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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease involving the accumulation of extracellular matrix (ECM) throughout alveoli and interstitial spaces, leading to the destruction of lung parenchyma and impaired gas exchange[1]
In response to chronic inflammation, M1 macrophages take on characteristics of alternatively-activated, or M2, m acrophages[14], which contribute to fibrosis and collagen synthesis via production of transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF), and upregulation of L-arginine metabolism[13]
Compared to bone marrow and colon; tissues in which we have previously demonstrated enhanced regeneration and wound healing via pharmacologic 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition, lung tissue shows greater expression and enzyme activity
Summary
15‐PGDH is highly expressed and active in healthy murine lung tissue. (+)SW033291 is known to increase systemic PGE2 levels and enhance tissue regeneration[26]. PGDHi attenuated early pulmonary inflammation, as evidenced by greater than 50% reductions in Il1b and Il6 expression in lung tissue 7 days post-bleomycin exposure, in addition to moderate reductions in the expression of other inflammation-associated genes (Fig. 2B) These data indicate that inhibiting 15-PGDH in the context of bleomycin-induced lung injury may limit pathologic inflammation in the lung. Analysis of the lungs of mice 14 days post-intratracheal bleomycin administration demonstrated similar morphological changes (Supplementary Fig. 1C) These data indicate that PGDHi limits both systemic and local inflammation during the early phase of bleomycininduced lung injury. Observed in mice exposed to bleomycin intratracheally, where 40% of vehicle- and 16% of PGDHi-treated mice succumbed to death (Supplementary Fig. 2C) Together these results suggest PGDHi therapy ameliorates systemic pathology during bleomycin-induced lung injury. The existence of PGDH+ cells in human lung tissue supports the notion that 15-PGDH inhibition may be a novel and effective therapy for IPF patients
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