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  • jc1 Our results demonstrated that ET a


    Our results demonstrated that ET-1, a Wnt ligand, stimulated the Wnt/β-catenin signaling pathway. First, ET-1/ETRA binds to Frizzled family cell-surface receptors, resulting in the activation of Dvl1, a Dishevelled (DSH) family protein. Next, activated DSH inhibits the Axin, GSK-3β, and APC protein complex (in our study, GSK-3β was universally downregulated in response to ET-1). Accumulated β-catenin, a key molecule in canonical Wnt signaling, translocates to the nucleus, where it combines with T cell factor-lymphoid enhancer factor to transactivate target gene promoters, including those of genes encoding matrix metalloproteinases and cyclin D1. These observations are consistent with our previous report [25], in which ET-1 was shown to increase the production of MMP-1 and MMP-13, resulting in CEP degeneration. Cyclin D1 regulates the jc1 G1/S transition, is involved in the promotion of cell proliferation, and is highly upregulated in response to ET-1 treatment in the present study. The CEP undergoes self-healing processes during its degeneration, although the self-renewal and proliferation mechanisms become impaired as the level of degeneration increases. The attenuation of the negative effects induced by ET-1 treatment by BQ-123 is of considerable interest, suggesting that ET-1 exerts a blocking effect on ECM synthesis via Wnt/β-catenin signaling in CECs.
    Acknowledgment This work was funded by grants from Shanghai Municipal Commission of Health and Family Planning (201440387); the project was funded by China Postdoctoral Science Foundation (2017M623343); the Training Planned Fund of Academic Leaders, Shanghai Pudong New Area Health System (PWRd2015-02); and the Natural Science Foundation of Shanghai Science and Technology Commission (14ZR1442300).
    Introduction Previous work from this laboratory has shown that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as an inflammatory cell “gatekeeper,” facilitating the influx of leukocytes into the lung [1], [2], [3], [4]. Treatment of lipopolysaccharide (LPS)-induced acute pulmonary injury with HJP272, an ET-1 receptor antagonist (ERA), significantly reduced lung histopathological changes, neutrophil content in bronchoalveolar lavage fluid (BALF), TNFR1 expression by BALF macrophages, and other parameters of inflammation [4]. These observations were supported by additional studies which showed that exogenous administration of ET-1 could have the opposite effect, significantly increasing the amount of BALF neutrophils following short-term exposure to cigarette smoke [2]. In terms of treating inflammatory lung diseases, blocking the activity of ET-1 could potentially reduce the levels of leukocyte-derived proinflammatory mediators, thereby ameliorating pulmonary injury. The BLM model is commonly used to investigate the pathogenesis of interstitial pulmonary fibrosis because it has morphological features that are similar to the human disease, including parenchymal inflammation of variable intensity, epithelial cell injury with reactive hyperplasia, basement membrane damage, fibroblast proliferation, and extracellular matrix deposition [5], [6]. However, the model cannot duplicate the gradual progression of the human disorder, and cessation of BLM treatment may reverse previously induced morphological changes [7]. The rapid development of lung injury following intratracheal instillation of BLM suggests that it may be more appropriately characterized as a wound healing phenomenon rather than actual remodeling of the lung. Nevertheless, the use of this model has provided insight into potential biochemical mechanisms that may be responsible for the development of the human disease. While the LPS and BLM models differ in terms of their pathogenetic mechanisms, the initial inflammatory events share common features. In particular, the initial 24–48 h period following instillation of either agent consists of a marked influx of neutrophils into the lung [8], [9]. In the LPS model, the number of these cells rapidly decreases, and the lung returns to normal with little remodeling of the parenchyma [8]. Maintenance of the neutrophil population within the lung requires repeated exposure to LPS, which can then lead to emphysematous changes due to continued release of elastases and other degradative enzymes by these cells [10].