Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A
Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A
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DOI：
10.1074/jbc.m113.546812
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发表时间：
2014-03-14
影响因子：
4.8
通讯作者：
Dulin, Nickolai O.
中科院分区：
文献类型：
--
作者：
Kach, Jacob;Sandbo, Nathan;Dulin, Nickolai O.
背景：诺斯汀是一种安全的口服止咳药，也可结合微管并诱导癌细胞死亡。结果：诺伐他汀通过前列腺素受体和PKA的激活抑制肌成纤维细胞分化和肺纤维化。结论：诺伐他汀是一种通过EP2前列腺素受体激活PKA而发挥抗纤维化作用的药物。意义：本研究描述了一种新的抗纤维化作用和新的作用机制。肌成纤维细胞分化是纤维化疾病发病机制中的一个关键过程。我们以前已经证明，肌成纤维细胞的分化受微管聚合状态的调节。在这项工作中，我们研究了止咳药物诺斯汀的潜在的抗纤维化作用，最近发现它可以结合微管并影响微管的动力学。诺斯汀抑制转化生长因子诱导的人肺成纤维细胞分化。在博莱霉素性肺纤维化模型中，治疗性诺伐他汀治疗可显著减轻肺纤维化。诺伐他汀不影响HLFS的微管含量，但可抑制转化生长因子诱导的应力纤维的形成和血清反应因子的激活，但不影响Smad信号转导。此外，诺斯汀刺激蛋白激酶A(PKA)的快速而深刻的激活，这介导了诺斯汀的抗肝纤维化作用，如PKA抑制剂PKI所评估的那样。相反，诺斯汀不能激活人支气管或肺泡上皮细胞中的PKA。最后，EP2前列腺素E-2受体拮抗剂PF-04418948可阻断PKA的激活和诺斯汀的抗纤维化作用，而EP4、前列腺素D-2或前列腺素受体拮抗剂不能阻断PKA的激活和诺斯汀的抗纤维化作用。总之，我们首次证实了诺斯汀在体外和体内的抗纤维化作用，并描述了一种新的作用机制，即通过EP2前列腺素E-2受体介导的肺成纤维细胞PKA的激活。
Background: Noscapine is a safe orally available anticough medicine also known to bind microtubules and induce cancer cell death. Results: Noscapine inhibits myofibroblast differentiation and pulmonary fibrosis through prostaglandin receptors and activation of PKA. Conclusion: Noscapine is an antifibrotic drug acting through PKA activation via EP2 prostaglandin receptors. Significance: This study describes a novel antifibrotic function and novel mechanism of action of noscapine.Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF--induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF--induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E-2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D-2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E-2 receptor-mediated activation of PKA in pulmonary fibroblasts.