The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
Open Access
- 5 August 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (16), 5595
- https://doi.org/10.3390/ijms21165595
Abstract
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.Keywords
Funding Information
- National Institutes of Health (RO1 HL127342)
- National Institute of Health (5R21AG060211-02)
- National Cancer Institute (P30-CA060553)
This publication has 55 references indexed in Scilit:
- The mitochondria in lung fibrosis: friend or foe?Translational Research, 2018
- Idiopathic pulmonary fibrosisNature Reviews Disease Primers, 2017
- Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosisJCI Insight, 2017
- Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damageFree Radical Biology & Medicine, 2016
- The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary FibrosisInternational Journal of Molecular Sciences, 2015
- Sphingolipids in pulmonary fibrosisAdvances in Biological Regulation, 2015
- Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial CellsJournal of Biological Chemistry, 2014
- Role of sphingosine 1-phosphate and lysophosphatidic acid in fibrosisBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2013
- Role of the Lysophospholipid Mediators Lysophosphatidic Acid and Sphingosine 1-Phosphate in Lung FibrosisProceedings of the American Thoracic Society, 2012
- Mortality from Pulmonary Fibrosis Increased in the United States from 1992 to 2003American Journal of Respiratory and Critical Care Medicine, 2007