TY  - JOUR
A1  - Bärnthaler, Thomas
A1  - Theiler, Anna
A1  - Zabini, Diana
A1  - Trautmann, Sandra
A1  - Stacher-Priehse, Elvira
A1  - Lanz, Ilse
A1  - Klepetko, Walter
A1  - Sinn, Katharina
A1  - Flick, Holger
A1  - Scheidl, Stefan
A1  - Thomas, Dominique Jeanette
A1  - Olschewski, Horst
A1  - Kwapiszewska, Grazyna
A1  - Schuligoi, Rufina
A1  - Heinemann, Akos
T1  - Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue
T2  - The journal of allergy and clinical immunology
N2  - 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.
KW  - PGE2
KW  - 15-PGDH
KW  - idiopathic pulmonary fibrosis
KW  - fibrocytes
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53067
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-530675
SN  - 1097-6825
SN  - 0091-6749
N1  - © 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
VL  - 145.2020
IS  - 3
SP  - 818
EP  - 833.e11
PB  - Elsevier
CY  - Amsterdam [u. a.]
ER  -