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目的观察应用巨噬细胞移动抑制因子(MIF)阻断剂及糖皮质激素(GC)后感染性休克大鼠心血管机能和 MIF 表达的变化。方法 56只 SD 大鼠250～300 g,随机分7组(n_1=8):空白组(Sham 组);CLP 组(盲肠结扎穿刺);ISO-1组(MIF 拓仆酶抑制剂);MIF-Ab 组(MIF 多克隆抗体);DEX-1、DEX-5和 DEX-20组(地塞米松分别1 mg/kg、5 mg/kg、和20 mg/kg)。CLP 后6 h 超声心动仪观察每组大鼠左室舒张末和收缩末直径(LVEDD、LVESD)、左室短轴缩短率(FS%)、心输出量(CO)及肺动脉血灌流量(PP)。继后监测 MAP 和去氧肾上腺素(PE,0.5、1.0、2.0和2.5μg/kg)引起的MAP 增长百分比(ΔMAP%)。活体实验结束后,取大鼠胸主动脉环做离体张力实验,建立 PE 的剂量一反应曲线并计算 E_(max)、EC_(50)值和检测心肌和主动脉中 MIF 蛋白质表达。第二部分大鼠(n_2=10)实验干预后观察其72 h 存活率。结果心脏 LVEDD、LVESD 在 CLP 后6 h 分别下降56%和54%,应用ISO-1、MIF-Ab 和 DEX-20后显著升高(P<0.05)。FS%、CO 及 PP 也相应地得到提高(P<0.001)。而应用 PE 后,ΔMAP%由 CLP 组的6%分别升高至 ISO-1 12.1%、MIF-Ab 10.4%和 DEX-20 9.3%(均 P<0.05)。PE 引起的动脉环最大张力在 ISO-1和 MIF-抗体组较 CLP 组的0.87 g 升高至1.25 g和1.18 g(均 P<0.05),大剂量 GC 组在 PE 1.0×10~(-7)～1.0×10~(-5)mol/L 之间对动脉环张力的影响较 CLP 有改善(P<0.05),而大于1.0×10~(-5)mol/L 时差异无统计学意义。ISO-1、MIF-Ab 和 DEX-20的应用使心肌和主动脉内MIF的表达明显较 CLP 下降(P<0.05);然而,DEX-1和 DEX-5引起 MIF表达较 DEX-20增加(P<0.05)。应用 ISO-1、MIF-Ab 后大鼠72 h 生存率由 CLP 的0%分别提高到70%和60%(P<0.05);而 DEX 的应用均不能使大鼠生存率得到改善。结论 MIF 在感染性休克循环功能障碍中起着重要的中介作用,对 MIF 的拮抗和阻断明显改善休克时血流动力学、血管反应性及预后;大、小剂量 GC 对感染性休克大鼠的血流动力学及血管反应性的影响截然相反,但均不能改善其预后。
Objective To observe the changes of cardiovascular function and MIF expression in septic shock rats after using macrophage migration inhibitory factor (MIF) blocker and glucocorticoid (GC). Methods Fifty-six SD rats (250-300 g) were randomly divided into seven groups (n = 8): blank group (Sham group); CLP group (cecal ligation); ISO-1 group -Ab group (MIF polyclonal antibody); DEX-1, DEX-5 and DEX-20 groups (dexamethasone 1 mg / kg, 5 mg / kg, and 20 mg / kg, respectively). The left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD), left ventricular fractional shortening (FS%), cardiac output (CO) and pulmonary arterial blood flow ). The percentage of MAP growth (ΔMAP%) induced by MAP and phenylephrine (PE, 0.5, 1.0, 2.0 and 2.5 μg / kg) was then monitored. After in vivo experiments, the rat thoracic aortic rings were used to do the in vitro tension test. The dose-response curve of PE was established and the E max, EC 50 values were calculated and the protein expression of MIF in myocardium and aorta was detected. The second part of rats (n_2 = 10) after 72 hours of experimental observation of the survival rate. Results LVEDD and LVESD in heart decreased 56% and 54% respectively at 6 h after CLP, and were significantly increased after ISO-1, MIF-Ab and DEX-20 (P <0.05). FS%, CO and PP were also increased accordingly (P <0.001). After application of PE, ΔMAP% increased from 6% in CLP group to 12.1% in ISO-1, 10.4% in MIF-Ab and 9.3% in DEX-20 (all P <0.05). The maximal arterial ring tension induced by PE increased to 1.25 g and 1.18 g in the ISO-1 and MIF-antibody groups compared with 0.87 g in the CLP group (all P <0.05) ) ~ 1.0 × 10 ~ (-5) mol / L had a better effect on the tension of the arterial rings than that of CLP (P <0.05), while there was no significant difference . The use of ISO-1, MIF-Ab, and DEX-20 resulted in a significant decrease in MIF expression in myocardium and aorta compared with CLP (P <0.05); however, MIF expression was increased in DEX-1 and DEX- P <0.05). Application of ISO-1, MIF-Ab after 72 h survival rate of rats increased from 0% CLP to 70% and 60% (P <0.05); while the application of DEX can not improve the survival rate of rats. Conclusions MIF plays an important mediating role in the functional disturbance of septic shock. The antagonism and blockade of MIF can significantly improve hemodynamics, vascular reactivity and prognosis in shock. Large and small doses of GC can inhibit septic shock rats Hemodynamic and vascular reactivity the opposite, but did not improve their prognosis.