Conjunctival Goblet Cell Secretion Stimulated by Leukotrienes Is Reduced by Resolvins D1 and E1 To Promote Resolution of Inflammation

摘要

The conjunctiva is a mucous membrane that covers the sclera and lines the inside of the eyelids. Throughout the conjunctiva are goblet cells that secrete mucins to protect the eye. Chronic inflammatory diseases such as allergic conjunctivitis and early dry eye lead to increased goblet cell mucin secretion into tears and ocular surface disease. The purpose of this study was to determine the actions of the inflammatory mediators, the leukotrienes and the proresolution resolvins, on secretion from cultured rat and human conjunctival goblet cells. We found that both cysteinyl leukotriene (CysLT) receptors, CysLT1 and CysLT2, were present in rat conjunctiva and in rat and human cultured conjunctival goblet cells. All leukotrienes LTB4, LTC4, LTD4, and LTE4, as well as PGD2, stimulated goblet cell secretion in rat goblet cells. LTD4 and LTE4 increased the intracellular Ca²⁺ concentration ([Ca²⁺]i), and LTD4 activated ERK1/2. The CysLT1 receptor antagonist MK571 significantly decreased LTD4-stimulated rat goblet cell secretion and the increase in [Ca²⁺]i. Resolvins D1 (RvD1) and E1 (RvE1) completely reduced LTD4-stimulated goblet cell secretion in cultured rat goblet cells. LTD4-induced secretion from human goblet cells was blocked by RvD1. RvD1 and RvE1 prevented LTD₄- and LTE₄-stimulated increases in [Ca²⁺]_i, as well as LTD₄ activation of ERK1/2. We conclude that cysteinyl leukotrienes stimulate conjunctival goblet cell mucous secretion with LTD₄ using the CysLT₁ receptor. Stimulated secretion is terminated by preventing the increase in [Ca²⁺]_i and activation of ERK1/2 by RvD1 and RvE1.