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Effect of simvastatin on MMPs and TIMPs in cigarette smoke-induced rat COPD model

Authors Sun J, Bao J, Shi Y, Zhang B, Yuan L, Li J, Zhang L, Sun M, Zhang L, Sun W

Received 13 April 2016

Accepted for publication 4 August 2016

Published 22 February 2017 Volume 2017:12 Pages 717—724

DOI https://doi.org/10.2147/COPD.S110520

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Charles Downs

Peer reviewer comments 2

Editor who approved publication: Dr Richard Russell

Jiawei Sun,1,* Jie Bao,2,* Yanan Shi,3 Bin Zhang,4 Lindong Yuan,5 Junhong Li,1 Lihai Zhang,1 Mo Sun,6 Ling Zhang,2 Wuzhuang Sun1

1Department of Respiratory Medicine, First Hospital of Hebei Medical University, 2Department of Respiratory Medicine, Chest Hospital of Hebei Province, 3Maternal and Child Health Care Center of Hebei Province, 4Department of Emergency, First Hospital of Hebei Medical University, Shijiazhuang, 5Department of Respiratory Medicine, People’s Hospital of Liaocheng, Liaocheng, 6Hebei Medical University, Shijiazhuang, People’s Republic of China

*These authors contributed equally to this work

Background: Proteases may play an important role in the development of chronic obstructive pulmonary disease and emphysema in response to cigarette smoke exposure (CSE). The current study was designed to investigate the expression of matrix metalloproteinase (MMP)-8, MMP-9, MMP-12, tissue inhibitor of MMP (TIMP)-1, and TIMP-4 in rat lung tissues in response to CSE, and assessed the effect of simvastatin in regulating expression of MMPs and TIMPs.
Methods: Thirty normal Sprague Dawley (SD) rats were divided into control (n=10), CSE (n=10), and CSE plus simvastatin (n=10) groups. Animals were whole-body exposed to the cigarette smoke in the box for 1 hour each time, twice a day, 5 days a week for 16 weeks. Animals of CSE + simvastatin group were intra-gastrically administered simvastatin at a dose of 5 mg/kg/day followed by CSE. Bronchoalveolar lavage fluid was harvested for inflammatory cell count and lung tissues were stained for morphologic examination. Expression of mRNA and protein level of MMP-8, MMP-9, MMP-12, TIMP-1, and TIMP-4 was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry, respectively.
Results: CSE resulted in a significant increase of mean linear intercept (MLI: 34.6±2.0 µm) and bronchial wall thickness and diameter (BWT/D, 0.250±0.062) compared to control (MLI: 24.0±1.7 µm, BWT/D: 0.160±0.034, P<0.01). In contrast, mean alveolar number was significantly decreased in the CSE group than that in the control group (13.5±2.0 of CSE vs 21.5±2.0 N/µm2 of control, P>0.01). Simvastatin slightly but not significantly prevented alteration of MLI, BWT/D, and mean alveolar number (MLI: 33.4±1.4 µm; BWT/D: 0.220±0.052; mean alveolar number: 15.5±2.5 N/µm2, P>0.05). Total white blood cell was significantly increased in the bronchoalveolar lavage fluid of smoking group (3.3±2.5×109 cells/L vs 1.1±1.3×109 cells/L of control, P<0.01), and it was significantly reduced by simvastatin (2.3±2.1×109 cells/L, P<0.01). CSE resulted in significantly increased accumulation of neutrophils and macrophages (neutrophils: 14.5%±1.3% of CSE group vs 9.1%±1.5% of control; macrophage: 91%±3% of CSE group vs 87%±2% of control, P<0.05), and simvastatin significantly reduced neutrophils (12.9%±2.0%, P<0.05) in the bronchoalveolar lavage fluid, but had no effect on macrophage (89%±1.6%, P>0.05). In response to CSE, MMP-8, MMP-9, and MMP-12 mRNA were upregulated more than sevenfold, while TIMP-1 and TIMP-4 increased two- to fivefold. Simvastatin significantly blocked upregulation of MMP-8 and -9 (P<0.01), but had no effect on MMP-12, TIMP-1 and TIMP-4 mRNA (P>0.05). In addition, simvastatin significantly blocked cigarette smoke-induced MMP-8 and -9 protein synthesis, while it had no significant effect on TIMP-1 and -4 protein synthesis even in the presence of cigarette smoke.
Conclusion: CSE resulted in imbalance of MMPs and TIMPs, and by which mechanism, cigarette smoke may lead to insufficient lung tissue repair. Simvastatin partially blocked airway inflammation and MMP production and, thus, statins may modulate composition of the lung extracellular matrix.

Keywords: tissue injury, tissue repair, smoking

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