Open Access

Artesunate protects against a mouse model of cerulein and lipopolysaccharide‑induced acute pancreatitis by inhibiting TLR4‑dependent autophagy

  • Authors:
    • Dan Liu
    • Chao Liu
    • Fei Deng
    • Fumin Ouyang
    • Rongxin Qin
    • Zhaoxia Zhai
    • Yan Wang
    • Yu Zhang
    • Mengling Liao
    • Xichun Pan
    • Yasi Huang
    • Yanyan Cen
    • Xiaoli Li
    • Hong Zhou
  • View Affiliations

  • Published online on: December 3, 2024     https://doi.org/10.3892/ijmm.2024.5466
  • Article Number: 25
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Severe acute pancreatitis (SAP) is a severe clinical condition associated with high rates of morbidity and mortality. Multiple organ dysfunction syndrome that follows systemic inflammatory response syndrome is the leading cause of SAP‑related death. Since the inflammatory mechanism of SAP remains unclear, there is currently a lack of effective drugs available for its treatment. Therefore, it is important to study effective therapeutic drugs and their molecular mechanisms based on studying the inflammatory mechanism of SAP. In the present study, in vivo, a mouse model of AP induced by cerulein (CR) combined with lipopolysaccharide (LPS) was established to clarify the therapeutic effect of artesunate (AS) in AP mice by observing the gross morphological changes of the pancreas and surrounding tissues, calculating the pancreatic coefficient, and observing the histopathology of the pancreas. The serum amylase activity in AP mice was detected by iodine colorimetry and the superoxide dismutase activity in the pancreas was detected by WST‑1 assay. The levels of proinflammatory cytokines in the serum, the supernatant of pancreatic tissue homogenates and the peritoneal lavage fluid were detected by ELISA assay. The total number of peritoneal macrophages was assessed using the cellular automatic counter, and the expression of proteins related to autophagy, and the TLR4 pathway was detected by immunohistochemistry and western blotting. In vitro, the effect of trypsin (TP) combined with LPS was observed by detecting the release of proinflammatory cytokine levels from macrophages by ELISA assay, and detecting the expression of proteins related to autophagy and the TLR4 pathway by immunofluorescence and western blotting. The present study revealed that AS reduced pancreatic histopathological damage, decreased pancreatic TP and serum amylase activities, increased superoxide dismutase activity, and inhibited pro‑inflammatory cytokine levels in a mouse model of AP induced by cerulein combined with lipopolysaccharide. In vitro, TP combined with LPS was found to synergistically induce pro‑inflammatory cytokine release from mouse macrophages and RAW264.7 cells, while AS could inhibit cytokine release. Furthermore, CR combined with LPS synergistically increased amylase activity in acinar cells, whereas AS decreased amylase activity. Autophagy serves an important role in the release of pro‑inflammatory cytokines. In the present study, it was revealed that the autophagy inhibitor LY294002 suppressed the release of pro‑inflammatory cytokines from macrophages treated with TP combined with LPS, and pro‑inflammatory cytokine release was not further reduced by AS combined with LY294002. Furthermore, AS not only inhibited the expression of important molecules in the Toll‑like receptor 4 (TLR4) signaling pathway, but also inhibited autophagy proteins and reduced the number of autolysosomes in mice with AP and in macrophages. In conclusion, these results suggested that AS may protect against AP in mice via inhibition of TLR4‑dependent autophagy; therefore, AS may be considered a potential therapeutic agent against SAP.
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February-2025
Volume 55 Issue 2

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Copy and paste a formatted citation
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Spandidos Publications style
Liu D, Liu C, Ouyang F, Qin R, Zhai Z, Wang Y, Zhang Y, Liao M, Pan X, Huang Y, Huang Y, et al: Artesunate protects against a mouse model of cerulein and lipopolysaccharide‑induced acute pancreatitis by inhibiting TLR4‑dependent autophagy. Int J Mol Med 55: 25, 2025.
APA
Liu, D., Liu, C., Ouyang, F., Qin, R., Zhai, Z., Wang, Y. ... Deng, F. (2025). Artesunate protects against a mouse model of cerulein and lipopolysaccharide‑induced acute pancreatitis by inhibiting TLR4‑dependent autophagy. International Journal of Molecular Medicine, 55, 25. https://doi.org/10.3892/ijmm.2024.5466
MLA
Liu, D., Liu, C., Ouyang, F., Qin, R., Zhai, Z., Wang, Y., Zhang, Y., Liao, M., Pan, X., Huang, Y., Cen, Y., Li, X., Zhou, H., Deng, F."Artesunate protects against a mouse model of cerulein and lipopolysaccharide‑induced acute pancreatitis by inhibiting TLR4‑dependent autophagy". International Journal of Molecular Medicine 55.2 (2025): 25.
Chicago
Liu, D., Liu, C., Ouyang, F., Qin, R., Zhai, Z., Wang, Y., Zhang, Y., Liao, M., Pan, X., Huang, Y., Cen, Y., Li, X., Zhou, H., Deng, F."Artesunate protects against a mouse model of cerulein and lipopolysaccharide‑induced acute pancreatitis by inhibiting TLR4‑dependent autophagy". International Journal of Molecular Medicine 55, no. 2 (2025): 25. https://doi.org/10.3892/ijmm.2024.5466