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  • The goal of studying RvE in goblet cells is to


    The goal of studying RvE1 in goblet FRAX486 is to determine if it may be used to preserve ocular surface homeostasis and as a treatment of ocular inflammatory diseases. We found that RvE1 increased glycoconjugate secretion after 2 h, not at 4 h. This suggests that RvE1 has a short, but potent, action on regulating goblet cell secretion. Similar results were obtained for RvD1 and AT-RvD1, where glycoconjugate secretion was measured every hour for 0–4 h. Peak secretion was observed for both RvD1 and AT-RvD1 after 1 h (Li et al., 2013). This time dependency is similar to that of EGF but shorter than the effect of histamine that was still effective after 4 h in rat conjunctival goblet cells (Hayashi et al., 2012; Hodges et al., 2012a). Thus, RvE1 could function to provide short-term stimulation of high molecular weight glycoconjugates including MUC5AC secretion without overproducing mucin that can be harmful to the ocular surface. The data presented in this manuscript along with studies by Lippested et al. using RvD1 (Lippestad et al., 2017) and Hodges et al. (2017) using LXA4, support the hypothesis that these SPMs play a dual role in the conjunctival goblet cells. The first role is to maintain homeostasis in normal, non-inflamed conjunctiva. In support of this, we demonstrated that resolvins RvE1, RvD1, and LXA4alone stimulate [Ca2+]i and secretion. In these experiments, the resolvins were added (with no other additions) and [Ca2+]i or secretion were measured. The second role is the resolution of inflammation and as such they inhibit histamine- and leukotriene-stimulated increase in [Ca2+]i and secretion. This was demonstrated by incubation of goblet cells for 30 min with resolvins prior to addition of either histamine or leukotrienes (Dartt et al., 2011; Li et al., 2013). In summary, RvE1 stimulates conjunctival goblet cells to secrete high molecular weight glycoconjugates including MUC5AC secretion by increasing [Ca2+]i. which in turns activates the PLC, PLD and PLA2 signaling pathways. Previous results have shown that RvE1, like RvD1 and LXA4, counter-regulate inflammatory mediator induced glycoconjugate secretion (Dartt et al., 2011; Hodges et al., 2016a). RvE1, RvD1 and LXA4 appear to act in similar ways to regulate glycoconjugate mucin secretion during physiological conditions using different GPCR to evoke intracellular signals. We conclude that RvE1, as well as other SPMs, help to maintain stable, normal glycoconjugate mucin production in the ocular surface. Thus, RvE1 may be useful both to maintain ocular surface health and as a treatment of ocular surface inflammatory diseases.
    Funding This work was supported by The Norwegian Research Council to M.L., National Institute of Health GrantEY019470 to D.A.D, and R01GM038765 to C.N.S.