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 ... -  《-》

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 ... -  《-》

Modificated Mahuang-Tang, a traditional herbal medicine suppresses inflammatory responses induced by cigarette smoke in human airway epithelial cell and mice.

Cigarette smoke (CS) is a major contributor to the high incidence of chronic obstructive pulmonary disease (COPD) featured as chronic inflammation and airway obstruction. Mahuang-Tang is a traditional polyherbal mixture composed of four different herbs. It is widely used in Asia as a remedy for allergic reaction and inflammation. We investigated the effects of a modificated Mahuang-Tang water extract (MTWE) against airway inflammation caused by CS and lipopolysaccharide (LPS) in mice and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells. CS exposed to animals for 1 h per day from day 1 to day 7 and treated with LPS intranasally on day 4. One hour before CS exposure, animals were received MTWE (50 or 100 mg/kg) by oral gavage. Inflammatory cell count and cytokines levels were measured in the bronchoalveolar lavage fluid. Expression levels of matrix metalloprotease-9 (MMP-9) and extracellular signal-regulated kinase (Erk) were analyzed by western blotting. MTWE markedly decreased the neutrophil and other inflammatory cell counts in the bronchoalveolar lavage fluid and reduced proinflammatory mediators as evidenced by the decreases in inflammatory cell recruitment in lung tissue. Furthermore, MTWE meaningfully declined MMP-9 expression and reduced the Erk phosphorylation, caused by the CS and LPS exposure. In in vitro experiments, MTWE suppressed the elevated expression of proinflammatory cytokines induced by CSC treatment. MTWE reduced Erk phosphorylation and MMP-9 expression in CSC-stimulated H292 cells. Overall, MTWE effectively inhibited the pulmonary inflammation and MMP-9 expression caused by the CS and LPS exposure, which was closely involved in suppression of Erk phosphorylation. These results suggest that MTWE possesses a potential for the treatment of COPD.

Ko JW ，Seo CS ，Shin NR ，Kim JS ，Lee SI ，Kim JC ，Kim SH ，Shin IS ... -  《-》

Inhibitory effects of Pycnogenol® (French maritime pine bark extract) on airway inflammation in ovalbumin-induced allergic asthma.

Pycnogenol® (PYC) is a standardized extracts from the bark of the French maritime pine (Pinus maritime) and used as a herbal remedy for various diseases. In this study, we evaluated the effects of PYC on airway inflammation using a model of ovalbumin (OVA)-induced allergic asthma and RAW264.7 cells. PYC decreased nitric oxide production and reduced the interleukine (IL)-1β and IL-6 levels in LPS-stimulated RAW264.7 cells. PYC also reduced the expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase (MMP)-9 and enhanced the expression of hemeoxygenase (HO)-1. In the in vivo experiment, PYC decreased the inflammatory cell count and the levels of IL-4, IL-5, IL-13, and immunoglobulin (Ig) E in BALF or serum. These results are consistent with the histological analysis findings, which showed that PYC attenuated the airway inflammation and mucus hypersecretion induced by OVA challenge. In addition, PYC enhanced the expression of HO-1. In contrast, PYC inhibited the elevated expression of iNOS and MMP-9 proteins induced by OVA challenge. In conclusion, PYC exhibits protective effects against OVA-induced asthma and LPS-stimulated RAW264.7 cells. These results suggest that PYC has potential as a therapeutic agent for the treatment of allergic asthma.

Shin IS ，Shin NR ，Jeon CM ，Hong JM ，Kwon OK ，Kim JC ，Oh SR ，Hahn KW ，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 ... -  《-》