Sennello Joseph A, Fayad Raja, Pini Maria, Gove Melissa E, Ponemone Venkatesh, Cabay Robert J, Siegmund Britta, Dinarello Charles A, Fantuzzi Giamila
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8085-90. doi: 10.1073/pnas.0804091105. Epub 2008 May 30.
Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.
肥胖与急性胰腺炎（AP）病情加重有关。细胞因子白细胞介素-18（IL-18）和白细胞介素-12（IL-12）在AP患者中升高，且肥胖患者的IL-18水平较高。我们旨在建立一个与病理相关的模型来研究肥胖相关的重症AP。瘦的野生型（WT）小鼠和肥胖的瘦素缺乏型ob/ob小鼠接受两次IL-12加IL-18注射。测量生存率、胰腺炎症以及AP的生化标志物。给予IL-12加IL-18导致ob/ob小鼠100%死亡；WT小鼠未观察到死亡。ob/ob小鼠的胰腺外分泌组织破坏、腺泡细胞死亡以及血清淀粉酶和脂肪酶水平显著高于WT小鼠。WT小鼠发生水肿性AP，而肥胖的ob/ob小鼠发生坏死性AP。细胞因子注射的ob/ob小鼠出现脂肪组织坏死和皂化，而WT小鼠未出现。ob/ob小鼠出现严重低钙血症和急性期反应升高。细胞因子组合在WT小鼠而非ob/ob小鼠的胰腺中诱导高水平的再生蛋白1和胰腺炎相关蛋白表达。为了区分肥胖和瘦素缺乏的作用，小鼠接受短期和长期瘦素替代治疗。在体重未显著减轻的情况下进行短期瘦素重建并不能保护ob/ob小鼠，而在无肥胖情况下的瘦素缺乏导致胰腺炎严重程度显著降低。总之，我们建立了一个与病理相关的AP模型，其中肥胖本身与病情加重有关。
