Caspase-1抑制剂对实验性重症急性胰腺炎的治疗作用

Therapeutic effect of Caspase-1 inhibitor in experimental severe acute pancreatitis

目的评价Caspase-1抑制剂在实验性重症急性胰腺炎(SAP)中的治疗作用。方法采用5%牛磺胆酸钠逆行注入胰胆管诱发SAP模型。SD大鼠42只,随机分3组:健康对照组(HC组,n=6);SAP造模+腹腔注射生理盐水组(SAP S组,n=18);SAP造模+Caspase1抑制剂组(SAP-ICE-I组,n=18)。SAP-S组于造模后2h腹腔注射生理盐水1ml,12h后重复1次;SAP-ICE- I组于造模后2h腹腔注射ICE抑制剂。HC组模拟胰胆管穿刺操作,但不注射药物。SAP S组与SAP -ICE- I组于6、12、18h腹主动脉取血测血清淀粉酶、IL1β水平,留取标本测胰腺内Caspase-1、IL-1β、IL-18mRNA表达情况并行病理组织学观察,将结果与HC组进行比较。另取大鼠24只,随机均分SAP -S组和SAP- ICE -I组,观察24h死亡率。结果与HC组比较,SAP- S组与SAP- ICE- I血清淀粉酶和IL-1β水平显著升高(P<0.01),SAP S组SAP- ICE -I组又显著高于(P<0.05或0.01)。HC组胰腺组织内可见Caspase1及IL18mRNA表达,但IL1βmRNA表达很弱;与HC组比较,SAP S组胰腺组织内Caspase-1、IL-1β及IL18mRNA的表达显著增强(P<0.0);SAP ICE- I组与SAP S组比较,IL1β及IL18mRNA的表达显著减弱(P<0.01),而Caspase-1mRNA表达无显著改变(P>0.05)。应用Caspase-1抑制剂,可减轻胰腺组织的病理损害程度,并使24h动物死亡率由91.

Objective To study the effect of Caspase-1 inhibitor on severe acute pancreatitis (SAP) in experimental SD rat model. Methods A model of SAP was reproduced by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Heathy control (HC) rats underwent identical surgical procedure and duct cannulation without the injection of sodium taurocholate. Forty-two SD rats were randomly divided into three groups: healthy controls (HC, n=6); SAP-S group (n=18); SAP-ICE-I group (n=18). In SAP-S group, rats received intraperitoneal injection of isotonic saline 2 hours after induction of acute pancreatitis, and saline injection was repeated after 12 hours. In SAP-ICE-I group, rats were given ICE inhibitor intraperitoneally 2 hours after induction of pancreatitis. As in SAP-S group, this was repeated 12 hours laten. Surviving rats were killed at certain time, and all samples were obtained for subsequent analysis. Also, twenty-four rats were randomly divided into two groups: SAP-S group and SAP-ICE-I group, and the 24-hour death rate after SAP induction was observed. Results The serum amylase levels were increased significantly in SAP-S group (P<0.01 vs HC), reaching the peak at 12h (11163.33±1537.55 U/L), but they were decreased significantly in SAP-ICE-I group (P<0.05 at 6h; P<0.01 at 12h and 18h vs SAP-S). The serum IL-1β levels were significantly higher in SAP-S group (P<0.01 vs HC), which were decreased significantly in SAP-ICE-I group (P<0.01 vs SAP-S). Intrapancreatic expressions of Caspase-1 and IL-18 mRNA were readily discernible, but IL-1β mRNA expression was weak in HC. In SAP-S group, the expressions of Caspase-1, IL-1β and IL-18 mRNA were increased significantly (P<0.01 vs HC). The expressions of IL-1β and IL-18 mRNA were decreased significantly in SAP-ICE-I group (P<0.01 vs SAP-S), whereas Caspase-1 mRNA expression showed no significant differences (P>0.05). Caspase-1 inhibition abated the severity of pancreatic tissue damage, and the 24-hour death rate was lowered from 91.7% to 41.7%. Conclusions The expressions of Caspase-1 activated cytokines IL-1β and IL-18 play a pivotal role in the pathogenesis of SAP. Caspase-1 inhibition significantly abates the severity and the mortality in SAP.