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Syringaresinol Resisted Sepsis-Induced Acute Lung Injury by Suppressing Pyroptosis Via the Oestrogen Receptor-β Signalling Pathway

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Abstract

Acute lung injury (ALI) is a common lung disease characterized by severe acute inflammatory lung injury in patients with sepsis. Syringaresinol (SYR) has been reported to have anti-apoptotic and anti-inflammatory effects, but whether it could prevent pyroptosis to improve sepsis-induced ALI remains unclear. The purpose of this work was to examine the impact of SYR on sepsis-induced ALI and investigate the underlying mechanisms. The ALI model was induced by caecal ligation and puncture (CLP) in C57BL/6 mice, structural damage in the lung tissues was determined using haematoxylin and eosin (HE) staining, and the levels of related inflammatory cytokines and macrophage polarization were examined by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry, respectively. The activation of the NLRP3 inflammasome and the protein levels of TLR4, NF-κB and MAPKs was measured by western blotting. The results demonstrated that SYR pretreatment significantly reduced lung tissue histological damage, inhibited the production of proinflammatory cytokines and albumin in bronchoalveolar lavage fluid (BALF), and decreased myeloperoxidase (MPO) levels, thereby alleviating lung tissue injury. Meanwhile, septic mice treated with SYR displayed a higher survival rate and lower percentage of M1 macrophages in the BALF and spleen than septic mice. In addition, lung tissues from the CLP + SYR group exhibited downregulated protein expression of NLRP3, ASC, GSDMD caspase-1 p20 and TLR4, along with decreased phosphorylated levels of NF-κB, ERK, JNK and P38, indicating that SYR administration effectively prevented CLP-induced pyroptosis in the lung. SYR also suppressed LPS-induced pyroptosis in RAW 264.7 cells by inhibiting the activation of the NLRP3 inflammasome, which was abolished by an oestrogen receptor-β (ERβ) antagonist (PHTPP). In conclusion, SYR exerted protective effects on CLP-induced ALI via the oestrogen receptor-β signalling pathway.

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All the data generated or analysed during this study are included in this published article.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81971858), Tianjin Natural Science Foundation Youth Fund (18JCQNJC13400; 19JCZDJC36200), the Science Foundation of Shenzhen Municipal Health Bureau (201902) and the Scientific Research Project of Integrated Traditional Chinese and Western Medicine of Tianjin Health Commission (201938).

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  1. Yuzhen Zhuo and Lei Yang contributed equally to this work.

Authors and Affiliations

  1. Tianjin Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin, 300100, China

    Yuzhen Zhuo, Lei Yang, Dihua Li, Lanqiu Zhang, Qi Zhang, Shukun Zhang, Caixia Li, Lihua Cui & Ximo Wang

  2. Department of Orthopaedics, Shenzhen Pingle Orthopaedics Hospital, Shenzhen, 518010, China

    Jian Hao

  3. Department of Nephrology, Tianjin Nankai Hospital, Tianjin, 300100, China

    Jiarui Li

  4. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Integrated Chinese and Western Medicine Hospital, Tianjin University, Tianjin, 300100, China

    Ximo Wang

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  1. Yuzhen Zhuo
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  3. Dihua Li
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Contributions

Jiarui Li and Ximo Wang designed this study. Yuzhen Zhuo and Lei Yang performed the experiment. Dihua Li analysed and interpreted the data, Lanqiu Zhang wrote the manuscript. Qi Zhang, Shukun Zhang, Caixia Li, Lihua Cui and Jian Hao participated in the experimental operation.

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Correspondence to Jiarui Li or Ximo Wang.

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Zhuo, Y., Yang, L., Li, D. et al. Syringaresinol Resisted Sepsis-Induced Acute Lung Injury by Suppressing Pyroptosis Via the Oestrogen Receptor-β Signalling Pathway. Inflammation 45, 824–837 (2022). https://doi.org/10.1007/s10753-021-01587-9

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