中华放射医学与防护杂志

赵沙沙,吴碧波,柏杰,王刚,刘瑶,王羽,胡银祥,欧阳伟炜,卢冰,苏胜发.程序性死亡受体1抑制剂通过促进细胞焦亡加重放射性心肌损伤的研究[J].中华放射医学与防护杂志,2024,44(4):255-261

程序性死亡受体1抑制剂通过促进细胞焦亡加重放射性心肌损伤的研究

Effect of PD-1 inhibitor on aggravating radiation-induced myocardial injury by catalyzing pyroptosis

投稿时间：2023-07-31

DOI：10.3760/cma.j.cn112271-20230731-00026

英文关键词:PD-1 inhibitor Pyroptosis Myocardial injury Irradiation

基金项目:贵州省基础研究计划重点项目ZK[(2022)重点040];国家自然科学基金(81960548)

作者	单位	E-mail
赵沙沙	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
吴碧波	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
柏杰	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
王刚	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
刘瑶	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
王羽	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
胡银祥	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
欧阳伟炜	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
卢冰	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004
苏胜发	贵州医科大学附属医院肿瘤科, 贵阳 550004 贵州医科大学附属肿瘤医院肿瘤科, 贵阳 550004 贵州医科大学肿瘤学教研室, 贵阳 550004	sushengfa2005@163.com

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中文摘要:

目的探讨程序性死亡受体1(PD-1)抑制剂通过细胞焦亡通路对放射性心肌损伤的影响。方法 20只C57BL/6雄性小鼠按随机数字表法分为4组:健康对照组;PD-1抑制剂组;单纯照射组(胸部单次照射20 Gy);照射联合PD-1抑制剂组,每组5只。超声心动测试评价受照后1个月小鼠左室射血分数(LVEF)、每搏输出量 (SV)、左室缩短率(FS);采用苏木精-伊红(HE)、Masson染色观察心肌组织病理学改变;蛋白免疫印迹、实时荧光定量反转录聚合酶链式反应(RT-qPCR)检测心肌组织焦亡关键因子半胱氨酸天冬氨酸蛋白水解酶1(Caspase-1)、消皮素D(GSDMD)、凋亡相关斑点样蛋白(ASC)表达水平;酶联免疫吸附实验(ELISA)检测白介素18(IL-18)、IL-1β表达;流式细胞术检测心肌淋巴细胞浸润情况。结果照射后1个月,照射联合PD-1抑制剂组的LVEF、FS、SV较单纯照射组下降(t = 4.50、27.93、3.11,P <0.05); 照射联合PD-1抑制剂组小鼠心肌损伤及纤维化较单纯照射组更明显,心肌胶原容积分数较单纯照射组升高[(2.88±0.27)% vs. (3.81±0.57)%,t = 2.90,P<0.05];与单纯照射组比较,照射联合PD-1抑制剂组心肌Caspase-1、Caspase-1 p20、GSDMD、GSDMD-N、ASC蛋白表达量增高(t=3.14、3.22、8.83、20.29、2.79,P <0.05),Caspase-1、GSDMD、ASC的mRNA表达量也升高(t = 3.09、2.91、2.53,P <0.05);照射联合PD-1抑制剂组心肌及血清IL-18、IL-1β表达较单纯照射组均升高(t = 3.46、3.75、7.58、8.24,P <0.05),CD8+T淋巴细胞百分比高于单纯照射组[(38.33 ± 7.92)% vs. (54.70 ± 4.01)%,t = 3.29,P <0.05],而CD4+T淋巴细胞在各组间的差异无统计学意义(P >0.05)。结论 PD-1抑制剂可通过Caspase-1/GSDMD促进细胞焦亡,进而加重放射性心肌损伤。

英文摘要:

Objective To investigate the effects of programmed cell death protein-1 (PD-1) inhibitor on radiation-induced myocardial injury through the pyroptosis pathway. Method Twenty male C57BL/6 mice were randomized into four groups, namely the control group, the PD-1 inhibitor group, the cardiac radiation group (with a single dose of 20 Gy), and the combined group treated with both cardiac radiation and PD-1 inhibitor, with five mice in each group. At 1 month post-irradiation, echocardiography was performed to assess left ventricular ejection fraction (LVEF), stroke volume (SV), and left ventricular fractional shortening (LVFS); Hematoxylin-eosin (HE) and Masson staining were employed to observe the pathological changes in myocardial tissue; Western blot and real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the expression of pyroptosis-related key factors in myocardial tissue such as cysteine aspartate specific proteinase-1 (Caspase-1), gasdermin D (GSDMD), and apoptosis-associated speck-like protein containing CARD (ASC). Enzyme-linked immunosorbent assay (ELISA) was performed to determine the expression of interleukin-18 (IL-18) and interleukin-1β (IL-1β). Furthermore, flow cytometry was used to evaluate the infiltration of myocardial lymphocytes. Results Compared to the radiation group, the mice in the combined group exhibited lower LVEF, FS and SV (t = 4.50, 27.93, 3.11, P < 0.05), more significant myocardial injury and fibrosis, elevated myocardial collagen volume fraction [(2.88 ± 0.27)% vs. (3.81 ± 0.57)%, t = 2.90, P < 0.05)], increased expression of Caspase-1, Caspase-1 p20, GSDMD, GSDMD-N, and ASC (t = 3.14, 3.22, 8.83, 20.29, 2.79, P < 0.05), increased mRNA expression of Caspase-1, GSDMD and ASC (t = 3.09, 2.91, 2.53, P <0.05), increased expression of IL-18 and IL-1β in myocardium and serum (t = 3.46, 3.75, 7.58, 8.24, P < 0.05), and higher percentage of CD8+ T lymphocytes [(38.33 ± 7.92)% vs. (54.70 ± 4.01)%, t = 3.29, P < 0.05]. However, there was no significant difference in the percentage of CD4+ T lymphocytes among the groups (P > 0.05). Conclusions PD-1 inhibitor may catalyze pyroptosis via caspase-1/GSDMD, thus aggravating radiation-induced myocardial injury.

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