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  • Numerous studies show that RvE reduces


    Numerous studies show that RvE1 reduces inflammation in the eye. We demonstrated that RvE1 blocks the pro-inflammatory leukotriene (LT) D4-stimulated increase in goblet cell secretion from cultured rat conjunctival goblet Repaglinide mg (Dartt et al., 2011). In a murine model of dry eye disease, topical application of RvE1 decreased inflammatory markers and increased the number of goblet cells and tear production (Li et al., 2010; de Paiva et al., 2012). In other studies, RvE1 decreased inflammation in the cornea (Lee et al., 2015; Rajasagi et al., 2011; Jin et al., 2009). The long acting RvE1 analog RX-10045 reduced postoperative complications after laser refractive surgery (Torricelli et al., 2014). Furthermore, multiple studies indicate that a dietary intake of omega-3 fatty acids including EPA has a beneficial effect on dry eye disease (Miljanovic et al., 2005; Viau et al., 2009). To date, RvE1 has been used in one clinical trial where an analog of RvE1 reduced symptoms in dry eye disease patients (Serhan et al., 2014). Studies on a molecular level, in animal models and a clinical trial implicate a role for RvE1 in terminating ocular surface inflammation. Recent results from our group found that SPMs, not only play a part in terminating inflammation, but also have a physiological role in conjunctival goblet cells to maintain ocular surface health in the absence of disease. Amongst the SPMs that are effective in the conjunctiva are resolvin D1 (RvD1), aspirin-triggered RvD1 (AT-RvD1), and lipoxin A4 (LXA4). All these SPMs, on their own, increase the intracellular [Ca2+] ([Ca2+]i) and stimulate glycoconjugate secretion (Lippestad et al., 2017; Li et al., 2013; Hodges et al., 2017). Both RvD1 and LXA4 stimulate an increase in [Ca2+]i through activation of phospholipase (PLC), phospholipase D (PLD), and phospholipase A2 (PLA2) (Lippestad et al., 2017; Hodges et al., 2017). Although numerous studies indicate that RvE1 can be a promising new treatment of ocular inflammatory diseases, the physiological functions of RvE1 in the eye to maintain health are unknown. In this study, we investigated the actions of RvE1 on glycoconjugate mucin secretion and [Ca2+]i from cultured conjunctival goblet cells and the signaling pathways used by RvE1 to do so.
    Materials and methods
    Discussion Herein we found that RvE1 stimulates glycoconjugate secretion from conjunctival goblet cells and did so by increasing [Ca2+]i, and activation of the PLC, PLD, and PLA2 signaling pathways. The PLC downstream molecules IP3 and PKC were also activated by RvE1 (Fig. 9). In multiple types of chronic inflammatory diseases RvE1 is an active component of the resolution of inflammation (Hasturk et al., 2006; Aoki et al., 2010; Salic et al., 2016; Herrera et al., 2015; Kim et al., 2012; Haworth et al., 2008). Here, we presented supportive results that RvE1 may also regulate glycoconjugate secretion in conjunctival goblet cells in physiological conditions to maintain ocular surface health. Our results are consistent with earlier studies of the SPMs RvD1 and LXA4, which we showed also play a role in stimulating conjunctival goblet cell secretion under normal, physiological conditions. Similarly to RvE1, RvD1 and LXA4 also stimulate glycoconjugate mucin secretion thorough an increase in [Ca2+]i (Lippestad et al., 2017; Hodges et al., 2016b). RvE1 binds to the receptor ERV-1/ChemR23 (Arita et al., 2007), RvD1 activates DRV1/GPR32 (in humans) and ALX/FPR2 (Krishnamoorthy et al., 2010, 2012) and LXA4 stimulates ALX/FPR2 (Chiang et al., 2006). Although RvE1, RvD1, and LXA4 activate different receptors, they act in a surprisingly similar manner. All the SPMs studied activated PLC, PLD and PLA2 pathways when interacting with goblet cells from the conjunctiva. The only significant difference we found was that RvD1 and LXA4 also induced [Ca2+]i through Ca2+/CaMK. Our results indicate that SPMs have a common regulating function on goblet cell glycoconjugate mucin secretion, which is key in maintaining a healthy ocular surface. A physiological role for the SPMs is strengthened by LXA4 and RvD1 being found in emotional tears from human (English et al., 2017). Although RvE1 was not identified in tears this may reflect the nutritional status of EPA of the individuals since 18-HEPE, the RvE1 precursor, was present in tears from males. Hence, RvE1 could still be effective in maintaining ocular surface health if added topically to the tear film.