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

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.

• Authors: Paul Cheresh, Seok-Jo Kim, Long Shuang Huang, Satoshi Watanabe, Nikita Joshi, Kinola J N Williams, Monica Chi, Ziyan Lu, Anantha Harijith, Anjana Yeldandi, Anna P Lam, Cara Gottardi, Alexander V Misharin, G R Scott Budinger, Viswanathan Natarajan, David W Kamp
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 16 (Aug 05 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32764262 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA, Mitochondrial
• PF-543
• Pyrrolidines
• SPHKAP protein, human
• Sulfones
• Bleomycin
• Asbestos
• Methanol

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics)
• Alveolar Epithelial Cells (drug effects)
• Animals
• Asbestos (toxicity)
• Bleomycin (pharmacology)
• DNA Damage (drug effects)
• DNA, Mitochondrial (drug effects, genetics)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, genetics, pathology)
• Lung (drug effects, metabolism)
• Methanol (analogs & derivatives, pharmacology)
• Mice
• Mitochondria (drug effects, genetics)
• Monocytes (drug effects)
• Pulmonary Fibrosis (chemically induced, drug therapy, genetics, pathology)
• Pyrrolidines (pharmacology)
• Signal Transduction (drug effects)
• Sulfones