Pulmonary Department, Meir Medical Center, Kfar Saba 44281, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Int J Mol Sci. 2023 Aug 3;24(15):12393. doi: 10.3390/ijms241512393.
The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM ( < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs ( = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied.
细胞外基质在特发性肺纤维化 (IPF) 中传播过程，导致进行性肺瘢痕形成。我们建立了 IPF 条件培养基 (IPF-CM) 系统作为测试候选药物的平台。在这里，我们测试了 PGE2 和 PDE4 抑制剂罗氟司特在 IPF-CM 系统中的作用。原代正常/IPF 组织来源的人肺成纤维细胞 (N/IPF-HLFs) 在 Matrigel 上培养，然后去除以创建 IPF-CM。N-HLFs 暴露于 IPF-CM/N-CM 中，有/没有 PGE2(1 nM)和罗氟司特 (1 µM)，培养 24 小时。测试了 IPF-CM 对细胞表型和促纤维化基因表达的影响。此外，回顾性分析了 107 例长达 15 年随访的患者的电子记录。根据用力肺活量 (FVC) 年下降率将患者定义为缓慢/快速进展者。检查了药物暴露情况。在 IPF-CM 上培养的 N-HLFs 由于增殖、迁移和分化增加而排列成大聚集体。PGE2 和罗氟司特联合阻断了由 IPF-CM 诱导的大聚集体形成（<0.001）以及细胞迁移、增殖和促纤维化基因表达。对患者记录的回顾显示，明显更多的缓慢进展患者暴露于 NSAIDs（=0.003）。PGE2/PDE4 信号可能参与了 IPF 的进展。这些发现应该进一步研究。
