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

Autor: Fűr G; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Bálint ER; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Orján EM; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Balla Z; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Kormányos ES; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Czira B; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Szűcs A; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Kovács DP; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Pallagi P; First Department of Medicine, University of Szeged, Szeged, Hungary.; Momentum Epithelial Cell Signalling and Secretion Research Group, Hungarian Academy of Sciences-University of Szeged, Szeged, Hungary., Maléth J; First Department of Medicine, University of Szeged, Szeged, Hungary.; Momentum Epithelial Cell Signalling and Secretion Research Group, Hungarian Academy of Sciences-University of Szeged, Szeged, Hungary., Venglovecz V; Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary., Hegyi P; Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs, Hungary.; Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged, Szeged, Hungary.; Szentágothai Research Centre, University of Pécs, Pécs, Hungary., Kiss L; Department of Pathophysiology, University of Szeged, Szeged, Hungary., Rakonczay Z Jr; Department of Pathophysiology, University of Szeged, Szeged, Hungary.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2021 Nov; Vol. 599 (22), pp. 4955-4971. Date of Electronic Publication: 2021 Oct 21.
DOI: 10.1113/JP281765
Abstrakt: 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 3 - 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.
(© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)
Databáze: MEDLINE
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