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 α2-antiplasmin (α2AP), 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 α2AP in the pathogenesis of SSc. The administration of α2AP in mice induced profibrotic changes, such as increased dermal thickness, collagen production, and myofibroblast differentiation. Conversely, the α2AP neutralization prevented not only profibrotic changes, but also the production of autoantibodies in bleomycin-induced mouse models of SSc. The expression of α2AP was elevated in dermal fibroblasts obtained from patients with SSc. Furthermore, α2AP treatment promoted profibrotic changes in human normal dermal fibroblasts, and α2AP neutralization reversed a profibrotic phenotype of SSc dermal fibroblasts, in the absence of plasmin. Our findings demonstrated that α2AP has a profibrotic effect probably not by the action as a plasmin inhibitor, and that the blocking of α2AP exerts an antifibrotic effect in humans and mice with SSc.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.