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首页> 外文期刊>Life sciences >Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors.
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Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors.

机译：通过4型磷酸二酯酶抑制剂调节人肺成纤维细胞产生的基质金属蛋白酶。

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摘要

Over-expression of matrix metalloproteinases by lung fibroblasts has been blamed for much of the tissue destruction associated with airway inflammation. Because cyclic AMP is known to regulate fibroblast proliferation, as well as cytokine and extracellular matrix protein production, the current study was designed to evaluate the ability of three selective phosphodiesterase (PDE) type 4 inhibitors, rolipram, cilomilast and CI-1044, to inhibit extracellular matrix degradation. Using zymography and ELISA, we found that pro-MMP-2 release was enhanced following 24 h treatment of human lung fibroblast (MRC-5) with TGF-beta1 (10 ng/ml) or TNF-alpha (10 ng/ml), whereas PMA (0.02 microM) had no effect. One hour of pre-incubation with PDE4 inhibitors (10 microM) induced an inhibition of TNF-alpha-stimulated pro-MMP-2 release. Zymography and immunoblotting revealed that fibroblasts cultured with PMA or TNF-alpha released increased amounts of pro-MMP-1, whereas TGF-beta1 had no effect. Incubation with CI-1044 or cilomilast significantly prevented the TNF-alpha increase in pro-MMP-1. These results suggest that PDE4 inhibitors are effective in inhibiting the pro-MMP-2 and pro-MMP-1 secretion induced by TNF-alpha and might underline a potential therapeutic benefit of selective PDE4 inhibitors in lung diseases associated with abnormal tissue remodelling.
机译：肺成纤维细胞过度表达基质金属蛋白酶被归咎于与气道炎症相关的许多组织破坏。由于已知环状AMP调节成纤维细胞的增殖以及细胞因子和细胞外基质蛋白的产生，因此本研究旨在评估三种选择性磷酸二酯酶（PDE）4型抑制剂rolipram，cilomilast和CI-1044的抑制能力。细胞外基质降解。使用酶谱法和ELISA，我们发现，用TGF-beta1（10 ng / ml）或TNF-alpha（10 ng / ml）处理人肺成纤维细胞（MRC-5）24小时后，pro-MMP-2的释放得以增强，而PMA（0.02 microM）无效。与PDE4抑制剂（10 microM）一起预孵育一小时，可抑制TNF-α刺激的pro-MMP-2释放。酶谱和免疫印迹法表明，与PMA或TNF-α培养的成纤维细胞释放的pro-MMP-1量增加，而TGF-beta1没有作用。与CI-1044或cilomilast一起孵育可显着阻止pro-MMP-1中的TNF-alpha升高。这些结果表明，PDE4抑制剂可有效抑制TNF-α诱导的pro-MMP-2和pro-MMP-1分泌，并可能强调选择性PDE4抑制剂在与异常组织重塑相关的肺部疾病中的潜在治疗益处。

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