Jakkampudi Aparna, Jangala Ramaiah, Reddy B Ratnakar, Mitnala Sasikala, Nageshwar Reddy D, Talukdar Rupjyoti
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India.
Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
Pancreatology. 2016 Jul-Aug;16(4):477-88. doi: 10.1016/j.pan.2016.05.001. Epub 2016 May 24.
The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.
全球范围内，急性胰腺炎（AP）的发病率正在上升，器官衰竭和感染性坏死患者的死亡率可能很高。导致AP发病和死亡的主要因素是全身炎症反应综合征和多器官功能障碍。尽管临床前研究表明，抗分泌剂（生长抑素）、抗氧化剂（S-腺苷甲硫氨酸[SAM]、硒）、蛋白酶抑制剂、血小板活化因子抑制剂（来昔帕泛）和抗炎免疫调节剂（如前列腺素E、吲哚美辛）在降低AP的严重程度和/或死亡率方面有益，但这些药物在临床研究中大多显示出不同的结果。数年的实验研究表明，核因子-κB（NF-κB）激活是AP炎症进展中的早期核心事件。在本手稿中，我们综述了关于NF-κB在AP发病机制中的作用、其早期腺泡内激活以及如何导致疾病进展的文献。我们还讨论了为什么抗蛋白酶、抗分泌和抗炎药物在临床急性胰腺炎中不太可能有效。NF-κB作为一个将初始腺泡损伤与全身炎症联系起来并使炎症持续的核心分子，我们建议更多的研究应集中于靶向抑制NF-κB活性。直接抑制NF-κB的策略已在各种癌症患者中尝试过。到目前为止，过氧化物酶体增殖物激活受体γ（PPAR-γ）配体、吡咯烷二硫代氨基甲酸盐（PDTC）、蛋白酶体抑制剂和钙蛋白酶I抑制剂已被证明在实验性AP中对NF-κB激活有直接抑制作用。
