Therapeutic Targeting of 15-PGDH in Murine Idiopathic Pulmonary Fibrosis
| Autor: | Thomas M. Raffay, Alvin P. Jogasuria, Julianne N.P. Smith, Witkin, Sanford D. Markowitz, Kelsey F. Christo, Amar Desai |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Lung business.industry Inflammation respiratory system medicine.disease respiratory tract diseases 3. Good health Pulmonary function testing Extracellular matrix 03 medical and health sciences Idiopathic pulmonary fibrosis 0302 clinical medicine medicine.anatomical_structure 030228 respiratory system Fibrosis Pulmonary fibrosis medicine Cancer research medicine.symptom business Myofibroblast 030304 developmental biology |
| DOI: | 10.1101/2019.12.16.878215 |
| Popis: | 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. Therapeutic strategies 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 IPF. 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 IPF, and may have clinical utility to treat human disease.Article summaryIn IPF, lung epithelial injury leads to local inflammation and fibrosis, which impairs pulmonary function. Inhibition of 15-PGDH using a well-tolerated small molecule attenuates inflammation and prevents pulmonary fibrosis and dysfunction in a mouse model of bleomycin-induced IPF. |
| Databáze: | OpenAIRE |
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