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The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation.

ABSTRACT: Objective:Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation. Methods:A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were exposed to PQ in dose-dependent and time-dependent manners. Cell viability was detected by CCK-8 assays. The expression levels of MUC5B were examined by dot blot enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Western blotting was used to detect the levels of proteins in the MAPK and NF-?B pathways. Inflammatory factors in the cell culture medium were measured by ELISA. NF-?B and MAPK pathway inhibitors and MUC5B siRNA (siMUC5B) were used to determine the function of MUC5B. Finally, N-acetyl-cysteine (NAC) was added and its regulatory effect on the MAPK-NF-?B-MUC5B pathway was examined in PQ-induced cell inflammation. Results:MUC5B was significantly upregulated accompanying the increases in TNF-? and IL-6 secretion following PQ treatment in mouse and also in A549 cells after treatment with 50??M PQ at 24 hours. Furthermore, MAPK and NF-?B pathway inhibitors could dramatically decrease the expression of MUC5B and the secretion of TNF-? and IL-6. Importantly, siMUC5B could significantly attenuate the secretion of TNF-? and IL-6 induced by PQ. As expected, the addition of NAC efficiently suppresses the TNF-? and IL-6 secretion stimulated from PQ and also downregulated ERK, JNK, and p65 phosphorylation (ERK/JNK MAPK and NF-?B pathways) as well as MUC5B expression. Conclusion:Our findings suggest that MUC5B participates in the process of PQ-induced cell inflammation and is downstream of the NF-?B and MAPK pathways. NAC can attenuate PQ-induced cell inflammation at least in part by suppressing the MAPK-NF-?B-MUC5B pathway. These results nominate MUC5B as a new biomarker and therapeutic target for PQ-induced lung inflammation.

SUBMITTER: Sun H

PROVIDER: S-EPMC7381986 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation.

Sun Hao H Jiang Yunfei Y Song Yang Y Zhang Xiaomin X Wang Jun J Zhang Jinsong J Kang Jian J

Oxidative medicine and cellular longevity 20200716

<h4>Objective</h4>Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation.<h4>Methods</h4>A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were expose ...[more]

PMID: 32724493

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Project description:Oxidative stress is an important mechanism in acute lung injury (ALI) induced by paraquat (PQ), one of the most widely used herbicides in developing countries. In clinical prophylaxis and treatment, licorice is a widely used herbal medicine in China due to its strong alexipharmic characteristics. However, the corresponding biochemical mechanism of antioxidation and detoxification enzymes induced by licorice's ingredients is still not fully demonstrated. In this study, the detoxification effect of licorice was evaluated in vivo and in vitro. The detoxification and antioxidation effect of its active ingredients involved in the treatment was screened systematically according to Absorption, Distribution, Metabolism, and Excretion (ADME): predictions and evidence-based literature mining methods in silico approach. Data shows that licorice alleviate pulmonary edema and fibrosis, decrease Malondialdehyde (MDA) contents and increase Superoxide Dismutase (SOD) activity in PQ-induced ALI mice, protect the morphologic appearance of lung tissues, induce cytochrome 3A4 (CYA3A4) and Nuclear factor erythroid 2-related factor 2 (Nrf2) expression to active detoxification pathways, reduce the accumulation of PQ in vivo, protect or improve the liver and renal function of mice, and increase the survival rate. The 104 genes of PPI network contained all targets of licorice ingredients and PQ, which displayed the two redox regulatory enzymatic group modules cytochrome P450 (CYP450) and Nrf2 via a score-related graphic theoretic clustering algorithm in silico. According to ADME properties, glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A were employed due to their oral bioavailability (OB) ≥ 30%, drug-likeness (DL) ≥ 0.1, and being highly associated with CYP450 and Nrf2 pathways, as potential activators to halt PQ-induced cells death in vitro. Both 3A4 inhibitor and silenced Nrf2 gene decreased the alexipharmic effects of those ingredients significantly. All these disclosed the detoxification and antioxidation effects of licorice on acute lung injury induced by PQ, and glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A upregulated CYP450 and Nrf2 pathways underlying the alexipharmic mechanisms of licorice.

Dataset Information

The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation.

Publications

The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation.

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