{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:17:55Z","timestamp":1788909475195,"version":"build-2803163510"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD0018070"],"award-info":[{"award-number":["S10OD0018070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016947","name":"Swim Across America","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine\u20101\u2010phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF\u2010\u03b2 signaling. Hence, decreasing lung S1P represents a potential therapeutic strategy for IPF. S1P is degraded by the intracellular enzyme S1P lyase (SPL). Here we find that a knock\u2010in mouse with a missense SPL mutation mimicking human disease resulted in reduced SPL activity, increased S1P, increased TGF\u2010\u03b2 signaling, increased lung fibrosis, and higher mortality after injury compared to wild type (WT). We then tested adeno\u2010associated virus 9 (AAV9)\u2010mediated overexpression of human\n                    <jats:italic>SGPL1<\/jats:italic>\n                    (AAV\u2010SPL) in mice as a therapeutic modality. Intravenous treatment with AAV\u2010SPL augmented lung SPL activity, attenuated S1P levels within the lungs, and decreased injury\u2010induced fibrosis compared to controls treated with saline or only AAV. We confirmed that AAV\u2010SPL treatment led to higher expression of SPL in the epithelial and fibroblast compartments during bleomycin\u2010induced lung injury. Additionally, AAV\u2010SPL decreased expression of the profibrotic cytokines TNF\u03b1 and IL1\u03b2 as well as markers of fibroblast activation, such as fibronectin (\n                    <jats:italic>Fn1<\/jats:italic>\n                    ),\n                    <jats:italic>Tgfb1<\/jats:italic>\n                    ,\n                    <jats:italic>Acta2<\/jats:italic>\n                    , and collagen genes in the lung. Taken together, our results provide proof of concept for the use of AAV\u2010SPL as a therapeutic strategy for the treatment of IPF. \u00a9 2024 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6256","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T03:16:18Z","timestamp":1707448578000},"page":"22-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gene therapy with\n                    <scp>\n                      AAV9\u2010\n                      <i>SGPL1<\/i>\n                    <\/scp>\n                    in an animal model of lung fibrosis"],"prefix":"10.1002","volume":"263","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7630-6805","authenticated-orcid":false,"given":"Aritra","family":"Bhattacharyya","sequence":"first","affiliation":[{"name":"Division of Pulmonary Critical Care, Allergy, and Sleep, Department of Medicine, University of California  San Francisco CA USA"},{"name":"Sandler Asthma Basic Research Center, University of California, San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjha","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna Y","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of California  San Francisco CA 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Yin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Critical Care, Allergy, and Sleep, Department of Medicine, University of California  San Francisco CA USA"},{"name":"Sandler Asthma Basic Research Center, University of California, San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier G","family":"Ortega","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Critical Care, Allergy, and Sleep, Department of Medicine, University of California  San Francisco CA USA"},{"name":"Sandler Asthma Basic Research Center, University of California, San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallar","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Critical Care, Allergy, and Sleep, Department of Medicine, University of California  San Francisco CA USA"},{"name":"Sandler Asthma Basic Research Center, University of California, San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie D","family":"Saba","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"797","article-title":"Idiopathic pulmonary fibrosis","volume":"379","author":"Lederer DJ","year":"2018","journal-title":"N Engl J 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