{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:13:48Z","timestamp":1780535628875,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T00:00:00Z","timestamp":1596585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United States Veterans Administration","award":["2IO1BX000786-05A2"],"award-info":[{"award-number":["2IO1BX000786-05A2"]}]},{"name":"United States National Institute of Health","award":["R01 HL134800"],"award-info":[{"award-number":["R01 HL134800"]}]},{"name":"National Institutes of Health\/ HLBI (Project 3)","award":["HL 126609"],"award-info":[{"award-number":["HL 126609"]}]},{"name":"National Institutes of Health\/HLBI (Project 4)","award":["P01 Hl 060678"],"award-info":[{"award-number":["P01 Hl 060678"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 HL127342"],"award-info":[{"award-number":["RO1 HL127342"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["5R21AG060211-02"],"award-info":[{"award-number":["5R21AG060211-02"]}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30-CA060553"],"award-info":[{"award-number":["P30-CA060553"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment\u2014both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U\/kg), crocidolite asbestos (100 \u00b5g\/50 \u00b5L) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg\/kg) or vehicle was intraperitoneally injected once every two days from day 7\u221221 following bleomycin and day 14\u221221 or day 30\u221260 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.<\/jats:p>","DOI":"10.3390\/ijms21165595","type":"journal-article","created":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T06:02:21Z","timestamp":1596607341000},"page":"5595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes"],"prefix":"10.3390","volume":"21","author":[{"given":"Paul","family":"Cheresh","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary &amp; Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok-Jo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary &amp; Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long Shuang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2579-8472","authenticated-orcid":false,"given":"Satoshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinola J.N.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary &amp; Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anantha","family":"Harijith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjana","family":"Yeldandi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna P.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara","family":"Gottardi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Misharin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3114-5208","authenticated-orcid":false,"given":"G.R. Scott","family":"Budinger","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary &amp; Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-8212","authenticated-orcid":false,"given":"Viswanathan","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612 USA"},{"name":"Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Kamp","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary &amp; Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17074","DOI":"10.1038\/nrdp.2017.74","article-title":"Idiopathic pulmonary fibrosis","volume":"3","author":"Martinez","year":"2017","journal-title":"Nat. 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