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Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis.
- Source :
-
Scientific reports [Sci Rep] 2020 Jul 15; Vol. 10 (1), pp. 11657. Date of Electronic Publication: 2020 Jul 15. - Publication Year :
- 2020
-
Abstract
- Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.
- Subjects :
- Animals
Bleomycin administration & dosage
Body Weight drug effects
Dinoprostone agonists
Disease Models, Animal
Endothelial Cells drug effects
Endothelial Cells enzymology
Endothelial Cells pathology
Extracellular Matrix drug effects
Extracellular Matrix enzymology
Female
Gene Expression
Humans
Hydroxyprostaglandin Dehydrogenases genetics
Hydroxyprostaglandin Dehydrogenases metabolism
Idiopathic Pulmonary Fibrosis chemically induced
Idiopathic Pulmonary Fibrosis enzymology
Idiopathic Pulmonary Fibrosis mortality
Inflammation
Lung drug effects
Lung enzymology
Lung pathology
Macrophages drug effects
Macrophages enzymology
Macrophages pathology
Mice
Mice, Inbred C57BL
Molecular Targeted Therapy methods
Respiratory Function Tests
Survival Analysis
Anti-Inflammatory Agents pharmacology
Dinoprostone metabolism
Enzyme Inhibitors pharmacology
Hydroxyprostaglandin Dehydrogenases antagonists & inhibitors
Idiopathic Pulmonary Fibrosis drug therapy
Pyridines pharmacology
Thiophenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 32669620
- Full Text :
- https://doi.org/10.1038/s41598-020-68336-0