摘要
特发性肺纤维化(IPF)是一种慢性进行性间质性肺病,具有复杂的发病机制和有限的治疗选择。尽管研究表明脂质代谢失调与IPF的进展相关,但其核心调控机制仍不明确。通过整合GEO数据库中的RNA测序数据,识别出4个与脂质相关的关键基因,即过氧化物酶体增殖物激活受体γ(PPARG)、分泌磷蛋白1(SPP1)、半胱氨酸天冬氨酸蛋白酶3(CASP3)和血小板内皮细胞黏附分子1(PECAM1)。通过单细胞RNA测序,进一步验证了这些基因的细胞特异性表达模式。结果发现,肺泡巨噬细胞中PPARG显著下调,SPP1显著上调。机制研究表明,PPARG对SPP1的表达具有负调控作用,SPP1与聚集分化抗原44(CD44)的相互作用激活了促进纤维化的细胞间信号通路。通过网络药理学和分子对接技术预测和分析到经典中药配方补阳还五汤的生物活性成分可能靶向PPARG来调节脂质代谢通路。利用博来霉素诱导大鼠IPF模型,将其随机分为6组(对照组、模型组、吡非尼酮组以及补阳还五汤低、中、高剂量组)。结果显示,补阳还五汤显著改善了组织病理损伤,减少了胶原沉积,并缓解了脂质代谢失调。Western blot分析证实了补阳还五汤可能通过介导PPARG上调抑制SPP1/CD44通路的活化。多组学研究阐明了PPARG/SPP1/CD44通路在IPF中作为脂质代谢的关键调控因子,并率先提供了补阳还五汤通过这一新机制发挥抗纤维化作用的证据,为中医药在IPF中的治疗前景提供了新的思路。
Idiopathic pulmonary fibrosis(IPF)is a chronic progressive interstitial lung disease characterized by a complex pathogenesis and limited treatment options.Although studies have indicated that lipid metabolism dysregulation is associated with the progression of IPF,the core regulatory mechanisms remain unclear.By integrating RNA sequencing data from the GEO database,we identified four key genes related to lipid metabolism:peroxisome proliferator-activated receptor gamma(PPARG),secreted phosphoprotein 1(SPP1),caspase 3(CASP3),and platelet endothelial cell adhesion molecule 1(PECAM1).Further validation using single-cell RNA sequencing revealed the cell-specific expression patterns of these genes.The results found that PPARG was significantly downregulated in alveolar macrophages while SPP1 was significantly upregulated.Mechanistic studies indicated that PPARG negatively regulated SPP1 expression,and the interaction between SPP1 and cluster of differentiation 44(CD44)activated intercellular signaling pathways that promoted fibrosis.Through network pharmacology and molecular docking,it was predicted that the bioactive components of the traditional Chinese medicine formula,namely Buyang Huanwu Decoction may target PPARG to modulate lipid metabolism pathways.In a bleomycin-induced rat model with IPF,this paper randomly divided the rats into six groups(control,group,model group,pirfenidone group,and low,middle,and high-dose groups of Buyang Huanwu Decoction).The results demonstrated that Buyang Huanwu Decoction treatment significantly improved tissue pathological damage,reduced collagen deposition,and alleviated lipid metabolism dysregulation.Western blot analysis confirmed that Buyang Huanwu Decoction mediated the upregulation of PPARG and inhibited the activation of the SPP1/CD44 pathway.The multi-omics study elucidated the role of the PPARG/SPP1/CD44 pathway as a key regulatory factor in lipid metabolism in IPF,providing evidence that Buyang Huanwu Decoction exerted its antifibrotic effects through this novel mechanism and thus offering new insights into the therapeutic prospects for IPF.
作者
李刚刚
潘晓川
王飞
杜全宇
LI Gang-gang;PAN Xiao-chuan;WANG Fei;DU Quan-yu(Department of Geriatrics,Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610072,China)
出处
《中国中药杂志》
北大核心
2025年第14期3821-3834,共14页
China Journal of Chinese Materia Medica
基金
国家自然科学基金项目(82104829,82174347)。
关键词
特发性肺纤维化
脂质代谢
肺泡巨噬细胞
补阳还五汤
idiopathic pulmonary fibrosis
lipid metabolism
alveolar macrophages
Buyang Huanwu Decoction
