Conjunctival Fluid Secretion Impairment via CaCC-CFTR Dysfunction Is the Key Mechanism in Environmental Dry Eye

Dry eye disease (DED) is a multifactorial disease with an incidence of approximately 50% worldwide. DED seriously affects quality of life and work. The prevalence of environmental DED (eDED) ranges from 35 to 48%. Conjunctival fluid secretion dysfunction may be one of the major causes of DED. Notably, the Cl^- flux corresponds to the conjunctival fluid secretion and could be affected by ATP. Both the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca²⁺-activated Cl^- channel (CaCC) are Cl^- channels involved in epithelial fluid secretion. Conjunctival fluid secretion could be increased by activating P2Y₂R (an ATP receptor) in DED. However, the role of the CaCC and CFTR channels regulated by P2Y₂R in eDED remains unclear. In this study, we established a rabbit eDED model using a controlled drying system. A Ussing chamber was used to perform a conjunctival short-circuit current induced by ATP to evaluate the reactivity of the ion channels to the ATP. Our results revealed that eDED accompanied by conjunctival fluid secretion impairment was caused by a P2Y₂R dysfunction, which is related to CaCC-CFTR signaling in the conjunctiva epithelium. Notably, the coupling effect of the ATP-induced CaCC-CFTR activation and intracellular Ca²⁺ may represent a promising therapeutic target for treating eDED.