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目的过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)激动剂对急性坏死性胰腺炎(acute necrotizing pancreatitis,ANP)具有保护作用,但具体作用机制尚不清楚。文中观察吡咯列酮对ANP大鼠P38丝裂原活化蛋白激酶(P38 mitogen-activated protein kinase,P38MAPK)的表达及有关细胞因子的影响,探讨其治疗机制。方法雄性Wistar大鼠54只,随机分为3组:假手术组、ANP组、吡咯列酮组。采用4%牛磺胆酸钠逆行胆胰管注射建立ANP模型;假手术组注射等量等渗盐水;吡咯列酮组在造模前2 h腹腔注射0.2%DMSO-吡咯列酮20 mg/kg。各组大鼠分别于术后3、6、12 h处死,检测血清淀粉酶、肿瘤坏死因子(tumor necrosis factorα,TNF-α)、白介素-1β(interleukin-1β,IL-1β)水平;常规胰腺病理检查和评分;并观察胰腺组织磷酸化p38MAPK的表达情况。结果①各时间点ANP组血清淀粉酶、TNF-α、IL-1β水平、胰腺病理损伤均高于假手术组(P<0.01),且随着病程进展而加重(P<0.01)。吡咯列酮组较ANP组血清淀粉酶、TNF-α、IL-1β水平有所下降(P<0.05),胰腺病理改变减轻。②假手术组胰腺P38MAPK微量表达,ANP组较假手术组胰腺P38MAPK含量显著升高,高峰出现在造模后3 h(P<0.01),随后逐渐下降。吡咯列酮组各时间点较ANP组胰腺P38MAPK表达降低(P<0.05)。结论吡咯列酮可能通过抑制P38MAPK活性来下调炎性细胞因子TNF-α、IL-1β水平,并减轻ANP大鼠胰腺损伤。
Objective Peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on acute necrotizing pancreatitis (ANP), but the mechanism of action is not yet clear. In this paper, the effect of pyrrolizidine on the expression of P38 mitogen-activated protein kinase (P38MAPK) and related cytokines in ANP rats was observed, and its therapeutic mechanism was also explored. Methods 54 male Wistar rats were randomly divided into 3 groups: sham operation group, ANP group and pioglitazone group. The ANP model was established by injecting 4% sodium taurocholate retrograde biliary and pancreatic ducts. The rats in the sham operation group were injected with equal volume of isotonic saline. The rats in the pyrrolostone group were intraperitoneally injected with 0.2% DMSO-pyrrolostone 20 mg / kg . The rats in each group were sacrificed at 3, 6, and 12 hours after operation, serum levels of amylase, tumor necrosis factorα (TNF-α) and interleukin-1β (IL-1β) Pathological examination and scoring; and observe the expression of phosphorylated p38MAPK in pancreatic tissue. Results ① The levels of serum amylase, TNF-α, IL-1β and pathological changes in pancreas of ANP group were higher than those of sham operation group at each time point (P <0.01), and increased with the course of disease (P <0.01). The levels of serum amylase, TNF-α and IL-1β in pioglitazone group were lower than those in ANP group (P <0.05), and the pathological changes in pancreas were alleviated. ② The P38MAPK expression in the pancreas of the sham operation group was slightly increased. The content of P38MAPK in the pancreas of the ANP group was significantly higher than that of the sham operation group. The peak appeared 3 h after modeling (P <0.01), then decreased gradually. The P38MAPK expression in the pioglitazone group was lower than that in the ANP group at each time point (P <0.05). Conclusion Pyrrolizidine may down-regulate the levels of inflammatory cytokines TNF-α and IL-1β by inhibiting the activity of P38MAPK and relieve the pancreatic injury in ANP rats.