Thoracic Diseases Research Unit, Departments of Medicine and Biochemistry, 8-24 Stabile, Mayo Clinic, Rochester, MN 55905, USA.
Cells. 2021 Dec 11;10(12):3502. doi: 10.3390/cells10123502.
Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-β1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-β1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required.
特发性肺纤维化（IPF）仍然是一种难以治愈的致命疾病，尽管最近出现了抗纤维化药物。像许多慢性疾病一样，IPF 的成功治疗可能受益于同时使用多种具有协同益处的药物。在这方面，磷酸二酯酶 5 抑制剂（PDE5-Is）在 IPF 中的研究主要是基于其已确立的肺血管作用。然而，最近的数据表明，某些 PDE5-Is，特别是伐地那非，也可能减少转化生长因子-β1（TGF-β1）的激活和细胞外基质（ECM）的积累，使其成为治疗 IPF 的潜在靶点。我们评估了成纤维细胞 TGF-β1 驱动的细胞外基质（ECM）生成和信号转导以及上皮间质转化（EMT），并用 PDE5-I 伐地那非进行预处理。此外，还使用纤维连接蛋白酶联免疫吸附试验（ELISA）评估了伐地那非与尼达尼布联合使用对 ECM 的协同抑制作用。最后，在博来霉素小鼠模型中研究了伐地那非对纤维化的影响。我们的研究结果表明，伐地那非单独抑制 ECM 的产生，并且与尼达尼布联合使用时还表现出显著的协同抑制 ECM 的作用。有趣的是，伐地那非被证明可以改善博来霉素处理的小鼠的纤维化标志物并提高其存活率。伐地那非可能是 IPF 的一种潜在治疗方法，单独使用或与尼达尼布联合使用。然而，还需要进一步的研究。
