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Biomed Pharmacother. 2019 Jul;115:108889. doi: 10.1016/j.biopha.2019.108889. Epub 2019 May 6.

Amiodarone induces cell proliferation and myofibroblast differentiation via ERK1/2 and p38 MAPK signaling in fibroblasts.

Author information

1
Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
2
Department of Medical laboratory, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325027, China.
3
Department of Geriatric Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
4
Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
5
Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA.
6
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
7
Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: wangzb@wmu.edu.cn.
8
Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: wzy1063@126.com.
9
Department of Geriatric Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: chenchan99@126.com.

Abstract

Amiodarone is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis. Accumulating evidence has demonstrated that myofibroblast differentiation is related to the pathogenesis of pulmonary fibrosis. In the present study, we treated human embryonic lung fibroblasts (HELFs) with amiodarone, and investigated the relative molecular mechanism of amiodarone-induced pulmonary fibrosis and pathway determinants PD98059 (extracellular signal-regulated kinase (ERK) inhibitor) and SB203580 (p38 mitogen-activated protein kinase (MAPK) inhibitor). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8). The secretion of collagen Ⅰ was detected by ELISA. The expressions of α-smooth muscle actin (α-SMA), vimentin, phosphorylated ERK1/2 (p-ERK1/2), ERK1/2, phosphorylated p38 MAPK (p-p38), and p38 MAPK were investigated using Western blot analysis. The levels of α-SMA and vimentin were also determined by immunofluorescence and qRT-PCR. We report that amiodarone promoted cell proliferation and collagen Ⅰ secretion, induced α-SMA and vimentin protein and mRNA expression accompanied by increased phosphorylation of ERK1/2 and p38 MAPK, and furthermore, PD98059 and SB203580 remarkably reduced the proliferative response of HELFs compared with amiodarone group and greatly attenuated α-SMA, vimentin and collagen Ⅰ protein production induced by amiodarone. Taken together, our study suggests that amiodarone regulates cell proliferation and myofibroblast differentiation in HELFs through modulating ERK1/2 and p38 MAPK pathways, and these signal pathways may therefore represent an attractive treatment modality in amiodarone-induced pulmonary fibrosis.

KEYWORDS:

Amiodarone; ERK1/2; HELFs; Myofibroblast differentiation; Pulmonary fibrosis; p38 MAPK

PMID:
31071512
DOI:
10.1016/j.biopha.2019.108889
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