Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090
Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues – cornea and conjunctiva. While systemic blockade of adhesion molecules...
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| Veröffentlicht in: | Experimental eye research 2016-02, Vol.143, p.1-8 |
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| description | Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues – cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p |
| doi_str_mv | 10.1016/j.exer.2015.10.008 |
| format | Article |
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•We assess ocular surface inflammation in a mouse model of Sjögren's syndrome.•Topical adhesion molecule blockade reduces ocular surface inflammation.•Reduced local inflammation correlates with improved corneal barrier integrity.•Local blockade of adhesion molecules is an effective strategy to treat dry eye.</description><identifier>ISSN: 0014-4835</identifier><identifier>EISSN: 1096-0007</identifier><identifier>DOI: 10.1016/j.exer.2015.10.008</identifier><identifier>PMID: 26463157</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Administration, Topical ; Animals ; Autoimmune ; Cell Count ; Chronic ; Conjunctiva ; Dexamethasone - therapeutic use ; Disease Models, Animal ; Dry Eye Syndromes - genetics ; Dry Eye Syndromes - pathology ; Dry Eye Syndromes - prevention & control ; Fluorescein - metabolism ; Glucocorticoids - therapeutic use ; Goblet Cells - pathology ; Inflammation ; Integrin alpha4beta1 - antagonists & inhibitors ; Interleukin-1beta - genetics ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics ; Ocular surface ; Ophthalmic Solutions ; Phenylalanine - administration & dosage ; Phenylalanine - analogs & derivatives ; Phenylalanine - therapeutic use ; Piperidines - administration & dosage ; Piperidines - therapeutic use ; Real-Time Polymerase Chain Reaction ; RNA, Messenger - genetics ; Sjogren's Syndrome - genetics ; Sjogren's Syndrome - pathology ; Sjogren's Syndrome - prevention & control ; Sjögren's syndrome ; Staining and Labeling ; Thrombospondin 1 - deficiency]]></subject><ispartof>Experimental eye research, 2016-02, Vol.143, p.1-8</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c271t-23326b70a568968cd9d6e0f59ff89fd811eeca043121c71fb796990f5b1b47a63</citedby><cites>FETCH-LOGICAL-c271t-23326b70a568968cd9d6e0f59ff89fd811eeca043121c71fb796990f5b1b47a63</cites><orcidid>0000-0001-9470-1075 ; 0000-0002-9347-8745</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.exer.2015.10.008$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26463157$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Contreras-Ruiz, Laura</creatorcontrib><creatorcontrib>Mir, Fayaz A.</creatorcontrib><creatorcontrib>Turpie, Bruce</creatorcontrib><creatorcontrib>Krauss, Achim H.</creatorcontrib><creatorcontrib>Masli, Sharmila</creatorcontrib><title>Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090</title><title>Experimental eye research</title><addtitle>Exp Eye Res</addtitle><description>Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues – cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.
•We assess ocular surface inflammation in a mouse model of Sjögren's syndrome.•Topical adhesion molecule blockade reduces ocular surface inflammation.•Reduced local inflammation correlates with improved corneal barrier integrity.•Local blockade of adhesion molecules is an effective strategy to treat dry eye.</description><subject>Administration, Topical</subject><subject>Animals</subject><subject>Autoimmune</subject><subject>Cell Count</subject><subject>Chronic</subject><subject>Conjunctiva</subject><subject>Dexamethasone - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Dry Eye Syndromes - genetics</subject><subject>Dry Eye Syndromes - pathology</subject><subject>Dry Eye Syndromes - prevention & control</subject><subject>Fluorescein - metabolism</subject><subject>Glucocorticoids - therapeutic use</subject><subject>Goblet Cells - pathology</subject><subject>Inflammation</subject><subject>Integrin alpha4beta1 - antagonists & inhibitors</subject><subject>Interleukin-1beta - genetics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics</subject><subject>Ocular surface</subject><subject>Ophthalmic Solutions</subject><subject>Phenylalanine - administration & dosage</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - therapeutic use</subject><subject>Piperidines - administration & dosage</subject><subject>Piperidines - therapeutic use</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Sjogren's Syndrome - genetics</subject><subject>Sjogren's Syndrome - pathology</subject><subject>Sjogren's Syndrome - prevention & control</subject><subject>Sjögren's syndrome</subject><subject>Staining and Labeling</subject><subject>Thrombospondin 1 - deficiency</subject><issn>0014-4835</issn><issn>1096-0007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kL1uFDEURi0EIkvCC1Agd9DMcj0_9lhKgyIIkSJRAEppeew7K69mxoPtRUzJI6XJC9DzTHiyCSWNr_XpnCvdj5BXDLYMGH-33-JPDNsSWJODLUD7hGwYSF4AgHhKNgCsLuq2ak7Iixj3Oa1qUT8nJyWvecUasSG_vux_3-0CTm8ijctkgx-R6hi9cTqhpTYsFBekbqKajv4QMb8WB-oi1SMOzod7rlto8rMzeqB6nof8Sc5P1PfZTLgL2f9zW1M9Jb3zk4uJXt40jQQJZ-RZr4eILx_mKfn28cPXi0_F9efLq4v314UpBUtFWVUl7wTohreSt8ZKyxH6RvZ9K3vbMoZoNNQVK5kRrO-E5FJmoGNdLTSvTsnb4945-O8HjEmNLhocBj1hvksx0ay2qERGyyNqgo8xYK_m4EYdFsVArdWrvVqrV2v1a5arz9Lrh_2HbkT7T3nsOgPnRwDzlT9c1qNxOBm0LqBJynr3v_1_AQOmlqc</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Contreras-Ruiz, Laura</creator><creator>Mir, Fayaz A.</creator><creator>Turpie, Bruce</creator><creator>Krauss, Achim H.</creator><creator>Masli, Sharmila</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9470-1075</orcidid><orcidid>https://orcid.org/0000-0002-9347-8745</orcidid></search><sort><creationdate>201602</creationdate><title>Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090</title><author>Contreras-Ruiz, Laura ; Mir, Fayaz A. ; Turpie, Bruce ; Krauss, Achim H. ; Masli, Sharmila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c271t-23326b70a568968cd9d6e0f59ff89fd811eeca043121c71fb796990f5b1b47a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Administration, Topical</topic><topic>Animals</topic><topic>Autoimmune</topic><topic>Cell Count</topic><topic>Chronic</topic><topic>Conjunctiva</topic><topic>Dexamethasone - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Dry Eye Syndromes - genetics</topic><topic>Dry Eye Syndromes - pathology</topic><topic>Dry Eye Syndromes - prevention & control</topic><topic>Fluorescein - metabolism</topic><topic>Glucocorticoids - therapeutic use</topic><topic>Goblet Cells - pathology</topic><topic>Inflammation</topic><topic>Integrin alpha4beta1 - antagonists & inhibitors</topic><topic>Interleukin-1beta - genetics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics</topic><topic>Ocular surface</topic><topic>Ophthalmic Solutions</topic><topic>Phenylalanine - administration & dosage</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - therapeutic use</topic><topic>Piperidines - administration & dosage</topic><topic>Piperidines - therapeutic use</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Sjogren's Syndrome - genetics</topic><topic>Sjogren's Syndrome - pathology</topic><topic>Sjogren's Syndrome - prevention & control</topic><topic>Sjögren's syndrome</topic><topic>Staining and Labeling</topic><topic>Thrombospondin 1 - deficiency</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Contreras-Ruiz, Laura</creatorcontrib><creatorcontrib>Mir, Fayaz A.</creatorcontrib><creatorcontrib>Turpie, Bruce</creatorcontrib><creatorcontrib>Krauss, Achim H.</creatorcontrib><creatorcontrib>Masli, Sharmila</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental eye research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Contreras-Ruiz, Laura</au><au>Mir, Fayaz A.</au><au>Turpie, Bruce</au><au>Krauss, Achim H.</au><au>Masli, Sharmila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090</atitle><jtitle>Experimental eye research</jtitle><addtitle>Exp Eye Res</addtitle><date>2016-02</date><risdate>2016</risdate><volume>143</volume><spage>1</spage><epage>8</epage><pages>1-8</pages><issn>0014-4835</issn><eissn>1096-0007</eissn><abstract>Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues – cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.
•We assess ocular surface inflammation in a mouse model of Sjögren's syndrome.•Topical adhesion molecule blockade reduces ocular surface inflammation.•Reduced local inflammation correlates with improved corneal barrier integrity.•Local blockade of adhesion molecules is an effective strategy to treat dry eye.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26463157</pmid><doi>10.1016/j.exer.2015.10.008</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9470-1075</orcidid><orcidid>https://orcid.org/0000-0002-9347-8745</orcidid></addata></record> |
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| subjects | Administration, Topical Animals Autoimmune Cell Count Chronic Conjunctiva Dexamethasone - therapeutic use Disease Models, Animal Dry Eye Syndromes - genetics Dry Eye Syndromes - pathology Dry Eye Syndromes - prevention & control Fluorescein - metabolism Glucocorticoids - therapeutic use Goblet Cells - pathology Inflammation Integrin alpha4beta1 - antagonists & inhibitors Interleukin-1beta - genetics Mice Mice, Inbred C57BL Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics Ocular surface Ophthalmic Solutions Phenylalanine - administration & dosage Phenylalanine - analogs & derivatives Phenylalanine - therapeutic use Piperidines - administration & dosage Piperidines - therapeutic use Real-Time Polymerase Chain Reaction RNA, Messenger - genetics Sjogren's Syndrome - genetics Sjogren's Syndrome - pathology Sjogren's Syndrome - prevention & control Sjögren's syndrome Staining and Labeling Thrombospondin 1 - deficiency |
| title | Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090 |
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