卡托普利对脓毒症小鼠心肌损伤的保护作用及机制研究

目的:研究卡托普利对脓毒症小鼠心肌损伤的保护作用并探讨其作用机制。方法:按随机数字表法将48只雄性C57BL/6J小鼠（6～8周龄）分为4组:对照组（Control组）、卡托普利组（Captopril组）、脂多糖组（LPS组）、卡托普利+脂多糖组（Captopril+LPS组），每组12只。实验前30 min，Captopril组和Captopril+LPS组预先经腹腔给予卡托普利（50 mg/kg）处理，Control组和LPS组给予等量生理盐水对照。采用腹腔注射脂多糖（LPS，15 mg/kg）的方法制备脓毒症模型（LPS组和Captopril+LPS组），Control组和Captopril组给予等量生理盐水。各组于制模后12 h采集标本，采用无创尾套测压法测量小鼠平均动脉压（MAP），酶联免疫吸附试验（ELISA）法检测血清炎性因子白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平，HE染色观察心肌组织病理形态改变，高分辨小动物超声成像系统检测心功能，Western印迹检测心肌组织磷酸化核因子-κB p65（p-NF-κB p65）蛋白表达。结果:造模后12 h，Captopril组各项指标与Control组比较差异均无统计学意义（均P＞0.05）。与Control组相比，LPS组MAP下降（q=4.377，P＜0.05）；血清IL-6 、TNF-α水平明显升高（q=4.966、10.440，均P＜0.05）； 左室射血分数（LVEF%）、左室短轴缩短率（LVFS%）水平明显降低（q=6.104、6.390，均P＜0.01）；心肌纤维断裂，间质水肿，炎性细胞浸润加重；心肌组织p-NF-κB p65蛋白表达水平明显升高（q=12.430，P＜0.001）。和LPS组比较，Captopril+LPS组MAP差异无统计学意义（q=2.617，P＞0.05）；血清IL-6、TNF-α水平下降（q=4.085、5.721，均P＜0.05）； LVEF%、LVFS%水平升高（q=4.366、4.297，均P＜0.05）；心肌损伤病理改变减轻；心肌组织p-NF-κB p65蛋白表达水平下降（q=5.124，P＜0.01）。结论:卡托普利可能通过抑制核因子-κB的活化，减少炎性细胞因子（IL-6和TNF-α）产生，抑制脓毒症引起的心肌炎症，从而减轻脓毒症心肌损伤。

The protective effect and mechanism of captopril on myocardial injury in septic mice

Objective: To investigate the protective effect of captopril on myocardial injury in septic mice and its mechanism. Methods: According to the random number table method，48 male C57BL/6J mice（6-8 weeks old） were divided into four groups:control group （Control group），captopril group（Captopril group），lipopolysaccharide group（LPS group），Captopril + lipopolysaccharide group（Captopril +LPS group），12 animals in each group. Captopril group and Captopril+LPS group were pre-treated with Captopril（50 mg/kg） via intraperitoneal administration 30 minutes before the experiment，and Control group and LPS group were given equal amount of saline control. The sepsis models（LPS and Captopril+LPS groups） were prepared by intraperitoneal injection of LPS（15 mg/kg），and the corresponding controls（Control and Captopril groups） were given equal amounts of saline. Specimens from each group were collected 12 h after modeling，and the mean arterial pressure（MAP） of mice was measured by non-invasive tail-sleeve manometry，serum levels of inflammatory factors interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） were measured by enzyme-linked immunosorbent assay （ELISA），myocardial histomorphological changes were observed by HE staining，cardiac function was detected by high-resolution small animal ultrasound imaging system，and myocardial phospho-NF-κB p65（p-NF-κB p65） protein expression was detected by protein immunoblotting assay（Western blotting）. Results: At 12 h post-modelling，there was no statistically significant difference between the indexes of Captopril group and Control group （all P＞0.05）. Compared with the Control group，MAP decreased in the LPS group （q=4.377，P＜0.05）；serum IL-6，TNF-α levels were significantly higher（q=4.966，10.44，both P＜0.05）； left ventricular ejection fraction（LVEF%） and left ventricular short axis shortening（LVFS%） levels were significantly lower（q=6.104，6.39，both P＜0.01）；myocardial fibre breakage，interstitial oedema and increased inflammatory cell infiltration；myocardial tissue p-NF-κB p65 protein expression levels were significantly increased（q=12.43，P＜0.001）. There was no statistically significant difference in MAP between the Captopril+LPS and LPS groups（q=2.617，P＞0.05）. Serum IL-6 ，TNF-α levels decreased in the Captopril+LPS group（q=4.085，5.721，both P＜0.05）； LVEF%，LVFS% levels increased（q=4.366，4.297，both P＜0.05）；pathological changes of myocardial injury were alleviated，and the expression level of p-NF-κB p65 protein in myocardial tissue was decreased（q=5.124，P＜0.01）. Conclusion: Captopril may reduce sepsis myocardial injury by inhibiting the downstream activation of NF-κB and reducing the production of inflammatory cytokines（IL-6 and TNF-α） to suppress the sepsis-induced myocardial inflammatory response.