Ivashchenko C Y, Duan S Z, Usher M G, Mortensen R M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G319-26. doi: 10.1152/ajpgi.00056.2007. Epub 2007 Apr 26.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR-gamma agonists have been shown to exert some of their actions independent of PPAR-gamma, the role of PPAR-gamma in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR-gamma in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR-gamma in the endodermal derivatives, we created a cell-type specific knock out of PPAR-gamma in pancreatic acini, ducts, and islets. PPAR-gamma knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR-gamma knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR-gamma in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis.
过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂，如噻唑烷二酮类（TZDs），可减轻胰腺细胞系和急性胰腺炎小鼠模型中的急性炎症。由于已证明PPAR-γ激动剂的某些作用独立于PPAR-γ发挥，PPAR-γ在胰腺炎症中的作用尚未得到直接验证。此外，与内皮细胞或炎症细胞相比，PPAR-γ在内胚层衍生物（腺泡、导管细胞和胰岛）中的不同作用尚不清楚。为了确定TZD罗格列酮对雨蛙肽诱导的急性胰腺炎的影响是否依赖于内胚层衍生物中的PPAR-γ，我们在胰腺腺泡、导管和胰岛中创建了细胞类型特异性的PPAR-γ基因敲除模型。PPAR-γ基因敲除动物在雨蛙肽攻击后，一些炎症基因的反应更大。与对照动物相比，罗格列酮对基因敲除动物胰腺中水肿、巨噬细胞浸润和促炎细胞因子表达的抗炎作用显著降低。然而，罗格列酮在胰腺特异性PPAR-γ基因敲除动物的肺中仍保留其作用，这可能是由于对肺实质的直接抗炎作用。这些数据表明，胰腺上皮细胞和胰岛中的PPAR-γ在抑制炎症中起重要作用，并且是TZDs在急性胰腺炎中发挥抗炎作用所必需的。
