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The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes

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 dete...

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Autores principales: Cheresh, Paul, Kim, Seok-Jo, Huang, Long Shuang, Watanabe, Satoshi, Joshi, Nikita, Williams, Kinola J.N., Chi, Monica, Lu, Ziyan, Harijith, Anantha, Yeldandi, Anjana, Lam, Anna P., Gottardi, Cara, Misharin, Alexander V., Budinger, G.R. Scott, Natarajan, Viswanathan, Kamp, David W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460639/
https://www.ncbi.nlm.nih.gov/pubmed/32764262
http://dx.doi.org/10.3390/ijms21165595
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author Cheresh, Paul
Kim, Seok-Jo
Huang, Long Shuang
Watanabe, Satoshi
Joshi, Nikita
Williams, Kinola J.N.
Chi, Monica
Lu, Ziyan
Harijith, Anantha
Yeldandi, Anjana
Lam, Anna P.
Gottardi, Cara
Misharin, Alexander V.
Budinger, G.R. Scott
Natarajan, Viswanathan
Kamp, David W.
author_facet Cheresh, Paul
Kim, Seok-Jo
Huang, Long Shuang
Watanabe, Satoshi
Joshi, Nikita
Williams, Kinola J.N.
Chi, Monica
Lu, Ziyan
Harijith, Anantha
Yeldandi, Anjana
Lam, Anna P.
Gottardi, Cara
Misharin, Alexander V.
Budinger, G.R. Scott
Natarajan, Viswanathan
Kamp, David W.
author_sort Cheresh, Paul
collection PubMed
description 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—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) 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 7−21 following bleomycin and day 14−21 or day 30−60 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.
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spelling pubmed-74606392020-09-03 The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes Cheresh, Paul Kim, Seok-Jo Huang, Long Shuang Watanabe, Satoshi Joshi, Nikita Williams, Kinola J.N. Chi, Monica Lu, Ziyan Harijith, Anantha Yeldandi, Anjana Lam, Anna P. Gottardi, Cara Misharin, Alexander V. Budinger, G.R. Scott Natarajan, Viswanathan Kamp, David W. Int J Mol Sci Article 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—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) 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 7−21 following bleomycin and day 14−21 or day 30−60 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. MDPI 2020-08-05 /pmc/articles/PMC7460639/ /pubmed/32764262 http://dx.doi.org/10.3390/ijms21165595 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cheresh, Paul
Kim, Seok-Jo
Huang, Long Shuang
Watanabe, Satoshi
Joshi, Nikita
Williams, Kinola J.N.
Chi, Monica
Lu, Ziyan
Harijith, Anantha
Yeldandi, Anjana
Lam, Anna P.
Gottardi, Cara
Misharin, Alexander V.
Budinger, G.R. Scott
Natarajan, Viswanathan
Kamp, David W.
The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title_full The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title_fullStr The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title_full_unstemmed The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title_short The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
title_sort sphingosine kinase 1 inhibitor, pf543, mitigates pulmonary fibrosis by reducing lung epithelial cell mtdna damage and recruitment of fibrogenic monocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460639/
https://www.ncbi.nlm.nih.gov/pubmed/32764262
http://dx.doi.org/10.3390/ijms21165595
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