Abstract
The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model.
Highlights
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by immune dysregulation, obliterative vasculopathy, and fibrosis of skin and internal organs
Hydroxyproline levels were significantly greater in lungs from mice treated with high dose BLM (60 and 110 U/kg) than those treated with PBS or low dose BLM (1 and 10 U/kg) (Fig 1A) 28 days post-implantation of the pumps
The mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the
Summary
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by immune dysregulation, obliterative vasculopathy, and fibrosis of skin and internal organs. It has the highest disease-related mortality and morbidity with an impaired quality of life among the rheumatologic illnesses [1, 2]. Fibrosis is caused by fibroblast activation, proliferation and increased deposition of extracellular matrix (ECM) proteins such as fibronectin and collagen in various organs [3, 4]. Progression of organ fibrosis leads to end-stage organ failure as a result of the loss of normal structure and function.
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