Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide ameliorates fibrosis in a murine model of systemic sclerosis.

Objective In patients with systemic sclerosis (SSc), activated fibroblasts produce reactive oxygen species (ROS) that stimulate their proliferation and collagen synthesis. By analogy with tumor cells that undergo apoptosis upon cytotoxic treatment that increases ROS levels beyond a lethal threshold, we tested whether activated fibroblasts could be selectively killed by the cytotoxic molecule arsenic trioxide (As2O3) in a murine model of SSc. Methods SSc was induced in BALB/c mice by daily intradermal injections of HOCl. Mice were simultaneously treated with daily intraperitoneal injections of As2O3. Results As2O3 limited dermal thickness and inhibited collagen deposition, as assessed by histologic examination and measurement of mouse skin and lung collagen contents. As2O3 abrogated vascular damage, as shown by serum vascular cell adhesion molecule 1 level, and inhibited the production of autoantibodies, interleukin-4 (IL-4), and IL-13 by activated T cells. These beneficial effects were mediated through ROS generation that selectively killed activated fibroblasts containing low levels of glutathione. Conclusion Our findings indicate that treatment with As2O3 dramatically improves skin and lung fibrosis in a mouse model of SSc, providing a rationale for the evaluation of As2O3 treatment in patients with SSc.