Derseh Habtamu B, Davies Andrew N, Young Alarna, Bischof Sylvie, Pelle Joseph, Rudd David, McIntosh Michelle, Piedrafita David, Bischof Robert J
Institute of Innovation, Science and Sustainability, Federation University, Berwick, VIC, 3806, Australia.
Biomedicine Discovery Institute, Monash University Peninsula Campus, Frankston, VIC, 3199, Australia.
BMC Pulm Med. 2025 Aug 5;25(1):374. doi: 10.1186/s12890-025-03803-w.
Poly (ADP‒ribose) polymerase (PARP) is a constitutive enzyme involved in regulating various biological processes in health and disease. In the present study, we investigated the role of PARP1 in pulmonary fibrosis and assessed the efficacy of a clinically approved PARP inhibitor, olaparib, for the treatment of pulmonary fibrosis in a large animal bleomycin model.
Sheep ( = 12) received two fortnightly instillations of bleomycin (3 U) and saline into separate lung lobes of the same animal. Two weeks after the second bleomycin/saline exposure, sheep were randomly assigned to two groups and treated twice/week orally with either olaparib (10 mg/kg; treated group) or vehicle solution (control group) for four weeks. Olaparib concentrations in plasma were analysed using ultra-high-performance liquid chromatography. The degree of inflammation and fibrosis was assessed using a semiquantitative histopathology scoring method. Masson’s trichrome staining and hydroxyproline assays were used to evaluate collagen deposition in the lungs. We also determined whether olaparib treatment was targeting the migration of sheep lung fibroblasts in vitro using a 2D wound scratch assay.
Olaparib was rapidly taken up into plasma following oral delivery, returning to baseline levels within 24 h. Therapeutically, olaparib treatment significantly reduced bleomycin-induced PARP1 overexpression and attenuated lung injury and fibrosis. Inflammation and fibrosis scores were significantly lower in bleomycin-injured lobes of sheep treated with olaparib compared to those treated with vehicle only. Additionally, a significant reduction in collagen deposition in the lungs of olaparib-treated sheep compared to vehicle-treated sheep was demonstrated by histopathology and hydroxyproline analyses. In vitro, olaparib significantly inhibited the migration of primary sheep lung fibroblasts.
Olaparib treatment reduced bleomycin-induced PARP1 overexpression and significantly attenuated established pulmonary fibrosis. Our data suggest that the activation of PARP1 plays a key role in the pathology of pulmonary fibrosis, and provides strong support for the potential repurposing of olaparib and similar PARP inhibitors for the treatment of pulmonary fibrosis.
聚（ADP - 核糖）聚合酶（PARP）是一种组成型酶，参与调节健康和疾病状态下的各种生物学过程。在本研究中，我们调查了PARP1在肺纤维化中的作用，并评估了一种临床批准的PARP抑制剂奥拉帕利在大型动物博来霉素模型中治疗肺纤维化的疗效。
12只绵羊在同一动物的不同肺叶中每隔两周分别注入博来霉素（3 U）和生理盐水。在第二次博来霉素/生理盐水暴露后两周，绵羊被随机分为两组，每周口服两次奥拉帕利（10 mg/kg；治疗组）或赋形剂溶液（对照组），持续四周。使用超高效液相色谱法分析血浆中的奥拉帕利浓度。使用半定量组织病理学评分方法评估炎症和纤维化程度。采用Masson三色染色和羟脯氨酸测定法评估肺组织中的胶原沉积。我们还使用二维伤口划痕试验在体外确定奥拉帕利治疗是否针对绵羊肺成纤维细胞的迁移。
口服给药后，奥拉帕利迅速进入血浆，并在24小时内恢复到基线水平。在治疗方面，奥拉帕利治疗显著降低了博来霉素诱导的PARP1过表达，并减轻了肺损伤和纤维化。与仅接受赋形剂治疗的绵羊相比，接受奥拉帕利治疗绵羊的博来霉素损伤肺叶的炎症和纤维化评分显著更低。此外，组织病理学和羟脯氨酸分析表明，与接受赋形剂治疗的绵羊相比，接受奥拉帕利治疗的绵羊肺组织中的胶原沉积显著减少。在体外，奥拉帕利显著抑制原代绵羊肺成纤维细胞的迁移。
奥拉帕利治疗降低了博来霉素诱导的PARP1过表达，并显著减轻了已形成的肺纤维化。我们的数据表明，PARP1的激活在肺纤维化的病理过程中起关键作用，并为奥拉帕利和类似PARP抑制剂用于治疗肺纤维化的潜在重新应用提供有力支持。
