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

• Published in: Drug design, development and therapy development and therapy, 2019-01, Vol.13, p.3391-3404
• Main Authors: Wang, Yu-Ming, Ji, Ran, Chen, Wei-Wei, Huang, Shun-Wei, Zheng, Yan-Jun, Yang, Zhi-Tao, Qu, Hong-Ping, Chen, Hao, Mao, En-Qiang, Chen, Ying, Chen, Er-Zhen
• Format: Article
• Language: English
• Subjects: Activation; acute lung injury; Acute Lung Injury - drug therapy; Acute Lung Injury - metabolism; Alveoli; Animal tissues; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Biotechnology; Bronchus; Cecum; Cecum - surgery; Cell culture; Cell cycle; Cytokines; Drug dosages; Enzyme-linked immunosorbent assay; Epithelial cells; Gene expression; Hospitals; Inflammation; Injections, Intraperitoneal; Injuries; Injury prevention; Laboratory animals; Levels; Lipopolysaccharides; Lungs; Male; Medicine; Mice; Mice, Inbred C57BL; Mortality; MUC1; Mucin-1 - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; NF-κB protein; Original Research; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Pretreatment; Punctures - adverse effects; Sepsis; Sepsis - drug therapy; Sepsis - metabolism; siRNA; Surgery; Survival; Survival analysis; TLR 4; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - metabolism
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S222296

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. 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. 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. 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.