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Kraeuchi Missouri Endowed Chair Ophthalmology University of Missouri","award":["U01EY031650"],"award-info":[{"award-number":["U01EY031650"]}]},{"name":"Ruth M. Kraeuchi Missouri Endowed Chair Ophthalmology University of Missouri","award":["R01EY030774"],"award-info":[{"award-number":["R01EY030774"]}]},{"name":"Ruth M. Kraeuchi Missouri Endowed Chair Ophthalmology University of Missouri","award":["1I01BX00357"],"award-info":[{"award-number":["1I01BX00357"]}]},{"name":"Ruth M. Kraeuchi Missouri Endowed Chair Ophthalmology University of Missouri","award":["IK6BX005646"],"award-info":[{"award-number":["IK6BX005646"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in &gt;90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2\/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Na\u00efve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min\/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2\/3, pSMAD, and \u0251SMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGF\u03b2, pSMAD3, and SMAD2\/3 levels. On the contrary, inhibition of SMAD2\/3 signaling by SIS3 treatment significantly reduced SMAD2\/3, pSMAD3, and \u0251SMA expression in hCSFs. We conclude that SMAD2\/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure.<\/jats:p>","DOI":"10.3390\/cells12111533","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T03:25:54Z","timestamp":1685676354000},"page":"1533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mustard Gas Exposure Actuates SMAD2\/3 Signaling to Promote Myofibroblast Generation in the Cornea"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8358-8433","authenticated-orcid":false,"given":"Nishant R.","family":"Sinha","sequence":"first","affiliation":[{"name":"Departments of Veterinary Medicine & Surgery and Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA"},{"name":"Harry S. Truman Memorial Veterans\u2019 Hospital, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratnakar","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Medicine & Surgery and Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA"},{"name":"Harry S. Truman Memorial Veterans\u2019 Hospital, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8365-9991","authenticated-orcid":false,"given":"Praveen K.","family":"Balne","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Medicine & Surgery and Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA"},{"name":"Harry S. 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Truman Memorial Veterans\u2019 Hospital, Columbia, MO 65201, USA"},{"name":"Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1017\/S1049023X0000649X","article-title":"Mustard Gas or Sulfur Mustard: An Old Chemical Agent as a New Terrorist Threat","volume":"24","author":"Wattana","year":"2009","journal-title":"Prehospital Disaster Med."},{"key":"ref_2","unstructured":"OPCW Technical Secretariat Report of the OPCW Fact-Finding Mission in Syria Regarding the Incident of 2 August 2016 as Reported in the Note Verbale of the Syrian Arab Republic Number 69 Dated 16 August 2016. 2016\/12\/21 2016, S14442016, 30. 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