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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7460639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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