College of Integrated Chinese and Western Medicine, College of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
College of Integrated Chinese and Western Medicine, College of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
J Ethnopharmacol. 2023 Mar 1;303:115894. doi: 10.1016/j.jep.2022.115894. Epub 2022 Nov 7.
Shuangshen Pingfei formula (SSPF), a Chinese medicine prescription, has been prescribed to alleviate PF. However, little is known about the molecular mechanism underlying PF progression and the regulatory mechanism in SSPF.
To discriminate the molecular alterations underlying the development of pulmonary fibrosis (PF) and reveal the regulatory mechanism of Shuangshen Pingfei formula (SSPF).
An integrated analysis of a time-course pathology combined with proteomics and metabolomics was performed to investigate changes in body weight, survival rate, lung coefficient, histopathology, proteins, and metabolites of lung tissues at different time points upon bleomycin (BLM) exposure and SSPF treatment.
The results showed that PF progression was characterized by gradually aggravated fibrosis accompanied by inflammation with extended exposure (7, 14, and 21 days). SSPF significantly attenuated lung fibrosis, as evidenced by increased weight, and reduced lung coefficients and fibrosis scores. Moreover, 368 common differentially expressed proteins (DEPs) were identified, and 102 DEPs were continuously and monotonically upregulated via proteomics among the three BLM treatments. The DEPs were principally involved in extracellular matrix (ECM) remodeling and arginine and proline (AP) metabolic reprogramming. Additionally, metabolomics analyses revealed that BLM exposure mainly affected six metabolism pathways, including 34 differentially regulated metabolites (DRMs). Furthermore, correlation analysis found that several DEPs and DRMs, including L-ornithine, S-adenosyl-L-methionine, ARG, and AOC1, were associated with arginine and proline metabolism, and 8,9-EET, 8,9-DHET, CYP2B, etc., were involved in arachidonic acid (AA) metabolism, suggesting that these two pathways play a critical role in the development of fibrosis. After SSPF treatment, the related protein expression and metabolic disorders were regulated, implying that SSPF provides potential solutions to target these pathways for benefit in the treatment of PF.
Our data suggest that ECM remodeling, and metabolic reprogramming of AP and AA are distinctive features of PF development. Simultaneously, we confirmed that SSPF could effectively regulate metabolic disorders, indicating its potential clinical application for PF therapy. Our findings using multiple approaches provide a molecular-scale perspective on the mechanisms of PF progression and the amelioration of SSPF.
双参平喘配方（SSPF）是一种中药方剂，已被用于缓解 PF。然而，对于 PF 进展的分子机制以及 SSPF 的调节机制知之甚少。
辨别肺纤维化（PF）发展的分子变化，并揭示双参平喘配方（SSPF）的调节机制。
对时间进程病理学与蛋白质组学和代谢组学的综合分析，用于研究博莱霉素（BLM）暴露和 SSPF 治疗不同时间点时体重、存活率、肺系数、组织病理学、肺组织中的蛋白质和代谢物的变化。
结果表明，PF 进展的特征是纤维化逐渐加重，炎症随着暴露时间的延长而加重（7、14 和 21 天）。SSPF 显著减轻肺纤维化，表现为体重增加，肺系数和纤维化评分降低。此外，通过蛋白质组学鉴定出 368 个共同差异表达蛋白（DEPs），其中 102 个 DEPs 在三种 BLM 处理中连续且单调地上调。这些 DEPs 主要参与细胞外基质（ECM）重塑和精氨酸和脯氨酸（AP）代谢重编程。此外，代谢组学分析表明，BLM 暴露主要影响 6 条代谢途径，包括 34 个差异调节代谢物（DRMs）。此外，相关性分析发现，包括 L-鸟氨酸、S-腺苷-L-甲硫氨酸、ARG 和 AOC1 在内的几个 DEPs 和 DRMs 与精氨酸和脯氨酸代谢有关，而 8,9-EET、8,9-DHET、CYP2B 等与花生四烯酸（AA）代谢有关，表明这两条途径在纤维化发展中起关键作用。在 SSPF 治疗后，相关蛋白表达和代谢紊乱得到调节，表明 SSPF 为针对这些途径的 PF 治疗提供了潜在的解决方案。
我们的数据表明，ECM 重塑以及 AP 和 AA 的代谢重编程是 PF 发展的显著特征。同时，我们证实 SSPF 可以有效调节代谢紊乱，表明其在 PF 治疗中的潜在临床应用。我们使用多种方法的研究结果提供了 PF 进展机制和 SSPF 改善的分子视角。
