Background & Aims

Sjögren’s syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren’s syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl⁻ channel essential for ductal fluid and HCO₃⁻ secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function?

Methods

We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini.

Results

In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca²⁺ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR.

Conclusions

Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren’s syndrome and pancreatitis.

中文翻译：

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校正自身免疫性疾病小鼠模型中的导管CFTR活性可拯救腺泡细胞以及胰腺和唾液腺的功能

背景与目标

干燥综合征和自身免疫性胰腺炎是唾液，泪腺和外分泌胰腺功能下降的疾病。非肥胖糖尿病/ ShiLTJ小鼠和用细胞因子BMP6转导的小鼠发展为干燥综合征，慢性胰腺炎和MRL / Mp小鼠是自身免疫性胰腺炎的模型。囊性纤维化跨膜传导调节因子（CFTR）是导管氯^- 对导管流体和HCO通道必不可少₃ ^-分泌。我们使用这些模型来提出以下问题：这些疾病中CFTR的表达是否发生了改变，CFTR的矫正是否能纠正腺体功能，最显着的是，矫正导管的功能是否能矫正腺泡的功能？

方法

我们用CFTR校正剂C18和增强剂VX770处理了小鼠模型。在体内和分离的导管/腺泡中测量腺，导管和腺泡细胞的损伤，浸润，免疫细胞和功能。

结果

在疾病模型中，CFTR表达显着降低。唾液腺和胰腺发炎，纤维化和组织损伤增加。用VX770尤其是C18进行的治疗恢复了唾液分泌，挽救了CFTR的表达和定位，并几乎消除了炎症和组织损伤。仅在导管中的CFTR转基因过表达具有相似的作用。最值得注意的是，通过挽救导管CFTR，恢复了腺泡细胞Ca ²⁺信号，Orai1，肌醇三磷酸受体，水通道蛋白5表达和体液分泌的显着减少。

结论

我们的发现表明，矫正导管功能足以挽救腺泡细胞功能，并表明CFTR矫正器是治疗干燥综合征和胰腺炎的强有力候选者。