A novel TGF-β/Smad signaling inhibitor ameliorates bleomycin-induced skin fibrosis
Transforming growth factor-beta/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). We previously reported an artificial molecule HPH-15 that, as we now found, might be promising as anti-fibrotic agent. This study was aimed to clarify the effects of this drug for human skin fibroblasts and preclinical model of SSc. The effects of HPH-15 on migration, proliferation, release of extracellular matrix and TGF-beta signaling cascades of human dermal fibroblasts were analyzed. The antifibrotic properties of HPH-15 were also examined in bleomycin-induced skin fibrosis mouse model. HPH-15 suppressed the phospholyration of Smad3 induced by TGF-beta in human skin fibroblasts. HPH-15 inhibited the migration, proliferation, and expression of collagen and fibronectin in cultured human skin fibroblasts. In bleomycin-induced skin fibrosis model, the oral administration of HPH-15 protected the development of skin fibrosis and ameliorated the established skin fibrosis. In the treated group, the dermal infiltration of proinflammatory macrophages (CD11b+Ly6Chi) and M2 profibrotic macrophages (CD11b+CD206+ or CD11b+CD204+) was significantly decreased at the early and late stages, respectively. HPH-15 treatment inhibited the mRNA levels of M2 macrophage markers such as arginase 1 and Ym-1 in the skin, but it inversely augmented those of Fli1 and KLF-5, the transcription factors that repress collagen synthesis. No apparent adverse effects were found through the study. Our results demonstrated several advantages of HPH-15, including oral bioavailability and a good safety profile, as well as its therapeutic availability. This TGF-beta/Smad inhibitor is a potential candidate for clinical trials in SSc.

A novel TGF-beta/Smad signaling inhibitor ameliorates bleomycin-induced skin fibrosis