摘要目的:探讨IκB激酶抑制剂PS1145对脓毒症小鼠血管反应性的影响及机制。方法:采用区组随机法将45只雄性BALB/c小鼠分为对照组（腹腔注射等量0.9%生理盐水，即Con组）、脓毒症组［腹腔注射脂多糖（LPS）10 mg/kg，即LPS组］和实验干预组（小鼠尾静脉注射IκB激酶特异性阻断剂PS1145 50 mg/kg，6 h后腹腔注射LPS 10 mg/kg，即PT组），每组15只。在模型建立后6 h时每组再分为3个亚组（ n=5），分别监测小鼠基础收缩压、给予去甲肾上腺素（NE）（300 ng/kg静脉注射）后收缩压升高幅值、给予乙酰胆碱（Ach）（600 ng/kg静脉注射）后收缩压下降幅值。取3组中监测完基础收缩压亚组的小鼠，采用ELISA法检测血浆中肿瘤坏死因子α（TNF-α）、一氧化氮（NO）及血管内皮多糖-蛋白复合物（GCX）脱落标志物Syndecan-1（SDC-1）的水平，Western blot印迹法检测小鼠肠系膜动脉诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的表达情况。另取15只小鼠分3组（即对照组、LPS组、PT组）建模后采用伊文思蓝染料（EBD）法测定建模6 h时各组小鼠心肌组织、肺脏组织和肠系膜组织的EBD值。 结果:建模6 h时，LPS组和PT组小鼠基础收缩压均低于对照组［分别为（85.8±1.1）、（89.2±1.3）和（112.6±1.5）mmHg（1 mmHg=0.133 kPa），均 P<0.01］；使用NE后LPS组收缩压升高值［（6.40±0.16）mmHg］低于对照组［（13.75±0.43）mmHg］（ P<0.01），PT组［（8.93±0.17）mmHg］高于LPS组（ P<0.01）；使用Ach后收缩压降低幅度LPS组低于对照组［（4.16±0.10）mmHg比（9.52±0.53）mmHg， P<0.01］，PT组［（6.45±0.17）mmHg］高于LPS组（ P<0.01）。建模6 h时LPS组小鼠血浆TNF-α、SDC-1、NO浓度均高于对照组（均 P<0.01），PT组均低于脓毒症组（均 P<0.05）。3组小鼠血浆TNF-α和SDC-1浓度呈正相关（ r=0.99， P<0.05）。建模6 h时，LPS组小鼠肠系膜组织动脉内皮细胞上eNOS蛋白表达水平低于对照组（ P<0.01），PT组高于脓毒症组（ P<0.01）。建模6 h时，LPS组小鼠心脏组织、肺脏组织和肠系膜组织EBD含量均明显高于对照组（均 P<0.01），PT组上述组织EBD含量低于LPS组（均 P<0.01）。 结论:使用PS1145抑制核因子-κB信号通路可改善脓毒症小鼠模型的血管反应性，机制可能与其降低NO水平、抑制炎症反应、减轻血管内皮GCX损伤脱落从而保护血管内皮屏障功能有关。

abstractsObjective:To explore the effect of IκB kinase inhibitor PS1145 on vascular function in septic mice and its mechanism.Methods:Male BALB/C mice ( n=45) were divided into 3 groups with block random method: control (Con) group, mice were given intraperitoneal injection of equal amount of 0.9% saline; lipopolysaccharide stimulation (LPS) group: mice were intraperitoneal injected of lipopolysaccharide 10 mg/kg; PS1145 treatment (PT) group: mice were given PS1145 (50 mg/kg) injection via tail vein 6 hours before intraperitoneal injection of lipopolysaccharide 10 mg/kg. At 6 hours after LPS injection, mice in each group were again divided into 3 subgroups to monitor the basal systolic blood pressure, the increasing amplitude of systolic blood pressure after the administration of norepinephrine (NE) (300 ng/kg, iv) and the decreasing amplitude of systolic blood pressure after administration of achacetylcholine (Ach) (600 ng/kg, iv), respectively. After the basal systolic blood pressure was checked, the levels of tumor necrosis factor (TNF)-α, nitric oxide (NO) and vascular endothelial glycocalyx(GCX) shedding marker syndecan-1 (SDC-1) in plasma of mice were detected by using ELISA method, and the expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in mice mesenteric arteries were detected by western blot method. Another 15 mice were divided into 3 groups (Con group, LPS group, PT group) to detect the vascular permeability of myocardial tissue, lung tissue and mesenteric tissue of mice by using the evans blue dye (EBD) method at 6 h after the models were established. Results:At 6 hours after the model were established, the basic systolic blood pressure of mice in LPS group and in PT group were both lower than in Con group ((85.8±1.1), (89.2±1.3) and (112.6±1.5)mmHg, respectively, both P<0.01), and it was slightly higher in PT group than that in LPS group ( P<0.01); the increasing amplitude of systolic blood pressure of mice after administration of NE in LPS group ((6.40±0.16) mmHg) was lower than that in Con group ((13.75±0.43) mmHg) ( P<0.01), and it was (8.93±0.17) mmHg in PT group and was higher than that in LPS group ( P<0.01); the decreasing amplitude of systolic blood pressure of mice after administration of Ach in LPS group was lower than that in Con group[(4.16±0.10) mmHg vs (9.52±0.53) mmHg, P<0.01), which was higher in PT group ((6.45±0.17) mmHg) than that in LPS group ( P<0.01). At 6 hours after the model were established, the plasma concentrations of TNF-α, SDC-1 and NO in LPS group were all higher than those in Con group (all P<0.01), and these were lower in PT group than those in LPS group (all P<0.01). The levels of SDC-1 and TNF-α were positively correlated ( r=0.99, P<0.05). The relative expression level of eNOS protein on arterial endothelium of the mesenteric tissue of mice in LPS group was lower than that in Con group ( P<0.01), which was higher in PT group than that in LPS group ( P<0.01). The EBD values of heart tissue, lung tissue and mesenteric tissue of mice in LPS group were all significantly higher than those in Con group (all P<0.01), which were lower in PT group than those in LPS group (all P<0.01). Conclusions:The use of IκB kinase inhibitor PS1145 to inhibit nuclear factor-κB signaling pathway can improve the vascular function of sepsis mouse models. The mechanism is considered to be related to its reductions of NO levels and vascular endothelial GCX damage and shedding, thereby protecting the vascular endothelial barrier function.