title: Lipoxin A4activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion.
abstract: Conjunctival goblet cells play a major role in maintaining the mucus layer of the tear film under physiological conditions as well as in inflammatory diseases like dry eye and allergic conjunctivitis. Resolution of inflammation is mediated by proresolution agonists such as lipoxin A4(LXA4) that can also function under physiological conditions. The purpose of this study was to determine the actions of LXA4on cultured rat conjunctival goblet cell mucin secretion, intracellular [Ca2+] ([Ca2+]i), and identify signaling pathways activated by LXA4. ALX/FPR2 (formyl peptide receptor2) was localized to goblet cells in rat conjunctiva and in cultured goblet cells. LXA4significantly increased mucin secretion, [Ca2+]i, and extracellular regulated kinase 1/2 (ERK 1/2) activation. These functions were inhibited by ALX/FPR2 inhibitors. Stable analogs of LXA4increased [Ca2+]ito the same extent as LXA4. Sequential addition of either LXA4or resolvin D1 followed by the second compound decreased [Ca2+]iof the second compound compared with its initial response. LXA4activated phospholipases C, D, and A2and downstream molecules protein kinase C, ERK 1/2, and Ca2+/calmodulin-dependent kinase to increase mucin secretion and [Ca2+]i. We conclude that conjunctival goblet cells respond to LXA4to maintain the homeostasis of the ocular surface and could be a novel treatment for dry eye diseases.
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Hodges
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Shatos
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bair
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lippestad
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Dartt
mesh_terms: D000818:Animals; D012634:Bodily Secretions; D020013:Calcium Signaling; D002478:Cells, Cultured; D003228:Conjunctiva / Q000473:pathology*; D003233:Conjunctivitis, Allergic / Q000276:immunology*; D015352:Dry Eye Syndromes / Q000276:immunology*; D020397:Goblet Cells / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D044045:Lipoxins / Q000378:metabolism*; D008297:Male; D009077:Mucins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000378:metabolism*; D013666:Tears / Q000502:physiology
chemical_list: D044045:Lipoxins; D009077:Mucins; D044067:Receptors, Lipoxin; C482540:lipoxin A(4) receptor, rat; C040527:lipoxin A4; D011493:Protein Kinase C