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Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4/NF-κB pathway

Authors Wang YM, Ji R, Chen WW, Huang SW, Zheng YJ, Yang ZT, Qu HP, Chen H, Mao EQ, Chen Y, Chen EZ

Received 7 July 2019

Accepted for publication 1 September 2019

Published 24 September 2019 Volume 2019:13 Pages 3391—3404

DOI https://doi.org/10.2147/DDDT.S222296

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Professor Jianbo Sun


Yu-Ming Wang,1,* Ran Ji,1,* Wei-Wei Chen,1 Shun-Wei Huang,1 Yan-Jun Zheng,1 Zhi-Tao Yang,1 Hong-Ping Qu,2 Hao Chen,3 En-Qiang Mao,1 Ying Chen,1 Er-Zhen Chen1

1Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of General Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ying Chen; Er-Zhen Chen
Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai 200025, China
Tel +86 216 437 0045
Fax +86 216 433 3548
Email bichatlion@163.com; chenerzhen@hotmail.com

Purpose: It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms.
Materials and methods: The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot.
Results: Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1.
Conclusion: Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

Keywords: sepsis, acute lung injury, MUC1, TLR 4, NF-κB

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