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.
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
In-Sik
IS
Shin
Na-Rae
NR
Shin
Ji-Won
JW
Park
Chan-Mi
CM
Jeon
Ju-Mi
JM
Hong
Ok-Kyoung
OK
Kwon
Joong-Sun
JS
Kim
In-Chul
IC
Lee
Jong-Choon
JC
Kim
Sei-Ryang
SR
Oh
Kyung-Seop
KS
Ahn
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009093:Mucus / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012907:Smoking / Q000009:adverse effects / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016329:Sp1 Transcription Factor / Q000378:metabolism*
D000975:Antioxidants; D008070:Lipopolysaccharides; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin
Erk/Sp1; Melatonin; chronic obstructive pulmonary disease; cigarette smoke