血红素加氧酶-1促进导管相关性血栓溶解再通的实验研究
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广西医科大学第一附属医院 护理部,广西 南宁 530021

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韦佳妮,广西医科大学第一附属医院护师,主要从事血管通路并发症方面的研究。

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国家自然科学基金资助项目(81860032);广西自然科学基金资助项目(2018GXNSFAA050081);广西医科大学第一附属医院护理临床研究攀登计划项目基金资助项目(YYZS2020025)。


Experimental study of heme oxygenase-1 promoting clot dissolution and recanalization of catheter-related thrombolysis
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Department of Nursing, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China

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    摘要:

    背景与目的 导管相关性血栓(CRT)是中心静脉导管的主要并发症之一,目前CRT的治疗主要为抗凝、溶栓治疗。血栓的溶解对于血管恢复通畅至关重要,直接影响血栓后并发症的发生及患者预后。研究表明,血红素加氧酶-1(HO-1)在深静脉血栓形成后的血栓的溶解再通过程中发挥重要作用,但其在CRT中的作用鲜有研究。因此,本研究在大鼠CRT模型中探讨HO-1对血栓溶解的作用及相关机制,为临床治疗CRT提供新思路及理论依据。方法 将72只7~8周龄健康的雄性SD大鼠上腔静脉置管10 d构建CRT模型后,随机均分为模型组、HO-1激动剂组、HO-1抑制剂组,模型组不做任何干预,后两组分别腹腔注射HO-1激动剂钴原卟啉(CoPP)与HO-1抑制剂锡原卟啉(SnPP),剂量均为5 mg/kg。此后,于第1、7、14、28天每组分别取6只大鼠,腹主动脉采血,用ELISA检测血清HO-1、IL-6、IL-10浓度;取受累血管,用HE染色观察血栓溶解情况,计算血栓溶解率,用免疫组化检测血管内皮标志物CD31表达,用qPCR检测HO-1 mRNA表达。结果 HE染色结果显示,随着时间的增加,各组血栓的溶解均逐渐增加,HO-1激动剂组各时间点血栓溶解率均高于模型组,HO-1抑制剂组各时间点血栓溶解率均低于模型组(均P<0.05);在第28天,HO-1激动剂组接近完全再通,而HO-1抑制剂组仅部分再通。免疫组织化学染色结果显示,各时间点HO-1激动剂组CD31表达高于模型组,而HO-1抑制剂组CD31表达低于模型组(均P<0.05)。ELISA结果表明,各时间点与模型组比较,HO-1激动剂组血清中HO-1与IL-10含量升高、IL-6含量降低,而HO-1抑制剂组中这些指标则呈反向变化(均P<0.05)。qPCR结果显示,各时间点HO-1激动剂组血管组织中HO-1 mRNA表达量高于CRT对照组,HO-1抑制剂组则相反(均P<0.05)。结论 HO-1能促进大鼠CRT的溶解再通,其机制可能与其抑制炎症反应,促进血管新生的功能有关。

    Abstract:

    Background and Aims Catheter-related thrombosis (CRT) is one of the main complications of central venous catheterization. At present, the treatment of CRT is mainly based on anticoagulant and thrombolytic therapies. Clot dissolution is of great importance for restoring patency of the affected vessel, and directly affects the occurrence of post-thrombotic complications and the prognosis of patients. Studies have demonstrated that heme oxygenase 1 (HO-1) plays an important role in the process of thrombolysis and recanalization after the formation of deep venous thrombosis. However, its effects in CRT have rarely been reported. Therefore, this study was conducted to investigate the effect of HO-1 in clot dissolution and recanalization in rat model of CRT and the relevant mechanism, so as to provide new ideas and theoretical basis for clinical treatment of CRT.Methods A total of 72 healthy male SD rats aged 7-8 weeks underwent superior vena cava catheterization for 10 d to induce CRT models. Then, rats were equally randomized into model group, HO-1 agonist group and HO-1 inhibitor group. Rats in model control group did not receive any intervention, and those in the latter two groups received abdominal injection of HO-1 agonist cobalt protoporphyrin (CoPP) and inhibitor tin protoporphyrin (SnPP), respectively. Both treatment doses were 5 mg/kg. On the 1st, 7th, 14th and 28th d after that, 6 rats in each group were sacrificed, the blood was collected from the abdominal aorta, and the serum levels of HO-1, IL-6 and IL-10 were determined by ELISA assay; the affected vessels were harvested to observe the thrombolysis and calculate the thrombolysis rate by HE staining, to examine the expression of endothelial mark CD31 by immunohistochemical staining, and to detect the HO-1 mRNA expression by qPCR.Results The results of HE staining showed that thrombolysis was increased with time elapsed in each group, the thrombolysis rate was higher in HO-1 agonist group was lower in HO-1 inhibitor group than that in model group at each defined time point (all P<0.05), and on the 28th d, the vessels presented nearly complete recanalization in HO-1 agonist group, while only partial recanalization in HO-1 inhibitor group. The results of immunohistochemical staining showed that the expression of CD31 was higher in HO-1 agonist group and was lower in HO-1 inhibitor group than that in model group at each defined time point (all P<0.05). The results of ELISA assay showed that the serum levels of HO-1 and IL-10 were increased and the serum level of IL-6 was decreased in HO-1 agonist group compared with model group at each defined time point, while the opposite changes in these variables were observed in HO-1 inhibitor group (all P<0.05). The results of qPCR showed that the HO-1 mRNA expression in the vascular tissue in HO-1 agonist group was higher than that in model group at each defined time point, while the opposite view occurred in HO-1 inhibitor group (all P<0.05).Conclusion HO-1 can promote the clot dissolution and recanalization of CRT in rats, and its mechanism may be related to its inhibiting inflammatory response and promoting angiogenesis.

    图1 各组干预不同时间点大鼠血管内血栓HE染色(×50)Fig.1 HE staining of thrombosis in the blood vessel in rats in each group at different time points (×50)
    图2 各组不同时间点血管CD31免疫组织化学染色(×100)Fig.2 Immunohistochemical staining of CD31 at different time points in each group(×100)
    图3 各组不同时间点HO-1、IL-6、IL-10含量变化Fig.3 Changes of HO-1, IL-6 and IL-10 content in each group at different time points
    图4 各组不同时间点HO-1 mRNA表达情况变化Fig.4 Changes in HO-1mRNA expression in each group at different time points
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韦佳妮,赵慧函,蒋庆娟,文萃,黄欣欣,凌瑛,应燕萍.血红素加氧酶-1促进导管相关性血栓溶解再通的实验研究[J].中国普通外科杂志,2021,30(12):1460-1467.
DOI:10.7659/j. issn.1005-6947.2021.12.010

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  • 收稿日期:2021-07-30
  • 最后修改日期:2021-11-21
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  • 在线发布日期: 2022-01-07