Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a severe disease with limited treatment options and a high five-year mortality rate. Prostaglandin E2 (PGE2) has antifibrotic properties but is found in reduced levels in the bronchoalveolar lavage fluid of IPF patients. The enzyme 15-prostaglandin dehydrogenase (15-PGDH) plays a crucial role in PGE2 metabolism and is regulated by TGF-β and microRNA 218.

Objective
This study aimed to examine the expression of 15-PGDH in IPF and evaluate the therapeutic potential of its specific inhibition in a mouse model and human tissue.

Methods
In vitro experiments, including fibrocyte differentiation, 15-PGDH regulation, RT-PCR, and Western blot analysis, were conducted using peripheral blood from healthy donors and IPF patients, as well as A549 cells. Additional analyses—such as immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization—were performed on lung tissue from healthy donors and IPF patients. Ex vivo IPF tissue culture experiments and therapeutic evaluations of 15-PGDH inhibition were conducted using the bleomycin-induced pulmonary fibrosis mouse model.

Results
Our findings reveal increased 15-PGDH expression in specific regions of IPF patient lungs. Inhibition of 15-PGDH leads to elevated PGE2 levels and reduced collagen production in both IPF precision-cut lung slices and the bleomycin mouse model. Mice treated with the inhibitor demonstrated improved lung function, reduced alveolar epithelial cell apoptosis, and decreased fibroblast proliferation. Furthermore, pulmonary fibrocyte accumulation was reduced following inhibitor treatment, mirroring the effect of PGE2 in inhibiting fibrocyte differentiation from both healthy donors and IPF patients. Additionally, microRNA 218-5p, which is downregulated in IPF patients, was found to suppress 15-PGDH expression both in vitro and in vivo.

Conclusions
These findings underscore the role of 15-PGDH in IPF and suggest that SW033291 inhibiting this enzyme may serve as a promising therapeutic strategy.