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

• Main Authors: Wang YM (Author), Ji R (Author), Chen WW (Author), Huang SW (Author), Zheng YJ (Author), Yang ZT (Author), Qu HP (Author), Chen H (Author), Mao EQ (Author), Chen Y (Author), Chen EZ (Author)
• Format: Book
• Published: Dove Medical Press, 2019-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1177-8881
• Keywords: Sepsis; acute lung injury; MUC1; TLR 4; NF-κB; Therapeutics. Pharmacology; RM1-950
• Source: Drug Design, Development and Therapy, Vol Volume 13, Pp 3391-3404 (2019)

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 workCorrespondence: Ying Chen; Er-Zhen ChenDepartment of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai 200025, ChinaTel [phone]Fax [phone]Email [e-mail]; [e-mail]: 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