Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis.

Scientific Reports
Julianne N P SmithAmar Desai

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 decrea...Continue Reading

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Citations

Dec 10, 2020·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Kristy E Gilman, Kirsten H Limesand
Jun 3, 2021·Biomolecules·Ke LiYajuan Zheng

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Methods Mentioned

BETA
ELISA
bronchoalveolar
lavage
bronchoalveolar lavage
biopsies
PCR
Assay

Software Mentioned

Histowiz

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