Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
J Pineal Res. 2014 May;56(4):398-407. doi: 10.1111/jpi.12127. Epub 2014 Mar 28.
Mucus acts as a primary defense system in the airway against various stimuli. However, excess mucus production causes a reduction in lung function via limitation of the airflow in the airway of patients suffering from asthma or chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of melatonin on the production of MUC5AC, a major constituent of the mucin that is secreted from the airway, using epidermal growth factor (EGF)-stimulated NCI-H292 cells, a human mucoepidermoid carcinoma cell line, and an ovalbumin (OVA)-induced asthma murine model. Melatonin treatment significantly reduced the mRNA and protein levels of MUC5AC and reduced interleukin (IL)-6 production in EGF-stimulated H292 cells. Melatonin markedly decreased the phosphorylation of MAPKs, including ERK1/2, JNK, and p-38, induced by EGF stimulation. These findings were consistent with the results using MAPK inhibitors. Particularly, co-treatment with melatonin and a MAPK inhibitor more effectively suppressed MAPK phosphorylation than treatment with a MAPK inhibitor alone, which resulted in a reduction in MUC5AC expression. In the asthma murine model, melatonin-treated mice exhibited a marked reduction in MUC5AC expression in the airway compared with the OVA-induced mice. These reductions were accompanied by reductions in proinflammatory cytokine production and inflammatory cell infiltration. Collectively, these findings indicate that melatonin effectively inhibits MUC5AC expression. These effects may be closely associated with the inhibition of MAPK phosphorylation. Furthermore, our study suggests that melatonin could represent a potential therapeutic for chronic airway diseases, such as asthma and COPD.
黏液在气道中作为主要防御系统对抗各种刺激。然而，过量的黏液产生会通过限制哮喘或慢性阻塞性肺疾病（COPD）患者气道中的气流，导致肺功能下降。在这项研究中，我们使用表皮生长因子（EGF）刺激的 NCI-H292 细胞（一种人黏液表皮样癌细胞系）和卵清蛋白（OVA）诱导的哮喘小鼠模型，评估了褪黑素对气道分泌的黏蛋白主要成分 MUC5AC 产生的影响。褪黑素处理显著降低了 EGF 刺激的 H292 细胞中 MUC5AC 的 mRNA 和蛋白水平，并降低了白细胞介素（IL）-6 的产生。褪黑素显著降低了 EGF 刺激诱导的 MAPKs（包括 ERK1/2、JNK 和 p-38）的磷酸化。这些发现与使用 MAPK 抑制剂的结果一致。特别是，褪黑素和 MAPK 抑制剂的共同处理比单独使用 MAPK 抑制剂更有效地抑制了 MAPK 磷酸化，从而导致 MUC5AC 表达减少。在哮喘小鼠模型中，与 OVA 诱导的小鼠相比，褪黑素处理的小鼠气道中的 MUC5AC 表达明显减少。这些减少伴随着促炎细胞因子产生和炎症细胞浸润的减少。总之，这些发现表明褪黑素能有效抑制 MUC5AC 的表达。这些作用可能与 MAPK 磷酸化的抑制密切相关。此外，我们的研究表明，褪黑素可能成为哮喘和 COPD 等慢性气道疾病的潜在治疗方法。
