The therapeutic role of proteasome inhibition in bleomycin induced experimental scleroderma

Scleroderma is a chronic inflammatory disease characterized by widespread fibrosis. Bortezomib, a proteasome inhibitor, has anti-fibrotic properties by reducing collagen production and favoring collagen degradation, and attenuates experimentally induced renal and cardiac fibrosis. The aim of this study was to evaluate the preventive effects of bortezomib on early and later stages of bleomycin (BLM)-induced experimental scleroderma model.This study involved six groups Balb/c mice (n=10 in each group). Group A and D were only received subcutaneously 100 ?l phosphate-buffered saline (PBS), whereas group B, C, E and F mice were subcutaneously administered 100 ?g/day BLM (dissolved in 100 ?l PBS). In addition to BLM, group C mice were intraperitoneally administered 1.6 mg/kg bortezomib twice a week for the first three weeks, while group F mice were received same dose of bortezomib for the second three weeks.Groups A, B and C mice, at the end of the third week, and group D, E and F mice, at the end of sixth week, were sacrificed and blood and tissue samples were then obtained for further analysis. IL-4, and TGF-ß1 serum levels, type I collagen, nuclear factor-?B (Nf-?B), inhibitor of Nf-?B (I-?B) and c-Jun N-terminal kinase (JNK)1 protein levels of skin tissues, dermal thicknesses, the numbers of inflammatory cells on dermal layer and ?-smooth muscle actin-positive (?-SMA+) cells were determined.In early stage of fibrosis, inflammatory cell infiltrations of the skin are prominent, while this inflammatory status is decreased in the later stage of fibrosis. However, the expressions of Nf-?B and JNK1 were higher in the both stages. Bortezomib which downregulated the expressions of Nf-?B and JNK1 decreased dermal thickness, dermal inflammatory cell counts and ?-SMA+ cell counts in early stage, although it had no effects on the late stage of fibrosis.In conclusion, in BLM-induced dermal fibrosis, bortezomib has anti-fibrotic effect in early stage of fibrosis which may be related with its anti-inflammatory effects, although it is not effective on the established fibrosis.