Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition

Abstract

BackgroundPulmonary 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.MethodsA 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.ResultsLung 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.ConclusionsInhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0660-4) contains supplementary material, which is available to authorized users.

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

“…Since FBs also constitute the center of fibrotic disease etiology in other organs, this finding might have important implications beyond the skin. 1,60 In animal studies, DPP4 + FBs have been shown to be involved in fibrotic pathologies of several other organs, and inhibition of DPP4 activity by gliptins attenuated fibrotic processes in the lung, 61 heart, 62,63 kidney, 64 and liver. 65 Therefore, our transcriptome analysis of DPP4 + FBs in the human skin might represent an important step toward the development of novel anti-fibrotic therapeutic approaches, specifically targeting the DPP4 + FB subset.…”

Vildagliptin inhibits high free fatty acid (FFA)-induced NLRP3 inflammasome activation in endothelial cells

“…A recently published one-year randomized controlled clinical trial indicated that vildagliptin administration mitigates the reduction in the number of endothelial progenitor cells in type 2 diabetes patients [28]. Another recent study showed that vildagliptin treatment protects endothelial cells from loss of identity towards transformation into other cell types and improves pulmonary fibrosis in mice [29]. All these evidences demonstrate that vildagliptin possesses an array of vascular protective effects.…”

Lung infection caused by Pseudomonas aeruginosa in a CD26/DPP4 deficient F344 rat model

“…They found (1) a CD26 mediated costimulation of T-cells combined with production of the proinflammatory interleukin-2 (IL-2) [59], (2) a CD26 mediated co-stimulation of CD8 + T cells, which exert cytotoxic effects predominantly via TNF-α [18], (3) a DPP4 dependent cleavage of the chemokine substrate LD78ß into a very efficient monocyte attractant, enhancing lymphocyte and monocyte chemotactic activity [60], and (4) a CD26/DPP4inhibitor dependent increase of the anti-inflammatory peptide VIP (Vasointestinal peptide) in rats [61], diminishing inflammatory response [15,21]. Furthermore, using different CD26/DPP4 inhibitors signs of inflammation were reduced in different lung disease models [22,62,63]. Not at all, our group found a reduced inflammation in CD26/ DPP4 − rats [24].…”