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| Caspase-1选择性抑制剂VX-765在大鼠急性肾损伤相关性肺损伤中的作用 |
| Effect of VX-765 as a selective inhibitor of caspase-1 on acute kidney injury associated lung injury in rats |
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| DOI：10.12089/jca.2021.06.016 |
| 中文关键词: 急性肾损伤 肺损伤 细胞焦亡 Caspase-1 |
| 英文关键词: Acute renal injury Lung injury Cell pyroptosis Caspase-1 |
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| 中文摘要: |
目的 评价caspase-1选择性抑制剂VX-765在大鼠急性肾损伤（AKI）相关性肺损伤中的作用。
方法 SPF级SD雄性大鼠72只，9～10周龄，体重350～400 g。采用随机数字表法分为四组：假手术组（S组）、AKI组（A组）、DMSO+AKI组（D组）和VX-765+AKI组（V组），每组18只。S组暴露双肾45 min；A组采用切除右肾、夹闭左肾肾蒂45 min的方法建立AKI模型；D组建立AKI模型前经鼠尾静脉注射2% DMSO 0.5 ml/kg；V组建立AKI模型前经鼠尾静脉注射10% VX-765 0.5 ml/kg。AKI模型建立24 h后取主动脉血样，采用酶偶联速率法与肌氨酸氧化酶法检测血清尿素氮（BUN）和肌酐（Scr）浓度，ELISA法检测血清IL-1β和IL-18浓度。随后处死大鼠取左肾组织和左肺组织。采用免疫荧光法检测肾组织caspase-1/DAPI双阳性细胞百分比，Western blot法检测肾组织cleaved GSDMD蛋白及肺组织ZO-1蛋白含量，Paller评分法评估HE染色后的肾小管损伤情况，烘干法检测肺部干湿比重，计算肺含水率，ELISA法检测肺伊文斯蓝评估肺血管通透性，肺损伤评分评估MASSON染色后的肺组织损伤程度。
结果 与S组比较，A组、D组、V组血清BUN、Scr、IL-1β和IL-18浓度明显升高，肾组织caspase-1/DAPI双阳性细胞百分比明显升高，肾组织caspase-1和cleaved GSDMD蛋白含量明显升高，肾损伤Paller评分明显升高，肺组织ZO-1蛋白含量明显降低，肺含水率、肺血管通透性、肺损伤评分明显升高（P<0.05）。与A组比较，V组血清BUN、Scr、IL-1β和IL-18浓度明显降低，肾组织caspase-1/DAPI双阳性细胞百分比明显降低，肾组织caspase-1和cleaved GSDMD蛋白含量明显降低，肾损伤Paller评分明显降低，肺组织ZO-1蛋白含量明显升高，肺含水率、肺血管通透性、肺损伤评分明显降低（P<0.05）。A组、D组各指标差异无统计学意义。
结论 Caspase-1选择性抑制剂VX-765可以降低血清中BUN、Scr、IL-1β和IL-18浓度，减少肾组织细胞焦亡，改善肺水肿及肺血管通透性，减轻AKI相关性肺损伤。 |
| 英文摘要: |
Objective To evaluate the effect of VX-765, a selective inhibitor of caspase-1, on acute kidney injury (AKI) associated lung injury in rats.
Methods Seventy-two adult male SD rats, aged 9-10 weeks, weighing 350-400 g, were randomly divided into four groups: sham group (group S), AKI group (group A), DMSO+AKI group (group D) and VX-765+AKI group (group V). The AKI model was established by excising the right kidney and clamping the pedicle of the left kidney for 45 minutes. VX-765 (0.5 ml/kg) and 2% DMSO (0.5 ml/kg) were injected through tail vein respectively in group D and group V 1 hour before AKI. The kidneys were exposed for 45 minutes under anesthesia in sham operated animals. Twenty-four hours post-AKI, renal pathological changes, pulmonary vascular permeability, lung wet/dry weight were measured. Blood urea nitrogen (BUN) and serum creatinine (Scr) were detected with enzyme coupling rate method and sarcosine oxidase method. IL-1β and IL-18 in blood serum were evaluated by enzyme linked immunosorbent assay (ELISA). The expressions of caspase-1 in kidney 24 hours after AKI were assessed by immunofluorescence assay, the expressions of cleaved GSDMD in the kidney and ZO-1 in the lung were detected by western blot.
Results Compared with group S, serum concentrations of BUN, Scr, IL-1β and IL-18 were significantly increased, the expression of caspase-1 and cleaved GSDMD in renal tissue, renal cortex injury scores, Evans blue content in lung tissue and lung injury scores were also significantly increased in groups A, D, and V. But the expression of ZO-1 were statistically decreased (P < 0.05). Compared with group A, serum BUN, Scr, IL-1β, IL-18, caspase-1 and cleaved GSDMD expression, renal cortex injury scores, Evans blue content in lung tissue and lung injury scores were all significantly decreased, and the expression of protein ZO-1 were statistically increased in group V (P < 0.05). There was no significant difference between group A and group D.
Conclusion VX-765, a selective inhibitor of caspase-1, can alleviate renal cell pyroptosis and AKI related lung injury by reducing serum BUN, SCR, IL-1β and IL-18 concentrations and improving pulmonary edema and pulmonary vascular permeability. |
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