维达列汀通过抑制血管内皮细胞向间充质细胞转化改善脂多糖诱导的肺损伤肺纤维化。
Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.
机构信息
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
出版信息
Respir Res. 2017 Oct 16;18(1):177. doi: 10.1186/s12931-017-0660-4.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.
背景
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。最近，内皮到间充质转化（EndMT）被证明在肺纤维化中起重要作用。另一方面，二肽基肽酶（DPP）-4 被报道可改善实验性脓毒症模型中的血管功能障碍，尽管 DPP-4 是否影响脂多糖（LPS）诱导的肺损伤期间的 EndMT 和纤维化起始尚不清楚。本研究旨在探讨 DPP-4 抑制剂维格列汀在全身内毒素性肺损伤后肺纤维化中的抗 EndMT 作用。
方法
通过腹腔内注射脂多糖（LPS）（连续 5 天，每次 5mg/kg）建立脓毒症肺损伤模型。然后，将小鼠用载体或维格列汀（腹腔内，10mg/kg，从 LPS 首次给药前 1 天开始，连续 14 天，每天一次）处理。流式细胞术、免疫组织化学染色和定量聚合酶链反应（qPCR）分析用于评估小鼠肺组织样本中的细胞动力学和 EndMT 功能。
结果
用 LPS 处理的小鼠肺组织样本在 LPS 攻击后 2 天和 28 天显示出明显的炎症反应和典型的间质纤维化。定量流式细胞术分析显示，在 LPS 攻击后 28 天，表达α-平滑肌肌动蛋白（α-SMA）或 S100 钙结合蛋白 A4（S100A4）的肺血管内皮细胞（PVECs）数量增加。从分离的 PVECs 中提取的 mRNA 的 qPCR 也证实了类似的表达增加。EndMT 细胞比间充质细胞具有更高的增殖活性和迁移活性。所有这些变化都通过腹腔内注射维格列汀得到缓解。有趣的是，维格列汀和利拉利汀在没有免疫细胞或 GLP-1 的情况下，显著减弱了 EndMT。
结论
通过抑制 DPP-4 信号通路，维格列汀可能通过下调 LPS 诱导的全身肺损伤中的 EndMT 来改善肺纤维化。
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