Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

Suzuki, Toshio; Tada, Yuji; Nishimura, Rintaro; Kawasaki, Takeshi; Sekine, Ayumi; Urushibara, Takashi; Kato, Fumiki; Kinoshita, T.; Ikari, Jun; West, James; Tatsumi, Koichiro

doi:10.1152/ajplung.00074.2016

Cited by 23 publications

(36 citation statements)

References 56 publications

(67 reference statements)

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“…Toshio Suzuki found that EndMT of pulmonary vascular endothelial cells is involved in the development of acute lung injury, partly mediated by ROS formation, and the process is closely affected by NAD(P)H oxidase-dependent ROS production 59 . The possible molecular mechanism, at least in part, is that oxidative stress increases the expression and secretion of TGFβ1 and TGFβ2 20 .…”

Section: Discussionmentioning

confidence: 99%

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

Chen¹,

Yuan²,

Zhang³

et al. 2017

Int. J. Biol. Sci.

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The endothelial-to-mesenchymal transition (EndMT) has been demonstrated to be involved in pulmonary vascular remodeling. It is partly attributed to oxidative and inflammatory stresses in endothelial cells. In current study, we conducted a series of experiments to clarify the effect of salvianolic acid A (SAA), a kind of polyphenol compound, in the process of EndMT in human pulmonary arterial endothelial cells and in vivo therapeutic efficacy on vascular remodeling in monocrotaline (MCT)-induced EndMT. EndMT was induced by TGFβ1 in human pulmonary arterial endothelial cells (HPAECs). SAA significantly attenuated EndMT, simultaneously inhibited cell migration and reactive oxygen species (ROS) formation. In MCT-induced pulmonary arterial hypertension (PAH) model, SAA improved vascular function, decreased TGFβ1 level and inhibited inflammation. Mechanistically, SAA stimulated Nrf2 translocation and subsequent heme oxygenase-1 (HO-1) up-regulation. The effect of SAA on EndMT in vitro was abolished by ZnPP, a HO-1 inhibitor. In conclusion, this study indicates a deleterious impact of oxidative stress on EndMT. Polyphenol antioxidant treatment may provide an adjunctive action to alleviate pulmonary vascular remodeling via inhibiting EndMT.

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Section: Discussionmentioning

confidence: 99%

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

Chen¹,

Yuan²,

Zhang³

et al. 2017

Int. J. Biol. Sci.

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“…Our recent study showed that one of the innate survival strategies for non-apoptotic injured PVECs is endothelial-to-mesenchymal transition (EndMT) [ 3 ], which is a process wherein endothelial cells lose an endothelial cell phenotype and acquire a mesenchymal cell phenotype [ 4 ]. There are many pathways, such as those that include the transforming growth factor β (TGFβ) superfamily, through which EndMT is induced [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We recently reported that transient EndMT was observed in mice with septic acute lung injury (ALI) that can be repaired [ 3 ]. LPS-induced EndMT was reported to be dependent on ROS levels in vitro [ 6 ], and in vivo [ 3 ]. In the repairable ALI mouse model, transient EndMT cells have a progenitor cell-like phenotype that could be involved in endothelial repair after pulmonary vascular injury [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…LPS-induced EndMT was reported to be dependent on ROS levels in vitro [ 6 ], and in vivo [ 3 ]. In the repairable ALI mouse model, transient EndMT cells have a progenitor cell-like phenotype that could be involved in endothelial repair after pulmonary vascular injury [ 3 ]. Some of pulmonary microvascular endothelial cells transform into mesenchymal phenotype with retaining reversibility to their original phenotype when endotoxin stimulation is transient.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Distinct effects of pharmacological inhibition of stromelysin1 on endothelial‐to‐mesenchymal transition and myofibroblast differentiation

Alharthi

Verma

Sabbineni

et al. 2020

Journal Cellular Physiology

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Endothelial‐to‐mesenchymal transition (EndMT) and fibroblast‐to‐myofibroblast (FibroMF) differentiation are frequently reported in organ fibrosis. Stromelysin1, a matrix metalloprotease‐3 (MMP3) has been indicated in vascular pathologies and organ injuries that often lead to fibrosis. In the current study, we investigated the role of stromelysin1 in EndMT and FibroMF differentiation, which is currently unknown. In our results, whereas TGFβ2 treatment of endothelial cells (ECs) induced EndMT associated with increased expression of stromelysin1 and mesenchymal markers such as α‐smooth muscle actin (αSMA), N‐cadherin, and activin linked kinase‐5 (ALK5), inhibition of stromelysin1 blunted TGFβ2‐induced EndMT. In contrast, treatment of NIH‐3T3 fibroblasts with TGFβ1 promoted FibroMF differentiation accompanied by increased expression of αSMA, N‐cadherin, and ALK5. Intriguingly, stromelysin1 inhibition in TGFβ1‐stimulated myofibroblasts further exacerbated fibroproliferation with increased FibroMF marker expression. Gene Expression Omnibus (GEO) data analysis indicated increased stromelysin1 expression associated with EndMT and decreased stromelysin1 expression in human pulmonary fibrosis fibroblasts. In conclusion, our study has identified that EndMT and FibroMF differentiation are reciprocally regulated by stromelysin1.

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Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

Abstract: Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.

Cited by 23 publications

References 56 publications

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

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

Distinct effects of pharmacological inhibition of stromelysin1 on endothelial‐to‐mesenchymal transition and myofibroblast differentiation

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