{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T17:33:45Z","timestamp":1768584825389,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T00:00:00Z","timestamp":1695686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K15975 19K16603 22K05984 20H05678"],"award-info":[{"award-number":["19K15975 19K16603 22K05984 20H05678"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011041","name":"Asahi Group Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008670","name":"Terumo Foundation for Life Sciences and Arts","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008670","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012020","name":"Sekisui Chemical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012020","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Allergic conjunctivitis (AC) is a common ophthalmologic disorder that causes symptoms that often reduces a patient\u2019s quality of life (QOL). We investigated the effects of the eicosapentaenoic acid metabolite (\u00b1)5(6)-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid ((\u00b1)5(6)-DiHETE) on AC using a mouse model.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> BALB\/c mice were sensitized with two injections of short ragweed pollen in alum, challenged fifth with pollen in eyedrops. The clinical signs and tear volume were evaluated at 15\u00a0min after the final challenge. Histamine-induced ocular inflammation model was prepared by instilling histamine onto the surface of the eye. Fifteen minutes after histamine application, tear volume was measured using the Schirmer tear test. Miles assay was performed to investigate vascular permeability. To cause scratching behavior 10\u00a0\u03bcg of serotonin was injected in the cheek.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Repeated topical application of pollen induced conjunctivitis, accompanied by eyelid edema and tearing in mice. Pollen application typically degranulates mast cells and recruits eosinophils to the conjunctiva. Intraperitoneal administration of 300\u00a0\u03bcg\/kg of (\u00b1)5(6)-DiHETE significantly inhibited pollen-induced symptoms. The administration of (\u00b1)5(6)-DiHETE also attenuated mast cell degranulation and eosinophil infiltration into the conjunctiva. To assess the effects of (\u00b1)5(6)-DiHETE on the downstream pathway of mast cell activation in AC, we used a histamine-induced ocular inflammation model. Topical application of 4\u00a0\u03bcg\/eye histamine caused eyelid edema and tearing and increased vascular permeability, as indicated by Evans blue dye extravasation. Intraperitoneal administration of 300\u00a0\u03bcg\/kg or topical administration of 1 \u03bcg\/eye (\u00b1)5(6)-DiHETE inhibited histamine-induced manifestations. Finally, we assessed the effects of (\u00b1)5(6)-DiHETE on itching. An intradermal injection of 10\u00a0\u03bcg serotonin in the cheek caused scratching behavior in mice. Intraperitoneal administration of 300\u00a0\u03bcg\/kg (\u00b1)5(6)-DiHETE significantly inhibited serotonin-induced scratching.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Thus, (\u00b1)5(6)-DiHETE treatment broadly suppressed AC pathology and could be a novel treatment option for AC.<\/jats:p>","DOI":"10.3389\/fphar.2023.1217397","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T09:39:14Z","timestamp":1695807554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Alleviation of allergic conjunctivitis by (\u00b1)5(6)-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid in mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Nanae","family":"Nagata","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoka","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Takenouchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahisa","family":"Murata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/JID.2015.388","article-title":"Involvement of TRPV4 in serotonin-evoked scratching","volume":"136","author":"Akiyama","year":"2016","journal-title":"J. Investigative Dermatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"18174","DOI":"10.1073\/PNAS.1211946109","article-title":"Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca2+ events, and IKCa channels, reducing arteriolar tone","volume":"109","author":"Bagher","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B3","doi-asserted-by":"publisher","first-page":"10252","DOI":"10.1074\/JBC.M116.716464","article-title":"Transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch","volume":"291","author":"Chen","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1016\/J.PAIN.2013.04.004","article-title":"Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglion","volume":"154","author":"Chen","year":"2013","journal-title":"Pain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1096\/FJ.201700954R","article-title":"TRPV4 heats up ANO1-dependent exocrine gland fluid secretion","volume":"32","author":"Derouiche","year":"2018","journal-title":"FASEB J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"H1096","DOI":"10.1152\/AJPHEART.00241.2009","article-title":"TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure","volume":"297","author":"Earley","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"108257","DOI":"10.1016\/J.EXER.2020.108257","article-title":"The role of TRPV4 channels in ocular function and pathologies","volume":"201","author":"Guarino","year":"2020","journal-title":"Exp. Eye Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1194\/JLR.M079095","article-title":"Production of lipid mediators across different disease stages of dextran sodium sulfate-induced colitis in mice","volume":"59","author":"Hamabata","year":"","journal-title":"J. Lipid Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1864","DOI":"10.1194\/jlr.M085233","article-title":"5,6-DiHETE attenuates vascular hyperpermeability by inhibiting Ca2+ elevation in endothelial cells","volume":"59","author":"Hamabata","year":"","journal-title":"J. Lipid Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/J.NUT.2018.11.010","article-title":"Dietary intake of fish and \u03c9-3 polyunsaturated fatty acids and physician-diagnosed allergy in Japanese population: The Japan Environment and Children\u2019s Study","volume":"61","author":"Hamazaki","year":"2019","journal-title":"Nutrition"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3392","DOI":"10.1096\/FJ.201801805R","article-title":"Dietary \u03c9-3 fatty acids alter the lipid mediator profile and alleviate allergic conjunctivitis without modulating T h 2 immune responses","volume":"33","author":"Hirakata","year":"","journal-title":"FASEB J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1097\/ACI.0000000000000561","article-title":"The roles of omega-3 fatty acids and resolvins in allergic conjunctivitis","volume":"19","author":"Hirakata","year":"","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1080\/02713683.2021.1934878","article-title":"Development of allergic conjunctivitis induced by Acanthamoeba excretory-secretory protein and the effect of resolvin D1 on treatment","volume":"46","author":"Kang","year":"2021","journal-title":"Curr. Eye Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1111\/1750-3841.15179","article-title":"A novel eicosapentaenoic acid-derived anti-inflammatory lipid mediator 5,6-DiHETE is abundant in blue back fish intestines","volume":"85","author":"Kida","year":"2020","journal-title":"J. Food Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0090-6980(91)90093-U","article-title":"Urinary excretion of diols derived from eicosapentaenoic acid during n-3 fatty acid ingestion by man","volume":"42","author":"Knapp","year":"1991","journal-title":"Prostaglandins"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e21238","DOI":"10.1096\/fj.201903207RRR","article-title":"5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling","volume":"35","author":"Kobayashi","year":"","journal-title":"FASEB J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/S41598-020-79965-W","article-title":"Automated detection of mouse scratching behaviour using convolutional recurrent neural network","volume":"11","author":"Kobayashi","year":"","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1161\/01.ATV.0000225698.36212.6A","article-title":"Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation","volume":"26","author":"K\u00f6hler","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/J.BBAPAP.2010.09.009","article-title":"Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids","volume":"1814","author":"Konkel","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"B20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/0014-2999(94)00780-B","article-title":"Scratching behavior induced by pruritogenic but not algesiogenic agents in mice","volume":"275","author":"Kuraishi","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"547","DOI":"10.3390\/ph15050547","article-title":"Therapeutic targets in allergic conjunctivitis","volume":"15","author":"Labib","year":"2022","journal-title":"Ther. Targets Allerg. Conjunctivitis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1006\/CLIN.1997.4507","article-title":"A novel murine model of allergic conjunctivitis","volume":"87","author":"Magone","year":"1998","journal-title":"Clin. Immunol. Immunopathol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1016\/J.JID.2016.10.046","article-title":"TRPV4 mediates mast cell activation in cathelicidin-induced rosacea inflammation","volume":"137","author":"Mascarenhas","year":"2017","journal-title":"J. Investigative Dermatology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1007\/S00418-012-0924-5","article-title":"Calcium regulation by thermo- and osmosensing transient receptor potential vanilloid channels (TRPVs) in human conjunctival epithelial cells","volume":"137","author":"Mergler","year":"2012","journal-title":"Histochem Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/J.ALIT.2020.03.005","article-title":"Japanese guidelines for allergic conjunctival diseases 2020","volume":"69","author":"Miyazaki","year":"2020","journal-title":"Allergol. Int."},{"key":"B26","doi-asserted-by":"publisher","first-page":"107133","DOI":"10.1016\/J.VASCN.2021.107133","article-title":"Optimization of a histamine-induced allergic conjunctivitis model in Guinea pigs","volume":"113","author":"Mochizuki","year":"2022","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"B27","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/COD.13497","article-title":"Allergic contact dermatitis in response to ketotifen fumarate contained in eye drops","volume":"83","author":"Romita","year":"2020","journal-title":"Contact Dermat."},{"key":"B28","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1146\/annurev-physiol-021115-105323","article-title":"Glucocorticoid signaling: An update from a genomic perspective","volume":"78","author":"Sacta","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.pain.2008.08.002","article-title":"Behavioral differentiation between itch and pain in mouse","volume":"139","author":"Shimada","year":"2008","journal-title":"Pain"},{"key":"B30","doi-asserted-by":"publisher","first-page":"421","DOI":"10.5935\/0004-2749.20180081","article-title":"Oral omega 3 in different proportions of EPA, DHA, and antioxidants as adjuvant in treatment of keratoconjunctivitis sicca in dogs","volume":"81","author":"Silva","year":"2018","journal-title":"Arq. Bras. Oftalmol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/J.JACI.2010.06.050","article-title":"The epidemiology of ocular and nasal allergy in the United States, 1988-1994","volume":"126","author":"Singh","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3239","DOI":"10.1167\/IOVS.05-0138","article-title":"Role of interferon-gamma in a mouse model of allergic conjunctivitis","volume":"46","author":"Stern","year":"2005","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"S73","DOI":"10.1016\/J.JACI.2009.11.017","article-title":"IgE, mast cells, basophils, and eosinophils","volume":"125","author":"Stone","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"9295","DOI":"10.3390\/IJMS22179295","article-title":"Efficient attenuation of dextran sulfate sodium-induced colitis by oral administration of 5,6-Dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid in mice","volume":"22","author":"Takenouchi","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3980\/J.ISSN.2222-3959.2015.01.01","article-title":"Semaphorin 3A controls allergic and inflammatory responses in experimental allergic conjunctivitis","volume":"8","author":"Tanaka","year":"2015","journal-title":"Int. J. Ophthalmol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"165","DOI":"10.3390\/CELLS10010165","article-title":"TRPing to the point of clarity: Understanding the function of the complex TRPV4 ion channel","volume":"10","author":"Toft-Bertelsen","year":"2021","journal-title":"Cells"},{"key":"B37","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S0168-0102(99)00070-X","article-title":"Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice","volume":"35","author":"Yamaguchi","year":"1999","journal-title":"Neurosci. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1093\/TOXSCI\/KFY285","article-title":"Transient receptor potential ion channels mediate adherens junctions dysfunction in a toluene diisocyanate-induced murine asthma model","volume":"168","author":"Yao","year":"2019","journal-title":"Toxicol. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1159\/000524740","article-title":"Clinical characteristics, health Care resource utilization, and prescription patterns of Japanese patients with physician-diagnosed allergic rhinitis: A secondary use of database study","volume":"1","author":"Yoshisue","year":"2022","journal-title":"Int. Arch. Allergy Immunol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1217397\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T09:39:23Z","timestamp":1695807563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1217397\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,26]]},"references-count":39,"alternative-id":["10.3389\/fphar.2023.1217397"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1217397","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,26]]},"article-number":"1217397"}}