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

Abstract

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

Acknowledgment

This work was supported by Shanghai Shenkang Hospital Development Center of China (grant number SHDC12017116), Program for Outstanding Medical Academic, Shanghai Municipal Committee of Science and Technology (184119500900), Shanghai Municipal Commission of Health and Family Planning (2016ZB0206, ZHYY-ZXYJHZX-1-201702) and Shanghai Jiao Tong University School of Medicine (DLY201803) to Er-Zhen Chen. This work was also supported by Shanghai Municipal Commission of Health and Family Planning (201640089) to Zhi-Tao Yang.

Abbreviations

ALI, acute lung injury; CLP, cecal ligation and puncture; ELISA, enzyme-linked immunosorbent assay; BALF, bronchoalveolar lavage fluid; MODS, multi-organ dysfunction syndrome; PAMP, pathogen-associated molecular pattern; DAMP, danger-associated molecular pattern.

Disclosure

The authors report no conflicts of interest in this work.