Department of Pathophysiology, University of Szeged, Szeged, Hungary.
First Department of Medicine, University of Szeged, Szeged, Hungary.
J Physiol. 2021 Nov;599(22):4955-4971. doi: 10.1113/JP281765. Epub 2021 Oct 21.
Cystic fibrosis transmembrane conductance regulator (CFTR) has an essential role in maintaining pancreatic ductal function. Impaired CFTR function can trigger acute pancreatitis (AP) and exacerbate disease severity. We aimed to investigate the localization and expression of CFTR during AP, and determined the effects of a CFTR corrector (VX-661) and potentiator (VX-770) on disease severity. AP was induced in FVB/n mice by 6-10 hourly intraperitoneal injections of 50 μg/kg cerulein. Some mice were pre-treated with five to six daily injections of 2 mg/kg VX-661 + VX-770. Control animals were administered physiological saline instead of cerulein and dimethyl sulfoxide instead of VX compounds. AP severity was determined by measuring laboratory and histological parameters; CFTR and CK19 expression was measured. Activity of ion transporters was followed by intracellular pH or fluid secretion measurement of isolated pancreatic intra-/interlobular ducts. Cerulein-induced AP severity was greatest between 12 and 24 h. CFTR mRNA expression was significantly increased 24 h after AP induction. Immunohistochemistry demonstrated disturbed staining morphology of CFTR and CK19 proteins in AP. Mislocalization of CFTR protein was observed from 6 h, while expression increased at 24 h compared to control. Ductal HCO transport activity was significantly increased 6 h after AP induction. AP mice pre-treatment with VX-661 + VX-770 significantly reduced the extent of tissue damage by about 20-30%, but other parameters were unchanged. Interestingly, VX-661 + VX-770 in vitro administration significantly increased the fluid secretion of ducts derived from AP animals. This study described the course of the CFTR expression and mislocalization in cerulein-induced AP. Our results suggest that the beneficial effects of CFTR correctors and potentiators should be further investigated in AP. KEY POINTS: Cystic fibrosis transmembrane conductance regulator (CFTR) is an important ion channel in epithelial cells. Its malfunction has several serious consequences, like developing or aggravating acute pancreatitis (AP). Here, the localization and expression of CFTR during cerulein-induced AP in mice were investigated and the effects of CFTR corrector (VX-661) and a potentiator (VX-770) on disease severity were determined. CFTR mRNA expression was significantly increased and mislocalization of CFTR protein was observed in AP compared to the control group. Interestingly, pre-treatment of AP mice with VX-661 + VX-770 significantly reduced the extent of pancreatic tissue damage by 20-30%. In vitro administration of VX-661 + VX-770 significantly increased the fluid secretion of ducts derived from AP animals. Based on these results, the utilization of CFTR correctors and potentiators should be further investigated in AP.
囊性纤维化跨膜电导调节因子（CFTR）在维持胰腺导管功能方面具有重要作用。CFTR 功能障碍可引发急性胰腺炎（AP）并加重疾病严重程度。我们旨在研究 CFTR 在 AP 期间的定位和表达，并确定 CFTR 校正剂（VX-661）和增强剂（VX-770）对疾病严重程度的影响。通过每隔 6-10 小时给 FVB/n 小鼠腹腔内注射 50μg/kg 蛙皮素诱导 AP。一些小鼠在 5-6 天内每天接受两次 2mg/kg VX-661+VX-770 的预处理。对照组动物给予生理盐水而不是蛙皮素，二甲基亚砜而不是 VX 化合物。通过测量实验室和组织学参数来确定 AP 的严重程度；测量 CFTR 和 CK19 的表达。通过测量分离的胰腺内/小叶间导管的细胞内 pH 或流体分泌来跟踪离子转运体的活性。蛙皮素诱导的 AP 严重程度在 12 至 24 小时之间最大。AP 诱导后 24 小时，CFTR mRNA 表达显著增加。免疫组织化学显示 AP 中 CFTR 和 CK19 蛋白的染色形态受到干扰。CFTR 蛋白的定位错误在 6 小时时就可以观察到，而与对照组相比，其表达在 24 小时时增加。AP 诱导后 6 小时，HCO3 转运活性显著增加。AP 小鼠用 VX-661+VX-770 预处理可使组织损伤程度降低约 20-30%，但其他参数不变。有趣的是，VX-661+VX-770 在体外给药可显著增加来自 AP 动物的导管的流体分泌。本研究描述了 CFTR 在蛙皮素诱导的 AP 中的表达和定位错误的过程。我们的结果表明，CFTR 校正剂和增强剂的有益作用应在 AP 中进一步研究。
囊性纤维化跨膜电导调节因子（CFTR）是上皮细胞中重要的离子通道。其功能障碍会导致多种严重后果，例如发展或加重急性胰腺炎（AP）。本研究旨在研究在鼠类中，蛙皮素诱导的 AP 期间 CFTR 的定位和表达，以及 CFTR 校正剂（VX-661）和增强剂（VX-770）对疾病严重程度的影响。与对照组相比，AP 中 CFTR mRNA 表达显著增加且 CFTR 蛋白定位错误。有趣的是，AP 小鼠用 VX-661+VX-770 预处理可使胰腺组织损伤程度降低约 20-30%。在体外给予 VX-661+VX-770 可显著增加来自 AP 动物的导管的流体分泌。基于这些结果，CFTR 校正剂和增强剂在 AP 中的应用应进一步研究。
