Pharmacological Rescue of Ductal CFTR Rescue Pancreatic and Salivary glands Acinar Cells and Tissue Function in Mouse Models of Autoimmune diseases

Abstract Background & Aims Sjogren's syndrome and autoimmune pancreatitis (AIP) are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. NOD/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjogren's syndrome and chronic pancreatitis and MRL/Mp mice are models of AIP. CFTR is a ductal Cl - channel essential for ductal fluid and HCO 3 - secretion. We used these models to ask: 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 of 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, nearly eliminated the inflammation and tissue damage. Transgenic over-expression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca 2+ signaling, Orai1, IP 3 receptors, AQP5 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 Sjogren's syndrome and pancreatitis.