Systemic sclerosis (SSc) is a connective tissue disorder representing fibrosis in the skin and internal organs such as lungs. An activated differentiation of local progenitor cells to myofibroblasts is likely a key mechanism underlying overproduction of extracellular matrix and resultant tissue fibrosis in SSc. Calpains are family members of Ca2+-dependent cysteine proteases for which the biological action may contribute to fibrosis in various organs. However, the precise mechanism of calpain-dependent fibrosis and therapeutic utility of their inhibitors in SSc remain unclear. This study aimed to investigate if a potent calpain inhibitor ALLN could possess the antifibrotic effects on a bleomycin-induced SSc model mice and human cultured cells. Normal human dermal fibroblasts pretreated with ALLN were stimulated with recombinant TGF-β1, followed by assessment for expression properties of TGF-β1/Smad signaling and fibrogenic molecules. ALLN (3mg/kg/day) was intraperitoneally administered 3 times a week in bleomycin-induced SSc model mice. ALLN treatment significantly inhibited over-phosphorylation and nuclear transport of Smad2/3 in TGF-β1-stimulated dermal fibroblasts. TGF-β1-dependent increase of α-smooth muscle actin, collagen type 1, fibronectin 1, and representative mesenchymal markers were attenuated in mRNA and protein expression by ALLN. Likewise, ALLN reverted a TGF-β1-dependent change of epithelial/mesenchymal markers in human lung epithelial cells. Consistent with these, ALLN remarkably suppressed the development of skin and lung fibrosis, following decrease of infiltrating CD3+T cells, in bleomycin-induced SSc model mice. No obvious side effects were observed. Our data provide evidence that calpains may be a primary contributor and novel therapeutic target for skin and lung fibrosis in SSc, with a treatment perspective of its inhibitor ALLN.

ESDR024 - Antifibrotic effects of a calpain inhibitor ALLN on bleomycin-induced systemic sclerosis model via antagonizing TGF-β/Smad signaling pathway

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.