PDF(Pubmed)
Abstract：
BACKGROUND: Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well.
METHODS: Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker.
RESULTS: OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFβ1 or IL13, and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFβ1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment.
CONCLUSIONS: OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.
METHODS: Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker.
RESULTS: OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFβ1 or IL13, and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFβ1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment.
CONCLUSIONS: OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.
摘要：
背景：肺纤维化是一种具有高死亡率的慢性肺病，只有两种批准的药物（吡非尼酮和尼达尼布）可以减轻其进展。迄今为止,没有可靠的生物标志物来评估这两种药物的纤维化发展和/或治疗效果.骨保护素（OPG）被用作诊断肝纤维化的血清标志物，我们以前已经证明它也与肺纤维化有关。
方法：在这里，我们使用鼠和人类精确切割的肺切片来研究肺组织中OPG的调节，以阐明其是否跟踪（早期）纤维化发展并响应抗纤维化治疗，以评估其作为生物标志物的潜在用途。
结果：用促纤维化细胞因子TGFβ1或IL13治疗后，小鼠肺片中OPGmRNA的表达更高，并且与Fn和PAI1mRNA的表达密切相关。与对照小鼠切片相比,从纤维化的人肺切片释放更多的OPG蛋白,并且与对照小鼠切片相比,从TGFβ1和IL13刺激的小鼠肺切片释放更多的OPG蛋白。当用吡非尼酮或尼达尼布处理鼠切片时,这种OPG释放被抑制。吡非尼酮治疗抑制了人纤维化肺切片的OPG释放。
结论：OPG可以在纤维化发展的早期阶段被检测到，在早期和晚期纤维化中，用目前市场上的抗纤维化药物治疗肺纤维化。因此,应进一步研究OPG作为肺纤维化的潜在生物标志物和治疗效果的潜在替代标志物。
方法：在这里，我们使用鼠和人类精确切割的肺切片来研究肺组织中OPG的调节，以阐明其是否跟踪（早期）纤维化发展并响应抗纤维化治疗，以评估其作为生物标志物的潜在用途。
结果：用促纤维化细胞因子TGFβ1或IL13治疗后，小鼠肺片中OPGmRNA的表达更高，并且与Fn和PAI1mRNA的表达密切相关。与对照小鼠切片相比,从纤维化的人肺切片释放更多的OPG蛋白,并且与对照小鼠切片相比,从TGFβ1和IL13刺激的小鼠肺切片释放更多的OPG蛋白。当用吡非尼酮或尼达尼布处理鼠切片时,这种OPG释放被抑制。吡非尼酮治疗抑制了人纤维化肺切片的OPG释放。
结论：OPG可以在纤维化发展的早期阶段被检测到，在早期和晚期纤维化中，用目前市场上的抗纤维化药物治疗肺纤维化。因此,应进一步研究OPG作为肺纤维化的潜在生物标志物和治疗效果的潜在替代标志物。
