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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Pulmonary fibrosis in L-NAME-treated mice is dependent on an activated endothelin system.
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Pulmonary fibrosis in L-NAME-treated mice is dependent on an activated endothelin system.

机译：L-NAME处理的小鼠中的肺纤维化取决于激活的内皮素系统。

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Activation of the endothelin (ET) system promotes vasoconstriction, inflammation, and fibrosis in various tissues, including the lung. Therefore, ET-1 transgenic mice overexpressing ET-1 develop pulmonary fibrosis in a slow, age-dependent manner. In vivo, NO is the most important counterregulatory mediator of the ET system and decreases ET-1 promoter activity. The aim of our study was to elucidate the impact on pulmonary inflammation and fibrosis of the interaction between NO and the ET system in young ET-1 transgenic mice before the onset of pulmonary fibrosis. Male ET-1 transgenic mice and wild-type littermates at the age of 8 weeks were randomly allocated to the following 6 groups: WT (n = 11), wild-type animals without treatment; WT + L-NAME (n = 14), wild-type animals receiving L-NAME, an inhibitor of NO synthase; WT + L-NAME + LU (n = 13), wild-type animals receiving L-NAME and LU 302872, a dual ETA/ETB-receptor antagonist; ET1tg (n = 10), ET-1 transgenic mice; ET1tg + L-NAME (n = 13); and ET1tg + L-NAME + LU (n = 13). After 6 weeks, animals were euthanized, and hearts and lungs were harvested for histology and immunohistochemistry. No differences in pulmonary inflammation, as indicated by macrophage infiltration, or in interstitial fibrosis were observed between WT and ET1tg mice at baseline; however, inflammation and interstitial fibrosis were significantly enhanced in ET1tg mice, but not in WT groups, after L-NAME treatment. The combined ETA/ETB-receptor antagonist LU 302872 abolished inflammation and interstitial fibrosis in L-NAME-treated ET1tg mice. Perivascular fibrosis and media/lumen ratio of pulmonary bronchi and arteries did not differ between all study groups. In our study L-NAME induced pulmonary fibrosis and inflammation only in young ET1tg mice. Additional treatment with LU 302872 abolished these effects. We thus conclude that an imbalance between an activated ET system and a suppressed NO system contributes to pulmonary inflammation and fibrosis.
机译：内皮素（ET）系统的激活可促进包括肺在内的各种组织的血管收缩，炎症和纤维化。因此，过表达ET-1的ET-1转基因小鼠以缓慢的，年龄依赖性的方式发展为肺纤维化。在体内，NO是ET系统最重要的反调节介质，并且会降低ET-1启动子活性。我们研究的目的是阐明在肺纤维化发生之前，年轻的ET-1转基因小鼠中NO和ET系统之间的相互作用对肺部炎症和纤维化的影响。将8周龄的雄性ET-1转基因小鼠和野生型同窝小鼠随机分为以下6组：WT（n = 11），未经治疗的野生型动物; WT + L-NAME（n = 14），野生型动物，接受NO合酶抑制剂L-NAME; WT + L-NAME + LU（n = 13），野生型动物，接受L-NAME和LU 302872（双重ETA / ETB受体拮抗剂）; ET1tg（n = 10），ET-1转基因小鼠; ET1tg + L-NAME（n = 13）;和ET1tg + L-NAME + LU（n = 13）。 6周后，对动物实施安乐死，并收集心脏和肺以进行组织学和免疫组织化学检查。在基线时，WT和ET1tg小鼠之间未观察到巨噬细胞浸润所指示的肺部炎症或间质纤维化的差异。然而，经过L-NAME处理后，ET1tg小鼠的炎症和间质纤维化明显增强，而WT组则没有。联合使用的ETA / ETB受体拮抗剂LU 302872消除了L-NAME治疗的ET1tg小鼠的炎症和间质纤维化。在所有研究组之间，血管周纤维化以及肺支气管和动脉的中/腔比没有差异。在我们的研究中，L-NAME仅在年轻的ET1tg小鼠中诱导了肺纤维化和炎症。 LU 302872的进一步治疗消除了这些影响。因此，我们得出结论，活化的ET系统和NO抑制系统之间的不平衡会导致肺部炎症和纤维化。

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