title: Rosiglitazone attenuates the metalloprotease/anti-metalloprotease imbalance in emphysema induced by cigarette smoke: involvement of extracellular signal-regulated kinase and NFκB signaling.
abstract: OBJECTIVE
  We investigated how rosiglitazone attenuated cigarette smoke (CS)-induced emphysema in a rat model. In particular, we focused on its possible effects on the imbalance between metalloprotease (MMP) and anti-MMP activity, mitogen-activated protein kinase (MAPK) phosphorylation, and nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling pathway over-activation.
  
  
  METHODS
  A total of 36 Wistar rats were divided into three groups (n=12 each): animals were exposed to CS for 12 weeks in the absence (the CS group) or presence of 30 mg/kg rosiglitazone (the rosiglitazone-CS [RCS] group); a control group was treated with the rosiglitazone vehicle only, without any CS exposure. Histopathology of lung tissue in all groups was evaluated to grade severity of the disease. Expression levels of peroxisome proliferator-activated receptor γ (PPARγ), MMP2, and MMP9 in lung tissue were determined and compared using Western blotting and immunohistochemistry. Activation of MAPKs, NFκB, and the nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha (IκBα) phosphorylation in lung tissue was examined by Western blotting.
  
  
  RESULTS
  Emphysema-related pathology, based on inter-alveolar wall distance and alveolar density, was less severe in the RCS group than in the CS group. Compared with the CS group, levels of PPARγ were higher in the RCS group, and levels of MMP2 and MMP9 proteins were lower in the RCS rats. Levels of activated MAPKs and NFκB were also lower, while the IκBα phosphorylation was increased in the lung tissue of RCS rats.
  
  
  CONCLUSIONS
  Our findings suggest that oral administration of rosiglitazone attenuates the metalloprotease activity induced by CS, and the underlying mechanism might involve the activation of signaling pathways dependent on MAPKs or NFκB. Our results further suggest that PPARγ contributes to the pathogenesis of emphysema as well as airway inflammation induced by CS.
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hou
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Qiu-Yue
authors.initials: QY
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010766:Phosphorylation; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017208:Rats, Wistar; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D047495:PPAR gamma; D012906:Smoke; D045162:Thiazolidinediones; D014028:Tobacco Smoke Pollution; D000077154:Rosiglitazone; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: NFκB; PPAR; chronic obstructive pulmonary disease; emphysema; matrix metalloprotease2; matrix metalloprotease9