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Gastroenterology:NFAT蛋白或可导致胰腺炎

来源:医脉通 2012-09-06 12:15

近日,国际期刊Gastroenterology发表的一项新的研究发现,人体内存在的钙敏感蛋白质(例如磷酸酶)可促进炎症的发生,但其确切作用机制尚未清楚。在其他炎性疾病中该蛋白质可能也很明显。马尔默的大学临床科学系Henrik Thorlacius和Maria Gomez对此进行了较深入研究。焦点是一个与磷酸酶相关的蛋白质家族(名称为NFAT),既往还没有研究者对该蛋白质家族在急性胰腺炎中的作用进行过研究。

已知过量饮酒和胆结石是急性胰腺炎的危险因素,但研究者还无法解释发生急性胰腺炎时人体真正发生了什么。

“这种蛋白在胰腺发生炎症的过程中发挥了出乎意料的重要作用。因此,现在药物和治疗的开发有了一个明确的目标。” Henrik Thorlacius说。

在小鼠实验中,研究者发现NFAT和急性胰腺炎之间存在千丝万缕的联系。NFAT(尤其是变异体NFATc3)可调节胰蛋白酶原(消化酶胰蛋白酶的前体形式)的活性,后者可影响发生急性胰腺炎的风险。NFATc3的激活可通过各种其他方式促进胰腺的炎症和组织损害。在研究,主动脉、脾和肺也有受累。因此,这些结果提示NFAT蛋白在一个更普遍的水平参与了炎性疾病的发生。

上述结果为急性胰腺炎和其他急性炎性疾病(例如败血症和炎症性肠病)的治疗和药物研究带来了新机会。因此,可阻止NFATc3激活但不产生严重副作用的药物可成为有效药。

NFAT蛋白作为转录因子发挥功能,这意味着它们可结合于人体的DNA并调节特定不同细胞中特定基因的表达。目前,它们主要与免疫细胞相关。(生物谷Bioon.com))

NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.

Awla D, Zetterqvist AV, Abdulla A, Camello C, Berglund LM, Spégel P, Pozo MJ, Camello PJ, Regnér S, Gomez MF, Thorlacius H.

BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in development of AP in mice.

METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein-2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 h after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes.

RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an L-arginine-induced model of AP. Reverse transcriptase PCR and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium; activation was prevented by the calcineurin blocker cyclosporine A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells.

CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.


 

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