Melatonin attenuates neutrophil inflammation and mucus secretion in cigarette smoke-induced chronic obstructive pulmonary diseases via the suppression of Erk-Sp1 signaling.

The incidence of chronic obstructive pulmonary disease (COPD) has substantially increased in recent decade. Cigarette smoke (CS) is the most important risk factor in the development of COPD. In this study, we investigated the effects of melatonin on the development of COPD using a CS and lipopolysaccharide (LPS)-induced COPD model and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells, a human mucoepidermoid carcinoma cell. On day 4, the mice were treated intranasally with LPS. The mice were exposed to CS for 1 hr per day (8 cigarettes per day) from day 1 to day 7. Melatonin (10 or 20 mg/kg) was injected intraperitoneally 1 hr before CS exposure. Melatonin markedly decreased the neutrophil count in the BALF, with reduction in the proinflammatory mediators and MUC5AC. Melatonin inhibited Erk phosphorylation and Sp1 expression induced by CS and LPS treatment. Additionally, melatonin decreased airway inflammation with a reduction in myeloperoxidase expression in lung tissue. In in vitro experiments, melatonin suppressed the elevated expression of proinflammatory mediators induced by CSC treatment. Melatonin reduced Erk phosphorylation and Sp1 expression in CSC-stimulated H292 cells. In addition, cotreatment of melatonin and Erk inhibitors significantly limited the proinflammatory mediators with greater reductions in Erk phosphorylation and Sp1 expression than that observed in H292 cells treated with Erk inhibitor alone. Taken together, melatonin effectively inhibited the neutrophil airway inflammation induced by CS and LPS treatment, which was closely related to downregulation of Erk phosphorylation. These findings suggest that melatonin has a therapeutic potential for the treatment of COPD.

Shin IS ，Shin NR ，Park JW ，Jeon CM ，Hong JM ，Kwon OK ，Kim JS ，Lee IC ，Kim JC ，Oh SR ，Ahn KS ... -  《-》

Callicarpa japonica Thunb. attenuates cigarette smoke-induced neutrophil inflammation and mucus secretion.

Callicarpa japonica Thunb. (CJT) is traditionally used as an herbal remedy for the treatment of inflammatory diseases in Korea, China, and Japan. In this study, we evaluated the effects of C. japonica Thunb. (CJT) on the development of COPD using a Cigarette smoke (CS)-induced murine model and cigarette smoke condensate (CSC)-stimulated H292 cells, human pulmonary mucoepidermoid cell line. C. japonica Thunb. was isolated from the leaves and stem of C. japonica. The methanol extract profile was obtained by UPLC Q-TOF-MS analysis. In in vivo experiment, the mice received 1h of cigarette smoke for 10 days. C. japonica Thunb. was administered to mice by oral gavage 1h before cigarette smoke exposure for 10 days. In in vitro experiment, we evaluated the effect of C. japonica Thunb. on the expression of MUC5AC and proinflammatory cytokines in H292 cells stimulated with CSC. CJT treatment effectively suppressed the infiltration of neutrophils, and decreased the production of ROS and the activity of neutrophil elastase in the bronchoalveolar lavage fluid (BALF) induced by CS. CJT also significantly attenuated production of proinflammatory cytokines such as IL-6 and TNF-α in the BALF, and reduced the infiltration of inflammatory cells and the production of mucus in lung tissue induced by CS. In in vitro experiments, CJT decreased the expression of MUC5AC and proinflammatory cytokines in CSC-stimulated H292 cells. Furthermore, CJT attenuated the phosphorylation of ERK induced by CSC in H292 cells. Taken together, CJT effectively reduced the neutrophil airway inflammation and mucus secretion induced by CS in murine model, and inhibited the expression of MUC5AC in CSC-stimulated H292 human lung cell line. These findings suggest that CJT has a therapeutic potential for the treatment of COPD.

Lee JW ，Shin NR ，Park JW ，Park SY ，Kwon OK ，Lee HS ，Hee Kim J ，Lee HJ ，Lee J ，Zhang ZY ，Oh SR ，Ahn KS ... -  《-》

A standardized bark extract of Pinus pinaster Aiton (Pycnogenol(®)) attenuated chronic obstructive pulmonary disease via Erk-sp1 signaling pathway.

A standardized bark extract of Pinus pinaster Aiton (Pycnogenol®; PYC) used as an herbal medicine to treat various diseases in Europe and North America. This study evaluates the ability of PYC to inhibit chronic obstructive pulmonary disease (COPD) in the cigarette smoke extract (CSE)-stimulated human airway epithelial cell line NCI-H292 and in a cigarette smoke (CS) and lipopolysaccharide (LPS)-induced mouse model. To induce COPD, the mice intranasally received LPS on day 4 and were exposed to CS for 1h per day (total eight cigarettes per day) from days 1-7. The mice were administered PYC at a dose of 15mg/kg and 30mg/kg 1h before CS exposure. In the CSE-stimulated NCI-H292 cells, PYC significantly inhibited Erk phosphorylation, sp1 expression, MUC5AC, and pro-inflammatory cytokines in a concentration-dependent manner, as evidenced by a reduction in their mRNA levels. Co-treatment with PYC and Erk inhibitors markedly reduced the levels inflammatory mediators compared to only PYC-treatment. In the COPD mice model, PYC decreased the inflammatory cell count and the levels of pro-inflammatory cytokines in the broncho-alveolar lavage fluid compared with COPD mice. PYC attenuated the recruitment of inflammatory cells in the airways and decreased the expression levels of Erk phosphorylation and sp1. PYC also inhibited the expression of myeloperoxidase and matrix metalloproteinases-9 in lung tissue. Our results indicate that PYC inhibited the reduction in the inflammatory response in CSE-stimulated NCI-H292 cells and the COPD mouse model via the Erk-sp1 pathway. Therefore, we suggest that PYC has the potential to treat COPD.

Shin NR ，Ryu HW ，Ko JW ，Park JW ，Kwon OK ，Oh SR ，Kim JC ，Shin IS ，Ahn KS ... -  《-》

Silibinin Inhibits Neutrophilic Inflammation and Mucus Secretion Induced by Cigarette Smoke via Suppression of ERK-SP1 Pathway.

Silibinin, the main ingredient of silymarin, has been used as a traditional drug for over 2000 years to treat a range of liver diseases. Recent studies have also demonstrated that silibinin possesses antiinflammatory and anticancer properties. In the study, we researched the efficacy of silibinin on the development of COPD using a cigarette smoke (CS)-induced and lipopolysaccharide (LPS)-induced COPD model mice and stimulation of NCI-H292 cells with CS condensate. Silibinin was administered to mice by oral gavage 1 h before CS exposure for 10 days. In in vitro experiment, we evaluated the effect of silibinin on the expression of MUC5AC in H292 cells stimulated with CS condensate. Furthermore, silibinin suppressed the CS and LPS treatment-induced extracellular signal-regulated kinase (ERK) phosphorylation and SP-1 expression. Silibinin also decreased airway inflammation and reduced the expression of MUC5AC and myeloperoxidase. Furthermore, co-treatment with silibinin and ERK inhibitors considerably decreased the levels of pro-inflammatory mediators, ERK phosphorylation, and SP-1 expression. Taken together, the results indicate that silibinin effectively suppressed the neutrophilic airway inflammation provoked by treatment with LPS and CS, which was closely associated with downregulation of ERK phosphorylation. Therefore, our searching offers that silibinin has a remedical probable for COPD disease. Copyright © 2016 John Wiley & Sons, Ltd.

Park JW ，Shin NR ，Shin IS ，Kwon OK ，Kim JS ，Oh SR ，Kim JH ，Ahn KS ... -  《-》

Melatonin suppresses fibrotic responses induced by cigarette smoke via downregulation of TGF-β1.

Shin NR ，Park JW ，Lee IC ，Ko JW ，Park SH ，Kim JS ，Kim JC ，Ahn KS ，Shin IS ... -  《Oncotarget》