Wei Yi, Sun Lei, Liu Chao, Li Lujia
Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
Department of Pharmacy, Aoshanwei Hospital of Qingdao Jimo District, Qingdao, 266235, China.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Jun;396(6):1155-1169. doi: 10.1007/s00210-023-02390-z. Epub 2023 Jan 23.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that is characterized by abnormal proliferation of fibroblasts and extracellular matrix remodeling, ultimately leading to respiratory insufficiency or even death. Naringin (Nar), a natural compound derived from grapefruit and citrus fruits, has several pharmacological activities that are associated with therapeutic benefits for IPF. However, the specific molecular mechanisms underlying its pulmonary tissue-protective effects remain largely unknown. This study aimed to investigate the effects of Nar on endoplasmic reticulum stress (ERS) and mitophagy. A bleomycin (BLM)-induced mouse model of IPF was established for treatment with different doses of Nar. Histopathological changes in the lung were examined by hematoxylin and eosin (HE) staining and Masson staining. The extent of fibrosis was determined by measuring hydroxyproline and collagen expression levels. The levels of inflammatory cytokines and oxidative stress indicators were determined by Enzyme linked immunosorbent assay (ELISA) and biochemical kits. Western blot and immunofluorescence were used to evaluate the expression levels of the mitophagy-related markers. Cell apoptosis was estimated by western blot and TUNEL staining. Nar reduced the levels of inflammatory response, oxidative stress and decreased the proportion of apoptosis. Nar also inhibited the expression of the ERS and mitophagy-related genes and ERS-downstream proteins, thereby activating transcription factor (ATF) 3 and inhibiting the transcription of PTEN-induced kinase 1 (PINK1). Taken together, Nar is a promising therapeutic agent for treating IPF via inhibiting ERS, reducing apoptosis, and maintaining mitochondrial homeostasis, all of which may be associated with the regulation of the ATF3/PINK1 signaling axis.
特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，其特征是成纤维细胞异常增殖和细胞外基质重塑，最终导致呼吸功能不全甚至死亡。柚皮苷（Nar）是一种从葡萄柚和柑橘类水果中提取的天然化合物，具有多种药理活性，对IPF具有治疗益处。然而，其肺组织保护作用的具体分子机制仍 largely 未知。本研究旨在探讨 Nar 对内质网应激（ERS）和线粒体自噬的影响。建立博来霉素（BLM）诱导的 IPF 小鼠模型，用不同剂量的 Nar 进行治疗。通过苏木精和伊红（HE）染色及 Masson 染色检查肺组织的病理变化。通过测量羟脯氨酸和胶原蛋白表达水平来确定纤维化程度。采用酶联免疫吸附测定（ELISA）和生化试剂盒测定炎症细胞因子和氧化应激指标的水平。用 Western blot 和免疫荧光法评估线粒体自噬相关标志物的表达水平。通过 Western blot 和 TUNEL 染色评估细胞凋亡。Nar 降低了炎症反应、氧化应激水平，并减少了细胞凋亡比例。Nar 还抑制了 ERS 和线粒体自噬相关基因以及 ERS 下游蛋白的表达，从而激活转录因子（ATF）3 并抑制 PTEN 诱导激酶 1（PINK1）的转录。综上所述，Nar 通过抑制 ERS、减少细胞凋亡和维持线粒体稳态，有望成为治疗 IPF 的治疗药物，所有这些可能与 ATF3/PINK1 信号轴的调节有关。
