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Štorkánová H, Štorkánová L, Navrátilová A, et al. Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin. Biomedicines. 2021;9(6)doi: 10.3390/biomedicines9060650.
Štorkánová, H., Štorkánová, L., Navrátilová, A., Bečvář, V., Hulejová, H., Oreská, S., Heřmánková, B., Špiritović, M., Bečvář, R., Pavelka, K., Vencovský, J., Distler, J. H. W., Šenolt, L., & Tomčík, M. (2021). Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin. Biomedicines, 9(6), . https://doi.org/10.3390/biomedicines9060650
Štorkánová, Hana, et al. "Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin." Biomedicines vol. 9,6 (2021). doi: https://doi.org/10.3390/biomedicines9060650
Štorkánová H, Štorkánová L, Navrátilová A, Bečvář V, Hulejová H, Oreská S, Heřmánková B, Špiritović M, Bečvář R, Pavelka K, Vencovský J, Distler JHW, Šenolt L, Tomčík M. Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin. Biomedicines. 2021 Jun 07;9(6). doi: 10.3390/biomedicines9060650. PMID: 34200311; PMCID: PMC8226767.
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Biomedicines. 2021 Jun 07;9(6). doi: 10.3390/biomedicines9060650.

Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin.

Biomedicines

Hana Štorkánová, Lenka Štorkánová, Adéla Navrátilová, Viktor Bečvář, Hana Hulejová, Sabína Oreská, Barbora Heřmánková, Maja Špiritović, Radim Bečvář, Karel Pavelka, Jiří Vencovský, Jörg H W Distler, Ladislav Šenolt, Michal Tomčík

Affiliations

  1. Institute of Rheumatology, 12800 Prague, Czech Republic.
  2. Department of Rheumatology, First Faculty of Medicine, Charles University, 12800 Prague, Czech Republic.
  3. Department of Physiotherapy, Faculty of Physical Education and Sport, Charles University, 16252 Prague, Czech Republic.
  4. Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.

PMID: 34200311 PMCID: PMC8226767 DOI: 10.3390/biomedicines9060650

Abstract

Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.

Keywords: established dermal fibrosis; heat shock protein 90; systemic sclerosis; treatment

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