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Semren, N. ; Habel-Ungewitter, N.C. ; Fernandez, I.E. ; Königshoff, M. ; Eickelberg, O. ; Stöger, T. ; Meiners, S.

Validation of the 2nd generation proteasome inhibitor oprozomib for local therapy of pulmonary fibrosis.

PLoS ONE 10:e0136188 (2015)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ), provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ). OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter In-vivo; Constitutive Proteasome; Multiple-myeloma; Drug Development; Tgf-beta; Cells; Lung; Carfilzomib; Bleomycin; Models
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1932-6203
Zeitschrift PLoS ONE
Quellenangaben Band: 10, Heft: 9, Seiten: , Artikelnummer: e0136188 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort Lawrence, Kan.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
80000 - German Center for Lung Research
Forschungsfeld(er) Lung Research
PSP-Element(e) G-501600-004
G-501600-006
G-501600-001
G-551800-001
G-505000-006
G-505000-001
G-501800-805
PubMed ID 26340365
DOI 10.1371/journal.pone.0136188
WOS ID WOS:000360688200006
Erfassungsdatum 2015-09-06
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