Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue.
Animals
Apoptosis
/ drug effects
Cell Proliferation
/ drug effects
Dinoprostone
/ metabolism
Eicosanoids
/ metabolism
Enzyme Inhibitors
/ pharmacology
Gene Expression Regulation
Humans
Hydroxyprostaglandin Dehydrogenases
/ metabolism
Idiopathic Pulmonary Fibrosis
/ enzymology
Mice
MicroRNAs
/ metabolism
Pyridines
/ pharmacology
Thiophenes
/ pharmacology
15-PGDH
PGE(2)
fibrocytes
idiopathic pulmonary fibrosis
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
21
06
2019
revised:
26
10
2019
accepted:
07
11
2019
pubmed:
10
12
2019
medline:
1
12
2020
entrez:
9
12
2019
Statut:
ppublish
Résumé
Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E 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. 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. We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
Sections du résumé
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E
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 PGE
CONCLUSIONS
These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
Identifiants
pubmed: 31812575
pii: S0091-6749(19)31625-2
doi: 10.1016/j.jaci.2019.11.032
pii:
doi:
Substances chimiques
Eicosanoids
0
Enzyme Inhibitors
0
MIRN218 microRNA, human
0
MicroRNAs
0
Pyridines
0
SW033291
0
Thiophenes
0
Hydroxyprostaglandin Dehydrogenases
EC 1.1.1.-
15-hydroxyprostaglandin dehydrogenase
EC 1.1.1.141
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
818-833.e11Subventions
Organisme : Austrian Science Fund FWF
ID : P 26185
Pays : Austria
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.