铁死亡抑制剂liproxstatin-1和抗氧化剂N-乙酰半胱氨酸在博来霉素诱导的肺纤维化中的疗效对比  

Comparison of therapeutic efficacy of ferroptosis inhibitor liproxstatin-1 and antioxidant N-acetylcysteine in bleomycin-induced pulmonary fibrosis

作　　者：陈芳[1] 袁良 王歌 陈诗婷 郑则广[1] CHEN Fang;YUAN Liang;WANG Ge;GHEN Shiting;ZHENG Zeguang(Department of Pneumology,The First Affiliated Hospital,Guangzhou Medical University,Guangzhou 16006024,China)

机构地区：[1]广州医科大学附属第一医院医院呼吸内科,广东广州81873408

出　　处：《中国病理生理杂志》2025年第1期28-35,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81873408)。

摘　　要：目的:对比铁死亡抑制剂liproxstatin-1(LIP-1)和抗氧化剂N-乙酰半胱氨酸(N-acetylcysteine,NAC)在博来霉素(bleomycin,BLM)诱导的肺纤维化中的治疗效果。方法:将小鼠随机分为6组:对照组、BLM组、BLM+NAC组、BLM+LIP-1组、NAC组和LIP-1组。除对照组、NAC组和LIP-1组外,其余3组通过气管内滴注BLM建立肺纤维化模型。于建模前1 d,分别给予BLM+NAC组和BLM+LIP-1组灌服NAC、腹腔注射LIP-1。建模后14 d,评估各组小鼠的肺纤维化程度以及肺泡上皮细胞标志物、铁死亡相关分子的表达水平。结果:与NAC相比:(1)LIP-1更显著改善BLM诱导的小鼠体重及生存率下降;(2)LIP-1更显著减少肺纤维化范围、改善胶原沉积;(3)LIP-1更显著改善肺泡结构破坏,更显著抑制BLM引起的Ⅰ型肺泡上皮细胞标志物平足蛋白及Ⅱ型肺泡上皮标志物表面活性蛋白C的减少以及上皮-间充质转化;(4)LIP-1更显著抑制BLM诱导的铁死亡及相关分子血红素加氧酶1的增加。结论:与NAC相比,LIP-1改善肺纤维化的作用更为显著,机制上,可能与LIP-1能够抑制肺泡上皮细胞铁死亡有关。本研究为肺纤维化的治疗提供了新的见解,并为LIP-1的临床应用奠定了基础。AIM:To compare the therapeutic effects of liproxstatin-1(LIP-1)and N-acetylcysteine(NAC)in bleomycin(BLM)-induced pulmonary fibrosis.METHODS:The mice were randomly divided into the control,model(BLM),BLM+NAC,BLM+LIP-1,NAC and LIP-1 groups.The BLM+NAC and BLM+LIP-1 groups were treated with NAC by intratracheal drip and LIP-1 by intraperitoneal injection,respectively,1 day before BLM tracheal instillation.The other groups received intraperitoneal injection of the same volume of co-solvent and intragastric instillation of saline.Fourteen days after a BLM challenge,the degree of lung fibrosis and the expression levels of alveolar epithelial cell markers and ferroptosis-related molecules were assessed in each group.RESULTS:LIP-1 treatment more significantly improved the BLM-induced decrease in body weight(P<0.01)and survival rate in mice compared with NAC.LIP-1 more significantly reduced the severity of pulmonary fibrosis and improved collagen deposition compared with NAC.LIP-1 also more significantly alleviated alveolar structural disruption,and more significantly inhibited the decrease in the alveolar epithelial cell markers podoplanin and surfactant protein C,as well as epithelial-mesenchymal transition,compared with NAC.LIP-1 was a more potent inhibitor of the BLM-induced increase in ferroptosis and its related molecule Heme oxygenase-1 than NAC.CONCLUSION:LIP-1 treatment is more effective than NAC in alleviating pulmonary fibrosis.Mechanistically,this finding may be related to the ability of LIP-1 to inhibit ferroptosis in alveolar epithelial cells.This study provides new insights into the treatment of pulmonary fibrosis and lays the foundation for the clinical application of LIP-1.

关 键 词：liproxstatin-1 N-乙酰半胱氨酸 博来霉素 肺纤维化 铁死亡 

分 类 号：R563.92[医药卫生—呼吸系统] R363.2[医药卫生—内科学] R965[医药卫生—临床医学]