Mislocalization of CFTR expression in acute pancreatitis and the beneficial effect of VX‐661 + VX‐770 treatment on disease severity

Autor: Zoltán Rakonczay, Emese Réka Bálint, Gabriella Fűr, Viktória Venglovecz, Péter Hegyi, József Maléth, Attila Szűcs, Zsolt Balla, Petra Pallagi, Dénes Péter Kovács, Loránd Kiss, Erik Márk Orján, Beáta Czira, Eszter S. Kormányos
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Physiology. 599:4955-4971
ISSN: 1469-7793
0022-3751
DOI: 10.1113/jp281765
Popis: 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, we investigated the localization and expression of CFTR during cerulein-induced AP in mice and determined the effects of CFTR corrector (VX-661) and potentiator (VX-770) on disease severity. 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 our results, the utilization of CFTR correctors and potentiators should be further investigated in AP. Abstract Cystic fibrosis transmembrane conductance regulator (CFTR) has 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 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 50μg/kg cerulein. Some mice were pre-treated with 5-6 daily injections of 2mg/kg VX-661+VX-770. Control animals were administered physiological saline instead of cerulein and DMSO instead of VX compounds. AP severity was determined by measuring laboratory and histological parameters; CFTR and CK19 expressions were 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 12-24h. CFTR mRNA expression was significantly increased 24h after AP induction. Immunohistochemistry demonstrated disturbed staining morphology of CFTR and CK19 proteins in AP. Mislocalization of CFTR protein was observed from 6h, while expression increased at 24h compared to control. Ductal HCO3 - transport activity was significantly increased 6h 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. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
Externí odkaz: