Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Cells. 2021 Dec 24;11(1):54. doi: 10.3390/cells11010054.
CFTR, the cystic fibrosis (CF) gene-encoded epithelial anion channel, has a prominent role in driving chloride, bicarbonate and fluid secretion in the ductal cells of the exocrine pancreas. Whereas severe mutations in cause fibrosis of the pancreas in utero, CFTR mutants with residual function, or CFTR variants with a normal chloride but defective bicarbonate permeability (CFTR), are associated with an enhanced risk of pancreatitis. Recent studies indicate that CFTR function is not only compromised in genetic but also in selected patients with an acquired form of pancreatitis induced by alcohol, bile salts or smoking. In this review, we summarize recent insights into the mechanism and regulation of CFTR-mediated and modulated bicarbonate secretion in the pancreatic duct, including the role of the osmotic stress/chloride sensor WNK1 and the scaffolding protein IRBIT, and current knowledge about the role of CFTR in genetic and acquired forms of pancreatitis. Furthermore, we discuss the perspectives for CFTR modulator therapy in the treatment of exocrine pancreatic insufficiency and pancreatitis and introduce pancreatic organoids as a promising model system to study CFTR function in the human pancreas, its role in the pathology of pancreatitis and its sensitivity to CFTR modulators on a personalized basis.
CFTR 是囊性纤维化（CF）基因编码的上皮阴离子通道，在外分泌胰腺的导管细胞中，CFTR 对氯离子、碳酸氢根离子和液体分泌具有重要作用。虽然严重的 CFTR 基因突变会导致胎儿期胰腺纤维化，但具有残留功能的 CFTR 突变体或氯离子正常但碳酸氢根离子通透性缺陷的 CFTR 变异体（CFTR），与胰腺炎风险增加相关。最近的研究表明，CFTR 功能不仅在遗传形式中受到损害，而且在某些由酒精、胆汁盐或吸烟引起的获得性胰腺炎患者中也受到损害。在这篇综述中，我们总结了最近关于 CFTR 介导和调节胰腺导管中碳酸氢盐分泌的机制和调节的新见解，包括渗透压应激/氯离子传感器 WNK1 和支架蛋白 IRBIT 的作用，以及 CFTR 在遗传和获得性胰腺炎中的作用。此外，我们讨论了 CFTR 调节剂治疗外分泌胰腺功能不全和胰腺炎的前景，并介绍了胰腺类器官作为研究 CFTR 功能在人类胰腺中的作用、其在胰腺炎病理中的作用以及其对 CFTR 调节剂的敏感性的有前途的模型系统，这是基于个体化的。
