Therapeutic Targeting of 15-PGDH in Murine Idiopathic Pulmonary Fibrosis

Abstract

1Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial 2 remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but 3 involves pathologic inflammation and subsequent failure to resolve fibrosis in response to 4 epithelial injury. Therapeutic strategies for IPF are limited to anti-inflammatory and 5 immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts 6TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to 7 raise tissue PGE2 during IPF have been limited. We previously described the discovery of a 8 small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-9 hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we 10 evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-11 PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced IPF. Long-term 12PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular 13 matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, 14PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. 15 Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-16 PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine IPF, 17 and may have clinical utility to treat human disease. 18 19 Article summary: In IPF, lung epithelial injury leads to local inflammation and fibrosis, which 22 impairs pulmonary function. Inhibition of 15-PGDH using a well-tolerated small molecule 23 3 attenuates inflammation and prevents pulmonary fibrosis and dysfunction in a mouse model of 1 bleomycin-induced IPF. 2 3 15-PGDH is highly expressed and active in healthy murine lung tissue PGDHi attenuates pulmonary measurements of tissue stiffness in bleomycin-treated 24 mice