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

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

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.

Highlights

Introduction iationsSystemic sclerosis (SSc, scleroderma) is a rare chronic autoimmune connective tissue disease of a complex etiopathogenesis characterized by vasculopathy, dysregulation of the immune system, and tissue fibrosis [1]
Using the modified bleomycin model of experimental dermal fibrosis, we investigated the effect of heat shock protein 90 (Hsp90) inhibitor 17-DMAG on the progression of dermal fibrosis, and of particular interest, the treatment of established skin fibrosis, since the 17-DMAG treatment was initiated after the development of dermal fibrosis
Compared to mice treated with NaCl for six weeks, the challenge with bleomycin in the first three weeks resulted in an expected development of skin fibrosis, manifested by an increase in dermal thickening by 51.5 ± 3.9% (p < 0.0001), hydroxyproline content by 52.4 ± 13.2% (p = 0.0014), and myofibroblast count by 150.3

Summary

Introduction

Systemic sclerosis (SSc, scleroderma) is a rare chronic autoimmune connective tissue disease of a complex etiopathogenesis characterized by vasculopathy, dysregulation of the immune system, and tissue fibrosis [1]. Fibrosis of the skin and internal organs, such as the lungs, gastrointestinal tract, heart, and kidneys, is the most characteristic feature of SSc [1]. During the course of the disease, the abnormally activated innate and acquired immune system affects resident fibroblasts, which are the critical cellular contributors to tissue fibrosis in SSc [1,2]. Multiple lines of evidence suggest that transforming growth factor-beta (TGF-β) plays a crucial role in the activation of fibroblasts and the development of tissue fibrosis in SSc [3].

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