Suppression of the TGF-β pathway by a macrolide antibiotic decreases fibrotic responses by ocular fibroblasts in vitro .

Autor:	Stahnke T; Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany., Gajda-Deryło B; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany., Jünemann AG; Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany., Stachs O; Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany., Sterenczak KA; Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany., Rejdak R; Department of General Ophthalmology, Medical University in Lublin, Poland., Beck J; Chronix Biomedical GmbH, Göttingen, Germany., Schütz E; Chronix Biomedical GmbH, Göttingen, Germany., Möller S; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany., Barrantes I; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany., Warsow G; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany., Struckmann S; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.; SHIP-KEF, Institute for Community Medicine, Greifswald University Medical Center, Greifswald, Germany., Fuellen G; Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.
Jazyk:	angličtina
Zdroj:	Royal Society open science [R Soc Open Sci] 2020 Sep 16; Vol. 7 (9), pp. 200441. Date of Electronic Publication: 2020 Sep 16 (Print Publication: 2020).
DOI:	10.1098/rsos.200441
Abstrakt:	To elucidate and to inhibit post-surgical fibrotic processes after trabeculectomy in glaucoma therapy, we measured gene expression in a fibrotic cell culture model, based on transforming growth factor TGF-β induction in primary human tenon fibroblasts (hTFs), and used Connectivity Map (CMap) data for drug repositioning. We found that specific molecular mechanisms behind fibrosis are the upregulation of actins, the downregulation of CD34, and the upregulation of inflammatory cytokines such as IL6, IL11 and BMP6 . The macrolide antibiotic Josamycin (JM) reverses these molecular mechanisms according to data from the CMap, and we thus tested JM as an inhibitor of fibrosis. JM was first tested for its toxic effects on hTFs, where it showed no influence on cell viability, but inhibited hTF proliferation in a concentration-dependent manner. We then demonstrated that JM suppresses the synthesis of extracellular matrix (ECM) components. In hTFs stimulated with TGF-β1, JM specifically inhibited α-smooth muslce actin expression, suggesting that it inhibits the transformation of fibroblasts into fibrotic myofibroblasts. In addition, a decrease of components of the ECM such as fibronectin, which is involved in in vivo scarring, was observed. We conclude that JM may be a promising candidate for the treatment of fibrosis after glaucoma filtration surgery or drainage device implantation in vivo . Competing Interests: T.S., A.J., S.S. and G.F. are listed as inventors in a pending patent application on the use of Josamycin as an antifibrotic compound, submitted in behalf of the Rostock University Medical Center. The authors declare no other competing financial interests. (© 2020 The Authors.)
Databáze:	MEDLINE
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