title: Effect of simvastatin on MMPs and TIMPs in cigarette smoke-induced rat COPD model.
abstract: 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/μm2of 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±2.5×109cells/L vs 1.1±1.3×109cells/L of control,P<0.01), and it was significantly reduced by simvastatin (2.3±2.1×109cells/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Respiratory Medicine, First Hospital of Hebei Medical University.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Respiratory Medicine, Chest Hospital of Hebei Province.
authors.forename: Jie
authors.initials: J
authors.lastname: Bao
authors.affiliation: Maternal and Child Health Care Center of Hebei Province.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Emergency, First Hospital of Hebei Medical University, Shijiazhuang.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, People's Hospital of Liaocheng, Liaocheng.
authors.forename: Lindong
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Respiratory Medicine, First Hospital of Hebei Medical University.
authors.forename: Junhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, First Hospital of Hebei Medical University.
authors.forename: Lihai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Hebei Medical University, Shijiazhuang, People's Republic of China.
authors.forename: Mo
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Respiratory Medicine, Chest Hospital of Hebei Province.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, First Hospital of Hebei Medical University.
authors.forename: Wuzhuang
authors.initials: W
authors.lastname: Sun
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D000893:Anti-Inflammatory Agents; D053508:Matrix Metalloproteinase 12; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D019821:Simvastatin; D012906:Smoke; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C576839:TIMP1 protein, rat; C572337:Mmp9 protein, rat; C000602030:matrix metallopeptidase 12, rat
keywords: smoking; tissue injury; tissue repair