Sato N, Moore F A, Kone B C, Zou L, Smith M A, Childs M A, Moore-Olufemi S, Schultz S G, Kozar R A
Department of Surgery, Houston School of Medicine, University of Texas, 77030, USA.
Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G616-23. doi: 10.1152/ajpgi.00248.2005. Epub 2005 Oct 27.
Using a rodent model of gut ischemia-reperfusion (I/R), we have previously shown that the induction of inducible nitric oxide synthase (iNOS) is harmful, whereas the induction of heme oxygenase 1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is protective. In the present study, we hypothesized that the luminal nutrients arginine and glutamine differentially modulate these molecular events in the postischemic gut. Jejunal sacs were created in rats at laparotomy, filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 min of superior mesenteric artery occlusion and 6 h of reperfusion, and compared with shams. The jejunum was harvested for histology or myeloperoxidase (MPO) activity (inflammation). Heat shock proteins and iNOS were quantitated by Western blot analysis and PPAR-gamma by DNA binding activity. In some experiments, rats were pretreated with the PPAR-gamma inhibitor G9662 or with the iNOS inhibitor N-[3(aminomethyl)benzyl]acetamidine (1400W). iNOS was significantly increased by arginine but not by glutamine following gut I/R and was associated with increased MPO activity and mucosal injury. On the other hand, PPAR-gamma was significantly increased by glutamine but decreased by arginine, whereas heat shock proteins were similarly increased in all experimental groups. The PPAR-gamma inhibitor G9662 abrogated the protective effects of glutamine, whereas the iNOS inhibitor 1400W attenuated the injurious effects of arginine. We concluded that luminal arginine and glutamine differentially modulate the molecular events that regulate injurious I/R-mediated gut inflammation and injury. The induction of PPAR-gamma by luminal glutamine is a novel protective mechanism, whereas luminal arginine appears harmful to the postischemic gut due to enhanced expression of iNOS.
利用肠道缺血再灌注（I/R）的啮齿动物模型，我们之前已经表明，诱导型一氧化氮合酶（iNOS）的诱导是有害的，而血红素加氧酶1（HO-1）和过氧化物酶体增殖物激活受体γ（PPAR-γ）的诱导则具有保护作用。在本研究中，我们假设腔内营养物质精氨酸和谷氨酰胺对缺血后肠道中的这些分子事件具有不同的调节作用。在剖腹手术时在大鼠中创建空肠囊，分别填充60 mM谷氨酰胺、精氨酸或硫酸镁（渗透对照），随后进行60分钟的肠系膜上动脉闭塞和6小时的再灌注，并与假手术组进行比较。收获空肠用于组织学检查或髓过氧化物酶（MPO）活性（炎症）检测。通过蛋白质免疫印迹分析对热休克蛋白和iNOS进行定量，通过DNA结合活性对PPAR-γ进行定量。在一些实验中，大鼠用PPAR-γ抑制剂G9662或iNOS抑制剂N-[3（氨甲基）苄基]乙脒（1400W）进行预处理。肠道I/R后，精氨酸可显著增加iNOS，但谷氨酰胺则不会，且这与MPO活性增加和黏膜损伤有关。另一方面，谷氨酰胺可显著增加PPAR-γ，但精氨酸则使其降低，而所有实验组中的热休克蛋白均有类似增加。PPAR-γ抑制剂G9662消除了谷氨酰胺的保护作用，而iNOS抑制剂1400W减弱了精氨酸的损伤作用。我们得出结论，腔内精氨酸和谷氨酰胺对调节有害的I/R介导的肠道炎症和损伤的分子事件具有不同的调节作用。腔内谷氨酰胺诱导PPAR-γ是一种新的保护机制，而腔内精氨酸由于iNOS表达增强似乎对缺血后肠道有害。
