Jordan Maria, Schmidt Kevin, Fuchs Maximilian, Just Annette, Pfanne Angelika, Willmer Lena, Neubert Lavinia, Werlein Christopher, Zardo Patrick, Pich Andreas, Thum Thomas, Fiedler Jan
Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Hannover, Germany.
Front Pharmacol. 2025 May 22;16:1534989. doi: 10.3389/fphar.2025.1534989. eCollection 2025.
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with high mortality. Current therapies are very limited, with nintedanib and pirfenidone being the only non-invasive but non-curative interventions, ultimately bridging to lung transplantation.
modeling of dysregulated pathways in IPF and screening for putative interfering small molecules identified carvedilol as a promising anti-fibrotic agent. We validated drug-mediated effects on key features of fibroblast activation in functional assays and gene expression analyses in human embryonic lung fibroblasts (MRC-5). Precision-cut lung slices (PCLSs) generated from human lung tissue were assessed for secreted fibrotic markers' expression.
Treatment with carvedilol reduced metabolic activity, inhibited cell proliferation, and led to decreased migratory activity, as observed in scratch wound assays, in human lung fibroblasts. The functional profile was reflected at the transcriptional level as commonly known fibrotic marker genes, e.g., alpha smooth muscle actin and collagen 1, were robustly repressed. Proteomic profiling underlined a strong extracellular matrix interference with elevated syntheses of several collagen types and various integrins, which play a critical role in pro-fibrotic downstream signaling. Comparison of healthy and fibrotic lung tissue validated an upregulation of pro-fibrotic miR-21 secretion in the PCLS model, which remained unchanged upon carvedilol therapy.
Herein, carvedilol demonstrated significant anti-fibrotic effects on human lung fibroblasts , thus presenting great potential as an anti-IPF treatment. In addition, miR-21 was validated as a secreted pro-fibrotic biomarker in the PCLS model.
特发性肺纤维化（IPF）是一种死亡率很高的慢性纤维化肺部疾病。目前的治疗方法非常有限，尼达尼布和吡非尼酮是仅有的非侵入性但非治愈性的干预措施，最终通向肺移植。
对IPF中失调的信号通路进行建模，并筛选可能的干扰小分子，确定卡维地洛是一种有前景的抗纤维化药物。我们在功能试验和人胚肺成纤维细胞（MRC-5）的基因表达分析中验证了药物对成纤维细胞活化关键特征的介导作用。对从人肺组织产生的精密肺切片（PCLS）评估分泌的纤维化标志物的表达。
在人肺成纤维细胞中，卡维地洛治疗降低了代谢活性，抑制了细胞增殖，并导致迁移活性降低，如划痕试验中所观察到的。在转录水平上反映了这种功能特征，因为常见的纤维化标志物基因，如α平滑肌肌动蛋白和胶原蛋白1，被强烈抑制。蛋白质组学分析强调了对细胞外基质的强烈干扰，几种胶原蛋白类型和各种整合素的合成增加，它们在促纤维化下游信号传导中起关键作用。健康肺组织和纤维化肺组织的比较验证了在PCLS模型中促纤维化miR-21分泌的上调，卡维地洛治疗后该分泌保持不变。
在此，卡维地洛对人肺成纤维细胞显示出显著的抗纤维化作用，因此作为抗IPF治疗具有巨大潜力。此外，miR-21在PCLS模型中被验证为一种分泌型促纤维化生物标志物。
