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

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