Melatonin suppresses fibrotic responses induced by cigarette smoke via downregulation of TGF-β1
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Na-Rae Shin1,*, Ji-Won Park2,*, In-Chul Lee3, Je-Won Ko1, Sung-Hyeuk Park1, Joong-Sun Kim4, Jong-Choon Kim1, Kyung-Seop Ahn2 and In-Sik Shin1
1College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju 500-757, Republic of Korea
2Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea
3Natural Product Research Center, Jeonbuk Branch, Korea Research Institute of Biosciences and Biotechnology, Jeongeup 580-185, Republic of Korea
4Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan 619-953, Republic of Korea
*These authors contributed equally to this work
In-Sik Shin, email: firstname.lastname@example.org
Kyung-Seop Ahn, email: email@example.com
Keywords: melatonin, cigarette smoke, pulmonary fibrosis, TGF-β1, MAPK
Received: August 01, 2017 Accepted: September 22, 2017 Published: October 09, 2017
Cigarette smoke (CS) is the most important risk factor in the development of chronic obstructive pulmonary disease (COPD). Pulmonary fibrosis is an irreversible response and important feature of COPD. In this study, we investigated the effects of melatonin on fibrotic response in development of COPD using a CS and lipopolysaccharide (LPS) induced COPD model and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells, a human mucoepidermoid cell line. Mice were exposed to CS for 1 h per day (8 cigarettes per day) from day 1 to day 7 and were treated intranasally with LPS on day 4. Melatonin (10 or 20 mg/kg) was injected intraperitoneally 1 h before CS exposure. Melatonin decreased the inflammatory cell counts in bronchoalveolar lavage fluid (BALF), with a reduction in transforming growth factor (TGF)-β1. Melatonin inhibited the expression of TGF-β1, collagen I and SMAD3 phosphorylation in lung tissue exposed to CS and LPS. In CSC-stimulated H292 cells, melatonin suppressed the elevated expression of fibrotic mediators induced by CSC treatment. Melatonin reduced the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation in CSC-stimulated H292 cells. In addition, cotreatment with melatonin and TGF-β1 inhibitors significantly limited fibrotic mediators, with greater reductions in the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation than those of H292 cells treated with TGF-β1 inhibitor alone. Taken together, melatonin effectively inhibited fibrotic responses induced by CS and LPS exposure, which was related to the downregulation of TGF-β1. Therefore, our results suggest that melatonin may suppress the pulmonary fibrotic response induced by CS.
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