α2-antiplasmin is associated with the progression of fibrosis

Abstract

Systemic sclerosis results in tissue fibrosis due to the activation of fibroblasts and the ensuing overproduction of the extracellular matrix. We previously reported that the absence of α2-antiplasmin (α2AP) attenuated the process of dermal fibrosis; however, the detailed mechanism of how α2AP affects the progression of fibrosis remained unclear. The goal of the present study was to examine the role of α2AP in fibrotic change. We observed significantly higher levels of α2AP expression in the skin of bleomycininjected systemic sclerosis model mice in comparison with the levels seen in control mice. We also demonstrated that α2AP induced myofibroblast differentiation, and the absence of α2AP attenuated the induction of myofibroblast differentiation. Moreover, we found that connective tissue growth factor induced the expression of α2AP through both the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways in fibroblasts. Interestingly, α2AP also induced transforming growth factor-β expression through the same pathways, and the inhibition of ERK1/2 and JNK slowed the progression of bleomycin-induced fibrosis. Our findings suggest that α2AP is associated with the progression of fibrosis , and regulation of α2AP expression by the ERK1/2 and JNK pathways may be an effective antifibrotic therapy for the treatment of systemic sclerosis. Copyright © American Society for Investigative Pathology.