Abstract
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.
Highlights
Cigarette smoke (CS) is considered an important risk factor for the deterioration of the normal respiratory structure and function
We investigated the effects of melatonin on fibrotic response in development of chronic obstructive pulmonary disease (COPD) using a CS and lipopolysaccharide (LPS) induced COPD model and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells, a human mucoepidermoid cell line
Melatonin inhibited the expression of transforming growth factor (TGF)-β1, collagen I and SMAD3 phosphorylation in lung tissue exposed to CS and LPS
Summary
Cigarette smoke (CS) is considered an important risk factor for the deterioration of the normal respiratory structure and function. During the development of pulmonary fibrosis, extracellular matrix (ECM) deposition, including collagen and fibronectin, is markedly increased via the release of various cytokines [2]. Among these cytokines, www.impactjournals.com/oncotarget transforming growth factor (TGF)-β1 is closely associated with the progression of fibrotic changes [3]. Alteration of TGF-β1/SMAD signaling was observed with pulmonary fibrosis in a patient with COPD [9]. Considering these findings, the regulation of TGF-β1/ SMAD is an important strategy for controlling pulmonary fibrosis in COPD
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