）可改善特发性肺纤维化的恶化和临床结果，但其机制仍不清楚。本研究评估了 rhTM 在肺纤维化中的抑制活性的机制途径。过度表达人类转化生长因子-β1（自发性肺纤维化）的转基因小鼠和用博来霉素治疗的野生型小鼠被用作肺纤维化模型。 rhTM 通过腹腔注射给予小鼠。注射或通过鼻内途径。 rhTM治疗显着降低了高迁移率族蛋白1、干扰素-γ和纤溶标记物的浓度，以及包括转化生长因子-β1在内的生长因子的表达，以及肺纤维化程度。 rhTM 在体内和体外实验中显着抑制肺上皮细胞的凋亡。本研究结果表明rhTM可以抑制博来霉素诱导的肺纤维化和转化生长因子-M。导致肺纤维化的恶化和进展，除了其众所周知的抗凝和抗炎特性外，rhTM还可以抑制肺上皮细胞的凋亡。
Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin (rhTM) improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of rhTM in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor-beta 1 that develop spontaneously pulmonary fibrosis, and wild-type mice treated with bleomycin were used as models of lung fibrosis. rhTM was administered to mice by i.p. injection or by the intranasal route. Therapy with rhTM significantly decreased the concentration of high mobility group box1, interferon-gamma, and fibrinolytic markers, the expression of growth factors including transforming growth factor-beta 1, and the degree of Lung fibrosis. rhTM significantly suppressed apoptosis of Lung epithelial cells in in vivo and in vitro experiments. The results of the present study demonstrated that rhTM can inhibit bleomycin-induced pulmonary fibrosis and transforming growth factor-M. driven exacerbation and progression of pulmonary fibrosis, and that apart from its well-recognized anticoagulant and anti-inflammatory properties, rhTM can also suppress apoptosis of lung epithelial cells.