The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes
| Autor: | G. R. Scott Budinger, Long Shuang Huang, Satoshi Watanabe, Seok Jo Kim, Nikita Joshi, Viswanathan Natarajan, David W. Kamp, Anantha Harijith, Monica Chi, Anjana V. Yeldandi, Anna P. Lam, Ziyan Lu, Cara J. Gottardi, Paul Cheresh, Kinola J.N. Williams, Alexander V. Misharin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pyrrolidines medicine.disease_cause lcsh:Chemistry Mice Idiopathic pulmonary fibrosis chemistry.chemical_compound 0302 clinical medicine Pulmonary fibrosis oxidative stress Sulfones Lung lcsh:QH301-705.5 Spectroscopy biology General Medicine respiratory system Mitochondria Computer Science Applications medicine.anatomical_structure Sphingosine kinase 1 030220 oncology & carcinogenesis monocytes mtDNA damage Signal Transduction DNA damage Bleomycin DNA Mitochondrial SPHK1 Article Catalysis Inorganic Chemistry 03 medical and health sciences medicine Animals Humans Physical and Theoretical Chemistry alveolar epithelial cell Molecular Biology Adaptor Proteins Signal Transducing pulmonary fibrosis business.industry Methanol Monocyte Organic Chemistry Asbestos medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases 030104 developmental biology chemistry lcsh:Biology (General) lcsh:QD1-999 Alveolar Epithelial Cells Cancer research biology.protein business Oxidative stress DNA Damage |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 5595, p 5595 (2020) International Journal of Molecular Sciences Volume 21 Issue 16 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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&mdash both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µ g/50 µ L) 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&minus 21 following bleomycin and day 14&minus 21 or day 30&minus 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. |
| Databáze: | OpenAIRE |
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