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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
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