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TGF-β3 通过调节气道上皮细胞的自噬通路促进 MUC5AC 的过度表达。

TGF-β3 Promotes MUC5AC Hyper-Expression by Modulating Autophagy Pathway in Airway Epithelium.

机构信息

Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; First Department of Respiratory Disease, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.

Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.

出版信息

EBioMedicine. 2018 Jul;33:242-252. doi: 10.1016/j.ebiom.2018.06.032. Epub 2018 Jul 8.

DOI:10.1016/j.ebiom.2018.06.032
PMID:29997053
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6085582/
Abstract

Mucus secretion accumulation in the airways may act as a contributing factor for the development of airflow limitation in severe fetal asthma patients. Accumulated evidences showed that transforming growth factor beta (TGF-β) plays a regulatory role in airway remodeling including mucus hyper-secretion in asthma. However, the detailed molecular mechanisms of TGF-β3 induced MUC5AC hyper-expression in airway epithelium remains unclear. Here, we demonstrated the pivotal roles of autophagy in regulation of MUC5AC hyper-production induced by TGF-β3 in airway epithelium. Our experimental data showed that inhibiting autophagy pathway in repeated ovalbumin (OVA) exposed mice exhibited decreased airway hyper-response and airway inflammation, diminishing the expression of Muc5ac and TGF-β3. Furthermore, our studies demonstrated that autophagy was induced upon exposure to TGF-β3 and then mediated MUC5AC hyper-expression by activating the activator protein-1 (AP-1) in human bronchial epithelial cells. Finally, Smad2/3 pathway was involved in TGF-β3-induced MUC5AC hyper-expressions by promoting autophagy. These data indicated that autophagy was required for TGF-β3 induced airway mucous hyper-production, and that inhibition of autophagy exerted therapeutic benefits for TGF-β3 induced airway mucus secretion.

摘要

气道中黏液分泌的积累可能是导致严重胎儿哮喘患者气流受限发展的一个因素。越来越多的证据表明，转化生长因子-β（TGF-β）在气道重塑中发挥调节作用，包括哮喘中的黏液高分泌。然而，TGF-β3 诱导气道上皮细胞 MUC5AC 过度表达的详细分子机制尚不清楚。在这里，我们证明了自噬在 TGF-β3 诱导气道上皮细胞 MUC5AC 过度产生中的调节作用。我们的实验数据表明，在反复卵清蛋白（OVA）暴露的小鼠中抑制自噬途径可降低气道高反应性和气道炎症，减少 Muc5ac 和 TGF-β3 的表达。此外，我们的研究表明，自噬在 TGF-β3 暴露后被诱导，并通过激活人支气管上皮细胞中的激活蛋白-1（AP-1）来介导 MUC5AC 的过度表达。最后，Smad2/3 通路通过促进自噬参与 TGF-β3 诱导的 MUC5AC 过度表达。这些数据表明，自噬是 TGF-β3 诱导气道黏液高分泌所必需的，抑制自噬对 TGF-β3 诱导的气道黏液分泌具有治疗益处。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/42834ddcb76e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/2e6b7e406961/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/0e60ba42d416/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/ac2eadd19595/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/789271f3f4aa/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/964300cb18a7/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/42834ddcb76e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/2e6b7e406961/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/0e60ba42d416/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/ac2eadd19595/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/789271f3f4aa/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/964300cb18a7/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0dd/6085582/42834ddcb76e/gr6.jpg

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