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乌司他丁通过p38MAPK通路治疗脓毒症急性肝损伤的相关研究

发布时间:2018-03-28 20:03

  本文选题:脓毒症 切入点:急性肝损伤 出处:《山西医科大学》2017年硕士论文


【摘要】:目的:探讨乌司他丁对脂多糖诱导的大鼠脓毒症急性肝损伤的治疗作用以及相关机制,并与炎症通道阻断剂的疗效进行比较。方法:清洁级雄性SD大鼠32只,随机分为4组,每组8只,分别为:空白组,脂多糖组,脂多糖+乌司他丁组,脂多糖+通道阻断剂组。造模后24小时处死大鼠,取下腔静脉血测定大鼠血清中谷丙转氨酶、胆红素和碱性磷酸酶的浓度,利用ELISA法测定大鼠肝组织肿瘤坏死因子-α水平,Western-blot法测定大鼠肝组织磷酸化p38蛋白水平表达,以及肝组织病理切片和电镜切片观察肝细胞微结构的变化。结果:肝组织病理切片与空白组比较,LPS组存在明显的肝细胞肿胀,肝细胞水样变性,细胞间隙模糊不清,炎性细胞浸润,肝细胞再生;LPS+UTI组和LPS+UTI组肝细胞肿胀、水样变性、炎细胞浸润及肝细胞再生均较LPS组减轻,但较空白组严重。肝组织电镜片与空白组比较,LPS组肝细胞核固缩,细胞质疏松,出现空泡变性或脂肪变性,线粒体体积明显增大,外膜界限不清,线粒体嵴肿胀、断裂甚至消失,内质网结构不清。LPS+UTI组无明显的肝细胞核固缩,线粒体体积稍增大,外膜界限清楚,线粒体嵴清楚,部分有断裂,内质网结构清楚。LPS+SB组肝细胞核固缩,线粒体稍肿胀,线粒体外膜界限清晰,但线粒体嵴模糊不清或者断裂,内质网轮廓不清晰。与其他各组比较,LPS组肝脏组织TNF-α水平及磷酸化P38蛋白明显升高(P0.05),差异具有统计学意义;空白组、LPS+UTI组以及LPS+SB组之间肝脏组织TNF-α水平无明显差异(P0.05)。与空白组比较,LPS组血清ALT明显升高(P0.001),LPS+UTI组血清ALT较LPS组降低(P0.05),但较空白组及LPS+SB组升高(P0.001),LPS+SB组与空白组之间无显著性差异(P0.05)。四组血清AKP水平相比无显著性差异(P0.05)。LPS组血清BIL较空白组明显升高(P0.001),空白组与LPS+UTI组血清BIL相比、LPS组与LPS+SB组相比血清BIL无显著性差异(P0.05)。结论:乌司他丁可以减轻脂多糖引起的大鼠脓毒症急性肝损伤,使血清谷丙转氨酶、胆红素、肝组织肿瘤坏死因子-α水平降低,肝组织病理和电镜结果提示炎症反应减轻,P38MAPK通路下游蛋白磷酸化p38蛋白水平降低,考虑乌司他丁是通过P38MAPK通路来发挥炎症抑制作用的。与P38MAPK通路特异性阻断剂比较,两者减轻肿瘤坏死因子-α、磷酸化p38蛋白等炎症因子和蛋白的作用是相似的,但是对血清学指标的影响及镜下表现有一定差别。
[Abstract]:Objective: to investigate the therapeutic effect of ulinastatin on acute hepatic injury induced by lipopolysaccharide in rats and to compare the therapeutic effect with inflammatory channel blocker. Methods: Thirty-two clean male SD rats were randomly divided into 4 groups. Eight rats in each group were divided into blank group, lipopolysaccharide group, lipopolysaccharide ulinastatin group and lipopolysaccharide channel blocker group. The concentrations of bilirubin and alkaline phosphatase, the expression of phosphorylated p38 protein in rat liver tissue were determined by ELISA assay and Western-blot. Results: compared with the control group, lipopolysaccharide (LPS) group had obvious hepatocyte swelling, hepatocyte hydrophoretic degeneration and unclear cell space. Inflammatory cell infiltration, hepatocyte regeneration, hepatocyte swelling, water like degeneration, inflammatory cell infiltration and hepatocyte regeneration in lipopolysaccharide (UTI) group and LPS UTI group were less than those in LPS group, but more serious than those in blank group. The cytoplasm was loose, vacuolar degeneration or steatosis occurred, the volume of mitochondria increased obviously, the outer membrane boundary was unclear, the mitochondrial ridge was swollen, broken or even disappeared, and the endoplasmic reticulum structure was unclear. LPs UTI group had no obvious pyknosis of liver nucleus. The size of mitochondria was a little larger, the outer membrane boundary was clear, the mitochondrial ridge was clear, some of them were broken, the endoplasmic reticulum structure was clear. In LPS SB group, the nucleus of liver was constricted, the mitochondria was slightly swollen, and the outer membrane of mitochondria was clear, but the ridge of mitochondria was blurred or broken. Compared with other groups, the level of TNF- 伪 and phosphorylated P38 protein in lipopolysaccharide group increased significantly (P 0.05). There was no significant difference in the level of TNF- 伪 in liver tissue between UTI group and LPS SB group. Compared with the blank group, the serum level of TNF- 伪 in lipopolysaccharide group was significantly higher than that in the control group. Compared with the control group, the serum ALT level in the LPS UTI group was significantly lower than that in the LPS group, but it was higher than that in the blank group and LPS SB group. There was no significant difference in serum AKP level among the four groups. The serum BIL level in the four groups was significantly higher than that in the blank group (P 0.001). There was no significant difference in serum BIL between the LPS UTI group and the LPS UTI group compared with the LPS SB group. On: ulinastatin can alleviate acute liver injury induced by lipopolysaccharide in rats with sepsis. The levels of serum alanine aminotransferase, bilirubin, tumor necrosis factor- 伪 in liver tissue were decreased, and the pathological and electron microscopic results showed that inflammatory reaction reduced the level of phosphorylated p38 protein downstream of P38 MAPK pathway. It is considered that ulinastatin plays a role in inflammatory inhibition through the P38MAPK pathway. Compared with P38MAPK pathway specific blockers, both have similar effects on reducing inflammatory factors and proteins, such as tumor necrosis factor- 伪, phosphorylated p38 protein, and so on. However, there are some differences in the influence of serological indexes and the performance under microscope.
【学位授予单位】:山西医科大学
【学位级别】:硕士
【学位授予年份】:2017
【分类号】:R459.7

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