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Bioglass promotes wound healing by inhibiting endothelial cell pyroptosis through regulation of the connexin 43/reactive oxygen species (ROS) signaling pathway

Abstract

Bioactive glass (BG) has recently shown great promise in soft tissue repair, especially in wound healing; however, the underlying mechanism remains unclear. Pyroptosis is a novel type of programmed cell death that is involved in various traumatic injury diseases. Here, we hypothesized that BG may promote wound healing through suppression of pyroptosis. To test this scenario, we investigated the possible effect of BG on pyroptosis in wound healing both in vivo and in vitro. This study showed that BG can accelerate wound closure, granulation formation, collagen deposition, and angiogenesis. Moreover, western blot analysis and immunofluorescence staining revealed that BG inhibited the expression of pyroptosis-related proteins in vivo and in vitro. In addition, while BG regulated the expression of connexin43 (Cx43), it inhibited reactive oxygen species (ROS) production. Cx43 activation and inhibition experiments further indicate that BG inhibited pyroptosis in endothelial cells by decreasing Cx43 expression and ROS levels. Taken together, these studies suggest that BG promotes wound healing by inhibiting pyroptosis via Cx43/ROS signaling pathway.

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Fig. 1: Characterization of BG.
Fig. 2: BG accelerates wound closure and promotes neovascularization in mice.
Fig. 3: BG suppresses pyroptosis in vivo.
Fig. 4: BG suppresses pyroptosis in endothelial cells.
Fig. 5: BG affects Cx43 expression and ROS levels.
Fig. 6: Effects of GAP134 and GAP26 on wound healing in mice.
Fig. 7: BG rescues LPS-ATP-induced pyroptosis in HUVECs.
Fig. 8: BG inhibits pyroptosis in HUVECs by downregulating Cx43 expression and ROS levels.
Fig. 9: Schematic diagram showing that BG promotes wound healing by inhibiting endothelial cell pyroptosis through regulating Cx43/ROS signaling pathway.

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This study was jointly supported by the National Natural Science Foundation of China (81802251, 81772450, and 81801233), Zhejiang Provincial Natural Science Foundation of China (LQ18H150003, LQ18H090011, LY19H150001 LY17H090014, and LWY20H310001), Zhejiang Provincial Medical and Health Science and Technology Fund (2018KY186), and Wenzhou science and technology innovation project (ZY2020023 and ZY2020026).

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K.X., K.Z., H.J. and H.Z. were involved in the design and execution of experiments, data analysis, and manuscript writing. B.C., L.C., Y.M., L.Z., J.X., Y.L., Y.W., J.X., H.L. and Z.F. were all involved in the execution of experiments and data analysis. All authors provided the final approval of the version to be submitted.

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Correspondence to Jian Xiao or Hongyu Zhang or Ke Xu.

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The animal study was reviewed and approved by the animal welfare and usage management regulations of the Wenzhou Medical University [License No. SCXK [ZJ] 2015-0009].

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Zhang, K., Chai, B., Ji, H. et al. Bioglass promotes wound healing by inhibiting endothelial cell pyroptosis through regulation of the connexin 43/reactive oxygen species (ROS) signaling pathway. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00675-6

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