Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Centre for Integrative Biology, University of Trento, Trento, Italy.
Free Radic Biol Med. 2018 Feb 1;115:1-9. doi: 10.1016/j.freeradbiomed.2017.11.007. Epub 2017 Nov 9.
F-isoprostanes (F-IsoPs) have been considered markers of oxidative stress in various pulmonary diseases, but little is known about their possible role in pulmonary fibrosis. In this study, we have investigated the potential key role of F-IsoPs as markers and mediators of bleomycin (BLM)-induced pulmonary fibrosis in rats. During the in vivo study, plasma F-IsoPs showed a peak at 7 days and remained elevated for the entire experimental period. Lung F-IsoP content nearly tripled 7 days following the intratracheal instillation of BLM, and by 28 days, the value increased about fivefold compared to the controls. Collagen deposition correlated with F-IsoP content in the lung. Furthermore, from day 21 onwards, lung sections from BLM-treated animals showed α-smooth muscle actin (α-SMA) positive cells, which were mostly evident at 28 days. In vitro studies performed in rat lung fibroblasts (RLF) demonstrated that either BLM or F-IsoPs stimulated both cell proliferation and collagen synthesis. Moreover, RLF treated with F-IsoPs showed a significant increase of α-SMA expression compared to control, indicating that F-IsoPs can readily activate fibroblasts to myofibroblasts. Our data demonstrated that F-IsoPs can be mediators of key events for the onset and development of lung fibrosis, such as cell proliferation, collagen synthesis and fibroblast activation. Immunocytochemistry analysis, inhibition and binding studies demonstrated the presence of the thromboxane A receptor (TP receptor) on lung fibroblasts and suggested that the observed effects may be elicited through the binding to this receptor. Our data added a new perspective on the role of F-IsoPs in lung fibrosis by providing evidence of a profibrotic role for these mediators in the pathogenesis of pulmonary fibrosis.
F-型前列腺素（F-IsoPs）已被认为是各种肺部疾病中氧化应激的标志物，但它们在肺纤维化中的可能作用知之甚少。在这项研究中，我们研究了 F-IsoPs 作为博莱霉素（BLM）诱导的大鼠肺纤维化的标志物和介质的潜在关键作用。在体内研究中，血浆 F-IsoPs 在第 7 天达到峰值，并在整个实验期间保持升高。BLM 气管内滴注后第 7 天，肺 F-IsoP 含量几乎增加了三倍，而 28 天时，与对照组相比，增加了约五倍。胶原沉积与肺中的 F-IsoP 含量相关。此外，从第 21 天开始，BLM 处理的动物的肺切片显示出α-平滑肌肌动蛋白（α-SMA）阳性细胞，在第 28 天最为明显。在大鼠肺成纤维细胞（RLF）进行的体外研究表明，BLM 或 F-IsoPs 均可刺激细胞增殖和胶原合成。此外，与对照组相比，用 F-IsoPs 处理的 RLF 显示出α-SMA 表达的显著增加，表明 F-IsoPs 可以轻易地激活成纤维细胞向肌成纤维细胞转化。我们的数据表明，F-IsoPs 可以作为肺纤维化发生和发展的关键事件的介质，如细胞增殖、胶原合成和成纤维细胞激活。免疫细胞化学分析、抑制和结合研究表明，肺成纤维细胞上存在血栓素 A 受体（TP 受体），并表明观察到的效应可能是通过与该受体结合而引起的。我们的数据通过提供这些介质在肺纤维化发病机制中具有促纤维化作用的证据，为 F-IsoPs 在肺纤维化中的作用提供了新的视角。
