基于VEGFA/SDF-1/CXCR4通路探讨乌司他丁对脑卒中相关性肺炎大鼠肺组织的保护作用-现代医学

基于VEGFA/SDF-1/CXCR4通路探讨乌司他丁对脑卒中相关性肺炎大鼠肺组织的保护作用

单位：聊城市第二人民医院神经内科, 山东聊城 252600

关键词：血管内皮生长因子A/基质细胞衍生因子-1/CXC型趋化因子受体通路乌司他丁脑卒中相关性肺炎保护作用

分类号：R743.33

出版年·卷·期（页码）：2022·50·第八期（946-952）

摘要：

目的：基于血管内皮生长因子A(VEGFA)/基质细胞衍生因子-1(SDF-1)/CXC型趋化因子受体(CXCR4)通路探讨乌司他丁对脑卒中相关性肺炎大鼠肺组织的保护作用。方法：2021年1月至2021年6月，构建脑卒中相关性肺炎(SAP)大鼠模型共48只，将其随机平分为4组：模型组、乌司他丁(100 kU·kg^-1)组、AMD3100(CXCR4抑制剂，剂量：2.5 mg·kg^-1)组、乌司他丁(100 kU·kg^-1)＋AMD3100(2.5 mg·kg^-1)组，再选取12只SD大鼠设定为假手术组。以药物分组干预后，测定大鼠动脉血氧分压(PaO₂)和二氧化碳分压(PaCO₂)、肺泡灌洗液(BALF)中白细胞计数、肺组织湿干重比值、血清炎性介质活性氧(ROS)、白细胞介素(interleukin，IL)-18、IL-6水平及肺组织VEGFA/SDF-1/CXCR4通路蛋白表达，观察大鼠肺组织病理损伤改变并做Holfbauer评分。结果：与假手术组比较，模型组大鼠动脉血PaCO₂[(59.03±4.95)vs.(33.97±2.38) mmHg]、白细胞计数[(80.96±16.15) vs.(22.74±4.26)×10⁶/ml]、湿干重比值[(6.20±0.43)vs.(4.41±0.32)]、Holfbauer评分[(2.53±0.42)vs.(0.00±0.00)分]、血清ROS[(232.05±31.72)vs.(112.47±16.84) mmol·L^-1]、IL-18[(3.71±0.38)vs.(0.64±0.12) ng·ml^-1]和IL-6[(1.23±0.14)vs.(0.11±0.03) ng·ml^-1]水平显著升高，动脉血PaO₂[(65.75±5.09)vs.(98.12±8.25) mmHg]、肺组织VEGFA[(0.49±0.07)vs.(1.31±0.22)]、SDF-1[(0.41±0.09)vs.(1.28±0.15)]、CXCR4[(0.55±0.12)vs.(1.43±0.26)]蛋白表达水平显著降低，差异均有统计学意义(P＜0.05)。与模型组、乌司他丁+AMD3100组分别比较，乌司他丁组大鼠动脉血PaCO₂、白细胞计数、湿干重比值、Holfbauer评分、血清ROS、IL-18和IL-6水平均显著降低，动脉血PaO₂、肺组织VEGFA、SDF-1、CXCR4蛋白表达水平均显著升高，差异均有统计学意义(P＜0.05)，而AMD3100组大鼠动脉血PaCO₂、白细胞计数、湿干重比值、Holfbauer评分、血清ROS、IL-18和IL-6水平均显著升高，PaO₂、肺组织VEGFA、SDF-1、CXCR4蛋白表达水平动脉血均显著降低，差异均有统计学意义(P＜0.05)。结论：乌司他丁可通过激活VEGFA/SDF-1/CXCR4通路，抑制脑卒中引发的炎症，缓解肺组织损伤，修复肺功能，保护肺组织。

Objective: To explore the protective effect of ulinastatin on the lung tissue of rats with stroke-associated pneumonia based on the vascular endothelial growth factor A (VEGFA)/stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor (CXCR4) pathway.Methods: From January 2021 to June 2021,a total of 48 rats were used to establish a stroke-associated pneumonia (SAP) model and randomly grouped into four groups:model group,ulinastatin ((100 kU·kg^-1) group,AMD3100(CXCR4 inhibitor,dose:2.5 mg·kg^-1) group,and ulinastatin (100 kU·kg^-1)+AMD3100(2.5 mg·kg^-1) group,and another 12 SD rats were allocated into sham operation group.After grouping and intervention with drugs,the arterial blood oxygen partial pressure (PaO₂) and carbon dioxide partial pressure (PaCO₂),white blood cell count in alveolar lavage fluid (BALF),lung tissue wet-to-dry weight ratio,the levels of serum inflammatory mediator reactive oxygen species (ROS),interleukin (IL)-18 and IL-6,and the expressions of lung tissue VEGFA/SDF-1/CXCR4 pathway proteins were measured,the pathological changes of rat lung tissue were observed,and Holfbauer score was made.Results: Compared with the sham operation group,the arterial blood PaCO₂[(59.03±4.95)vs.(33.97±2.38) mmHg],white blood cell count[(80.96±16.15)vs.(22.74±4.26)×10⁶/ml],wet-to-dry weight ratio[(6.20±0.43)vs.(4.41±0.32)],Holfbauer score[(2.53±0.42)vs.(0.00±0.00) points],the levels of serum ROS[(232.05±31.72)vs.(112.47±16.84) mmol·L^-1],IL-18[(3.71±0.38)vs.(0.64±0.12) ng·ml^-1]and IL-6[(1.23±0.14)vs.(0.11±0.03) ng·ml^-1]in the model group were obviously higher,the arterial blood PaO₂[(65.75±5.09)vs.(98.12±8.25) mmHg],and the protein expression levels of lung tissue VEGFA[(0.49±0.07)vs.(1.31±0.22)],SDF-1[(0.41±0.09)vs.(1.28±0.15)]and CXCR4[(0.55±0.12)vs.(1.43±0.26)]were obviously lowered,the differences being statistically obvious (P<0.05).Compared with the model group and the ulinastatin+AMD3100 group,the arterial blood PaCO₂,white blood cell count,wet-to-dry weight ratio,Holfbauer score,and the levels of serum ROS,IL-18 and IL-6 in the ulinastatin group were obviously lowered,the arterial blood PaO₂,and the protein expression levels of lung tissue VEGFA,SDF-1 and CXCR4 were obviously elevated,the differences being statistically different (P<0.05);the arterial blood PaCO₂,white blood cell count,wet-to-dry weight ratio,Holfbauer score,and the levels of serum ROS,IL-18 and IL-6 in the AMD3100 group were obviously increased,the PaO₂,and the protein expression levels of lung tissue VEGFA,SDF-1 and CXCR4 were obviously reduced,the differences being statistically obvious (P<0.05).Conclusions:Ulinastatin can activate the VEGFA/SDF-1/CXCR4 pathway to inhibit the inflammation caused by stroke,relieve lung tissue damage,repair lung function and protect lung tissue.

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