title: Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation.
abstract: 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, CysLT(1) and CysLT(2,) were present in rat conjunctiva and in rat and human cultured conjunctival goblet cells. All leukotrienes LTB(4), LTC(4), LTD(4), and LTE(4), as well as PGD(2), stimulated goblet cell secretion in rat goblet cells. LTD(4) and LTE(4) increased the intracellular Ca(2+) concentration ([Ca(2+)](i)), and LTD(4) activated ERK1/2. The CysLT(1) receptor antagonist MK571 significantly decreased LTD(4)-stimulated rat goblet cell secretion and the increase in [Ca(2+)](i). Resolvins D1 (RvD1) and E1 (RvE1) completely reduced LTD(4)-stimulated goblet cell secretion in cultured rat goblet cells. LTD(4)-induced secretion from human goblet cells was blocked by RvD1. RvD1 and RvE1 prevented LTD(4)- and LTE(4)-stimulated increases in [Ca(2+)](i), as well as LTD(4) activation of ERK1/2. We conclude that cysteinyl leukotrienes stimulate conjunctival goblet cell mucous secretion with LTD(4) using the CysLT(1) receptor. Stimulated secretion is terminated by preventing the increase in [Ca(2+)](i) and activation of ERK1/2 by RvD1 and RvE1.
authors.affiliation: Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA. darlene.dartt@schepens.harvard.edu
authors.forename: Darlene A
authors.initials: DA
authors.lastname: Dartt
authors.forename: Robin R
authors.initials: RR
authors.lastname: Hodges
authors.forename: Dayu
authors.initials: D
authors.lastname: Li
authors.forename: Marie A
authors.initials: MA
authors.lastname: Shatos
authors.forename: Kameran
authors.initials: K
authors.lastname: Lashkari
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003228:Conjunctiva / Q000378:metabolism* / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use*; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D020397:Goblet Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000502:physiology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017999:Leukotriene E4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D018077:Receptors, Leukotriene; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; D015118:Eicosapentaenoic Acid; C412375:cysteinyl leukotriene receptor 2; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; C083169:leukotriene D4 receptor