eNOS is Protective in the Initiation of Pancreatitis

描述：(申请人提供)：硝酸的药理抑制 实验性急性脑损伤中一氧化氮合酶(NOS)或一氧化氮(NO)的升高 胰腺炎(AP)的结果好坏参半，部分原因是三种一氧化氮合酶亚型 存在：神经元型(NNOS)、内皮型(ENOS)和诱导型(INOS)。我们的 初步数据阐明了一氧化氮在AP启动过程中的作用，并显示 药理学上的一氧化氮合酶可阻断eNOS的缺失，但不能阻断nNOS或iNOS 缺失，增强体内雨蛙素过度刺激模型的启动 美联社。相比之下，体外实验中阻断一氧化氮合酶的药理作用有 对腺泡内胰酶原转化为胰酶没有影响，这是 AP，提示eNOS来源的NO来自非腺泡来源和/或ACTs 在一个非腺泡目标上。我们的数据还表明，内皮细胞的上调 辛伐他汀和细胞松弛素D可在体内减弱雨蛙素AP的作用。我们 假设eNOS衍生的NO间接抑制AP的启动 增强胰腺微血管灌注率。我们计划确认是否 内皮型一氧化氮合酶在体外对非腺泡靶点的作用 分离的eNOS KO腺泡与WT腺泡的AP模型。其次，我们计划评估 急性胰腺炎时内皮型一氧化氮合酶KO小鼠和WT小鼠胰腺灌注的差异 使用染料标记的微球。第三，我们计划确定增强的 ENOS KO小鼠(与WT小鼠相比)体内AP的启动可能是 在没有供体的情况下，通过增加胰腺灌注量来正常化。第四，我们计划 在WT和eNOS KO小鼠体内药理学上调eNOS以评估 对体内雨蛙素AP的保护作用。我们希望这项研究可以进一步 阐明NO在AP发病机制中的作用。

DESCRIPTION: (provided by applicant): Pharmacological inhibition of nitric oxide synthase (NOS) or enhancement of nitric oxide (NO) in experimental acute pancreatitis (AP) has yielded mixed results, in part because three NOS isoforms exist: neuronal- (nNOS), endothelial- (eNOS) and inducible- (iNOS). Our preliminary data clarifies the role of NO during the initiation of AP and shows that pharmacologic NOS blockade and eNOS deletion, but not nNOS or iNOS deletion, enhance the initiation of an in vivo caerulein hyperstimulation model of AP. By contrast pharmacologic NOS blockade during in vitro caerulein AP has no effect on conversion of intraacinar trypsinogen to trypsin, a hallmark of AP, suggesting that eNOS-derived NO arises from a non-acinar source and/or acts on a non-acinar target. Our data also suggests that upregulation of endothelial eNOS by Simvastatin and Cytochalasin D may attenuate in vivo caerulein AP. We hypothesize that eNOS-derived NO indirectly inhibits initiation of AP by enhancing pancreatic microvascular perfusion. We plan to confirm whether eNOS-derived NO acts on a non-acinar target by using an in vitro caerulein model of AP in isolated eNOS KO acini vs. WT acini. Secondly we plan to assess differences in pancreatic perfusion between eNOS KO mice and WT mice during AP using dye-labeled microspheres. Third we plan to determine whether the enhanced initiation of in vivo AP in eNOS KO mice (compared with WT mice) may be normalized by augmenting pancreatic perfusion with NO donors. Fourth we plan to upregulate eNOS pharmacologically in WT and eNOS KO mice to assess for protection against in vivo caerulein AP. We hope that this study may further clarify the role of NO in the pathogenesis of AP.