The Antifibrotic Effect of alpha 2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis

摘要

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by the fibrosis of skin and visceral organs, and peripheral circulatory disturbance. We recently demonstrated that alpha 2-antiplasmin (alpha 2AP), which is the physiological inhibitor of plasmin, is associated with the development of fibrosis. The aim of this study was to clarify the role of alpha 2AP in the pathogenesis of SSc. The administration of alpha 2AP in mice induced profibrotic changes, such as increased dermal thickness, collagen production, and myofibroblast differentiation. Conversely, the alpha 2AP neutralization prevented not only profibrotic changes, but also the production of autoantibodies in bleomycin-induced mouse models of SSc. The expression of alpha 2AP was elevated in dermal fibroblasts obtained from patients with SSc. Furthermore, alpha 2AP treatment promoted profibrotic changes in human normal dermal fibroblasts, and alpha 2AP neutralization reversed a profibrotic phenotype of SSc dermal fibroblasts, in the absence of plasmin. Our findings demonstrated that alpha 2AP has a profibrotic effect probably not by the action as a plasmin inhibitor, and that the blocking of alpha 2AP exerts an antifibrotic effect in humans and mice with SSc.