Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.
Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.
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DOI：
10.1186/s12931-017-0660-4
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发表时间：
2017-10-16
影响因子：
5.8
通讯作者：
West J
中科院分区：
文献类型：
--
作者：
Suzuki T;Tada Y;Gladson S;Nishimura R;Shimomura I;Karasawa S;Tatsumi K;West J
肺纤维化是急性呼吸窘迫综合征（ARDS）的晚期表现。脓毒症是ARDS的主要原因，其发病机制包括内毒素诱导的血管损伤。近年来，内皮细胞向间质细胞转化（EndMT）在肺纤维化中发挥重要作用。另一方面，据报道，二肽基肽酶（DPP）-4在实验性脓毒症模型中改善血管功能障碍，尽管DPP-4是否影响内毒素（LPS）诱导的肺损伤期间的EndMT和纤维化起始尚不清楚。本研究的目的是研究DPP-4抑制剂vildagelide在全身性内毒素血症损伤后肺纤维化中的抗EndMT作用。采用腹腔注射脂多糖（LPS）（5 mg/kg，连续5d）建立8周龄雄性小鼠脓毒性肺损伤模型。然后用载体或维格鲁肽处理小鼠（腹膜内，10 mg/kg，从第一次给予LPS前1天开始，每天一次，连续14天）。使用流式细胞术、免疫组织化学染色和定量聚合酶链反应（qPCR）分析来评估来自小鼠的肺样品中的细胞动力学和EndMT功能。LPS攻击后2天和28天，治疗组小鼠的肺组织样品显示明显的炎症反应和典型的间质纤维化。流式细胞术定量分析显示，LPS刺激后28天，表达α-平滑肌肌动蛋白（α-SMA）或S100钙结合蛋白A4（S100 A4）的肺血管内皮细胞（PVEC）数量增加。通过来自分离的PVEC的mRNA的qPCR也证实了类似的表达增加。EndMT细胞的增殖活性和迁移活性高于间充质细胞。腹腔注射维地奈德可减轻上述变化。有趣的是，在不存在免疫细胞或GLP-1的情况下，维格鲁肽和利格列汀显著减弱EndMT。在系统性LPS诱导的肺损伤中，通过抑制DPP-4信号转导，可以通过下调EndMT来改善肺纤维化。本文的在线版本（10.1186/s12931-017-0660-4）包含补充材料，可供授权用户使用。
Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor vildagliptin in pulmonary fibrosis after systemic endotoxemic injury. A septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice (5 mg/kg for five consecutive days). The mice were then treated with vehicle or vildagliptin (intraperitoneally, 10 mg/kg, once daily for 14 consecutive days from 1 day before the first administration of LPS.). Flow cytometry, immunohistochemical staining, and quantitative polymerase chain reaction (qPCR) analysis was used to assess cell dynamics and EndMT function in lung samples from the mice. Lung tissue samples from treated mice revealed obvious inflammatory reactions and typical interstitial fibrosis 2 days and 28 days after LPS challenge. Quantitative flow cytometric analysis showed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Similar increases in expression were also confirmed by qPCR of mRNA from isolated PVECs. EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Interestingly, vildagliptin and linagliptin significantly attenuated EndMT in the absence of immune cells or GLP-1. Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury. The online version of this article (10.1186/s12931-017-0660-4) contains supplementary material, which is available to authorized users.
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影响因子：
11.5
作者：
Choi, Seo-Hyun;Hong, Zhen-Yu;Lee, Yoon-Jin
通讯作者：
Lee, Yoon-Jin
DOI：
10.1007/s004290050070
发表时间：
1997-06-01
期刊：
ANATOMY AND EMBRYOLOGY
影响因子：
--
作者：
Maric, C;Ryan, GB;Alcorn, D
通讯作者：
Alcorn, D
影响因子：
2.5
作者：
Komala, Muralikrishna Gangadharan;Gross, Simon;Panchapakesan, Usha
通讯作者：
Panchapakesan, Usha
影响因子：
3.5
作者：
Nagamine, Akari;Hasegawa, Hiroshi;Takano, Hiroyuki
通讯作者：
Takano, Hiroyuki
影响因子：
3.4
作者：
Abu El-Asrar, Ahmed M.;De Hertogh, Gert;Struyf, Sofie
通讯作者：
Struyf, Sofie