Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Baernthaler, T.
The Role of 15-Prostaglandindehydrogenase in Idiopathic Pulmonary Fibrosis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 124
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Olschewski Andrea
- Schuligoi Rufina
- Altmetrics:
- Abstract:
- Idiopathic pulmonary fibrosis (IPF) is a disease linked to a high 5-year mortality, with few therapeutic options. Prostaglandin (PG)E2 exhibits antifibrotic properties and is reduced in the broncho-alveolar lavage from IPF patients. 15-prostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE2 metabolism under the control of transforming growth factor-β and microRNA 218. We observed that expression patterns of 15-PGDH differ between healthy and IPF lungs, with areas of more pronounced expression in IPF. Treatment of mice with SW033291, an inhibitor of 15-PGDH, was beneficial against bleomycin-induced lung fibrosis in mice, reducing collagen content and improving lung function. These favorable effects were also observed when treatment was started after lung injury and established fibrosis. Fibrocytes are bone marrow derived cells that have been implicated in fibrotic remodeling. We found that PGE2 inhibited human fibrocyte differentiation in vitro both in healthy donors and IPF patients, and observed a reduction of fibrocyte counts in bleomycin treated mice after treatment with 15-PGDH inhibitor, along with decreased alveolar epithelial cell apoptosis and fibroblast proliferation. In precision-cut lung slices from IPF patients, 15-PGDH inhibition increased PGE2 levels and decreased collagen secretion. Finally, microRNA 218-5p, which is downregulated in IPF patients, suppressed 15-PGDH expression in vivo and in vitro. In summary, these data suggest that 15-PGDH plays a crucial role in the metabolism of PGE2 and inhibition of its activity positively affects the development of lung fibrosis through the antifibrotic effects of PGE2. Thus 15-PGDH inhibition might be a promising novel approach for the treatment of IPF.