Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
Institute for Next Generation Healthcare, Department of Genetics and Genomic Sciences, and.
Am J Respir Crit Care Med. 2022 Dec 15;206(12):1463-1479. doi: 10.1164/rccm.202010-3832OC.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Using an data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: ) in normal human lung fibroblasts; ) in bleomycin and recombinant Ad-TGF-β (adenovirus transforming growth factor-β) murine models of pulmonary fibrosis; and ) in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
特发性肺纤维化（IPF）是一种慢性、进行性且常致命的疾病。美国食品和药物管理局批准的两种抗纤维化药物——尼达尼布和吡非尼酮——可以减缓肺功能下降的速度，但疗效因人而异，且常见副作用。我们采用一种数据驱动的方法，发现 IPF 疾病的转录组扰动与 saracatinib 诱导的扰动之间存在着强大的关联，saracatinib 是一种最初为肿瘤适应证开发的选择性Src 激酶抑制剂。基于这些观察结果，我们假设 saracatinib 在减轻肺纤维化方面会有效。我们在三种临床前模型中研究了 saracatinib 相对于尼达尼布和吡非尼酮的抗纤维化疗效：）在正常人类肺成纤维细胞中；）在博来霉素和重组 Ad-TGF-β（腺病毒转化生长因子-β）诱导的肺纤维化小鼠模型中；）在这两种小鼠模型以及来自 IPF 患者和健康供体的小鼠和人类精密切割肺切片中。在每个模型中，saracatinib 阻断纤维生成反应的有效性与尼达尼布和吡非尼酮相当或更优。对 TGF-β刺激的正常人类肺成纤维细胞的转录组分析确定了与纤维化相关的特定基因集，包括上皮-间充质转化、TGF-β 和 WNT 信号通路，而这些基因集是由 saracatinib 特异性改变的。对两种肺纤维化动物模型的全肺提取物的转录组分析显示，saracatinib 逆转了许多纤维化途径，包括上皮-间充质转化、免疫反应和细胞外基质组织。在人类精密切割肺切片中，纤维化和炎症级联的改善证实了 saracatinib 在人类肺纤维化中的潜在治疗效果。这些研究确定了新的 Src 依赖性纤维化途径，并支持研究 saracatinib 在 IPF 治疗中的治疗效果。
