title: Erythromycin attenuates metalloprotease/anti-metalloprotease imbalance in cigarette smoke-induced emphysema in rats via the mitogen-activated protein kinase/nuclear factor-κB activation pathway.
abstract: The present study investigated whether erythromycin (ERY) reduces cigarette smoke (CS)-induced emphysema in rats and aimed to determine the anti-inflammatory effect of ERY, which may identify potential treatments for chronic obstructive pulmonary disease. Furthermore, the current study focused on the potential effects on the imbalance between matrix metalloprotease (MMP) and anti-MMP activity, the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor‑κB (NF‑κB) signaling pathway. Wistar rats were divided into the following three groups (n=12 each): control (ERY vehicle only, without any CS exposure), CS (animals were exposed to CS for 12 weeks) and CS + ERY (animals were exposed to CS for 12 weeks and received 100 mg/kg/day ERY). The recruitment of inflammatory cells into the bronchoalveolar lavage fluid (BALF) and the histopathology of lung tissue from all groups was evaluated to grade the severity of the emphysema. The expression of MMP‑2, MMP‑9 and tissue inhibitor of metalloproteinase‑1 was evaluated by immunohistochemistry and western blotting. The activation of MAPKs, NF‑κB and inhibitor of NF‑κB (IκBα), in lung tissues was examined by western blotting. Treatment with ERY resulted in fewer inflammatory cells and cytokines in the BALF, and fewer emphysema‑associated changes in the lungs compared with control. The stimulus of CS promoted the phosphorylation of extracellular signal‑regulated kinase (ERK)1/2 and p38, but not c‑Jun NH2‑terminal kinase, thereby inducing the activation of the ERK/MAPK signaling pathway in rats. Furthermore, CS exposure increased the expression of NF-κB and decreased the expression of IκBα. The levels of phosphorylated ERK1/2 and p38 were significantly reduced in rats with CS‑induced emphysema when treated with ERY compared with the CS group. The results of the present study therefore indicate that oral administration of ERY may suppress CS‑induced emphysema by regulating inflammatory cytokines and the MMP/anti-MMP imbalance via the MAPK/NF-κB pathway.
authors.affiliation: Department of Respiratory Medicine, The Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China.
authors.forename: Dongxue
authors.initials: D
authors.lastname: Gu
authors.affiliation: The Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hou
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004917:Erythromycin / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000032:analysis; D008168:Lung / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012906:Smoke; D019715:Tissue Inhibitor of Metalloproteinase-1; D000072000:NF-KappaB Inhibitor alpha; D007975:Leukotriene B4; D004917:Erythromycin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9