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      Rosiglitazone attenuates the metalloprotease/anti-metalloprotease imbalance in emphysema induced by cigarette smoke: involvement of extracellular signal-regulated kinase and NFκB signaling

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          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 IκBαphosphorylation was increased in the lung tissue of RCS rats.

          Conclusion

          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.

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          Most cited references 34

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          Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA.

          The human gut microflora is important in regulating host inflammatory responses and in maintaining immune homeostasis. The cellular and molecular bases of these actions are unknown. Here we describe a unique anti-inflammatory mechanism, activated by nonpathogenic bacteria, that selectively antagonizes transcription factor NF-kappaB. Bacteroides thetaiotaomicron targets transcriptionally active NF-kappaB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-gamma abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.
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            Modulation of PPAR activity via phosphorylation.

            Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
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              The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study.

              Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density. We used a random coefficient model to assess predictors of both CT lung density and its longitudinal change over 3 years in 1928 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Lung density was measured for every voxel in the CT scan and after correcting for lung volume was expressed as the density at lowest 15th percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552. Lung density at baseline was influenced by age, sex, body-mass index, current smoking status and smoking history, and severity of airflow limitation. The observed decline in lung density was variable (mean decline -1·13 g/L [SE 0·06] per year). The annual decline in lung density was more rapid in women (additional -0·41 [SE 0·14] g/L per year, p=0·003) than men and in current smokers (additional -0·29 [SE 0·14] g/L per year, p=0·047) than in former smokers. Circulating levels of the biomarkers surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung density and its decline over time. This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender. We identified potential biochemical predictors of the presence and progression of emphysema. GlaxoSmithKline. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2015
                07 April 2015
                : 10
                : 715-724
                Affiliations
                Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang, People’s Republic of China
                Author notes
                Correspondence: Qiu-yue Wang, Department of Respiratory Medicine the First Hospital of China Medical University, 155 Nanjing North Street, Shenyang 110004, People’s Republic of China, Tel +86 24 8328 2219, Fax +86 24 8328 2002, Email qywangcmu@ 123456126.com
                Article
                copd-10-715
                10.2147/COPD.S77514
                4396520
                © 2015 Hou et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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