Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue
| Autor: | Anna Theiler, Holger Flick, Sandra Trautmann, Dominique Thomas, Horst Olschewski, Katharina Sinn, Stefan Scheidl, Thomas Bärnthaler, Ilse Lanz, Diana Zabini, Elvira Stacher-Priehse, Grazyna Kwapiszewska, Akos Heinemann, Walter Klepetko, Rufina Schuligoi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pyridines Immunology Apoptosis In situ hybridization Thiophenes Bleomycin Dinoprostone 03 medical and health sciences Idiopathic pulmonary fibrosis chemistry.chemical_compound Mice 0302 clinical medicine Fibrocyte Pulmonary fibrosis medicine Immunology and Allergy Animals Humans ddc:610 Enzyme Inhibitors Cell Proliferation A549 cell Lung medicine.diagnostic_test business.industry respiratory system medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases MicroRNAs 030104 developmental biology medicine.anatomical_structure Bronchoalveolar lavage 030228 respiratory system chemistry Gene Expression Regulation Cancer research Hydroxyprostaglandin Dehydrogenases Eicosanoids business |
| Popis: | Background Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-β and microRNA 218. Objective We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue. Methods In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis. Results We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro. Conclusions These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach. |
| Databáze: | OpenAIRE |
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