| First Author | Kanno Y | Year | 2013 |
| Journal | Arthritis Rheum | Volume | 65 |
| Issue | 2 | Pages | 492-502 |
| PubMed ID | 23124680 | Mgi Jnum | J:330445 |
| Mgi Id | MGI:6868351 | Doi | 10.1002/art.37767 |
| Citation | Kanno Y, et al. (2013) Alpha2-antiplasmin regulates the development of dermal fibrosis in mice by prostaglandin F(2alpha) synthesis through adipose triglyceride lipase/calcium-independent phospholipase A(2). Arthritis Rheum 65(2):492-502 |
| abstractText | OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs. Patients with SSc have enhanced plasma levels of the plasmin-alpha2-antiplasmin (alpha2AP) complex, and we recently implicated alpha2AP in the development of fibrosis through transforming growth factor beta (TGFbeta) production. This study was undertaken to clarify how alpha2AP induces TGFbeta production and the development of fibrosis. METHODS: To clarify the detailed mechanism by which alpha2AP induces TGFbeta production, we focused on adipose triglyceride lipase (ATGL)/calcium-independent phospholipase A(2) (iPLA(2)) and examined whether ATGL/ iPLA(2) is associated with alpha2AP-induced TGFbeta production. The mouse model of bleomycin-induced SSc was used to evaluate the role of alpha2AP in the development of fibrosis. Dermal thickness and collagen content were determined in mouse skin treated with phosphate buffered saline or bleomycin. Moreover, we cultured SSc-like fibroblasts from the bleomycin-treated mouse skin and examined the production of TGFbeta and prostaglandin F(2alpha) (PGF(2alpha)). RESULTS: We found that alpha2AP binding to ATGL promoted PGF(2alpha) synthesis through iPLA(2) in fibroblasts, and the PGF(2alpha) synthesis that was promoted by alpha2AP induced TGFbeta production in fibroblasts. In addition, the neutralization of alpha2AP attenuated the production of TGFbeta and PGF(2alpha) in SSc-like fibroblasts from mice. The alpha2AP deficiency attenuated bleomycin-induced fibrosis and PGF(2alpha) synthesis, while the administration of PGF(2alpha) to alpha2AP-deficient mice facilitated alpha2AP deficiency-attenuated fibrosis. CONCLUSION: These findings suggest that alpha2AP regulates the development of fibrosis by PGF(2alpha) synthesis through ATGL/iPLA(2). The inhibition of alpha2AP-initiated pathways might provide a novel therapeutic approach to fibrotic diseases. |
