show Abstracthide AbstractA well-characterized mouse model of SSc involves daily subcutaneous injections of the antitumor antibiotic bleomycin (BLM), which leads to localized dermal fibrosis as well as pulmonary fibrosis. We have termed this the “Systemic Bleomycin Model” to distinguish it from the already-established Intratracheal (IT) model. We utilize this model, which mimics several key features of human SSc, to examine the pathological mechanisms underlying the development and progression of fibrosis in SSc. Overall design: Female C57BL/6 mice (~12 weeks old) were used for this study. An electric shaver was used to shave the interscapular region on the back of each mouse, and a non-toxic permanent marker was used to draw two small circles on the skin within the shaved area on each mouse. Fibrosis was induced by daily subcutaneous injections of either bleomycin (10mg/kg/day; 100µl per injection site of 1mg/ml solution for these ~20gm mice) or PBS (vehicle control) within the marked interscapular regions. Injections began on Day 0 and were done five times per week for two weeks, using a 27-gauge needle. (Bhattacharyya S. et al., Sci Transl Med 2014 Apr 16;6(232):232ra50; Huang J. et al., Ann Rheum Dis 2015 Apr 9. pii: annrheumdis-2014-207109). Beginning on Day 12, the ALK5 inhibitor SB525334 (30mpk) or vehicle was delivered (PO, BID dosing). Note that Groups 1-2 and Groups 3-4 were sacrificed on Day 7 and Day 14, respectively, and thus did not receive oral dosing. Groups 5-7 were sacrificed on Day 21. The last oral doses were administered on Day 27. Groups 8-10 were sacrificed on Day 28. Groups 11-12 (which specifically serve to assess resolution in this model, and do not examine the effect of Alk5 inhibition) were sacrificed on Day 42.