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

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. 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. 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, 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/μm , >0.05). Total white blood cell was significantly increased in the bronchoalveolar lavage fluid of smoking group (3.3±2.5×10 cells/L vs 1.1±1.3×10 cells/L of control,