title: Alpha2-antiplasmin regulates the development of dermal fibrosis in mice by prostaglandin F(2α)  synthesis through adipose triglyceride lipase/calcium-independent phospholipase A(2).
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs. Patients with SSc have enhanced plasma levels of the plasmin-α2-antiplasmin (α2AP) complex, and we recently implicated α2AP in the development of fibrosis through transforming growth factor β (TGFβ) production. This study was undertaken to clarify how α2AP induces TGFβ production and the development of fibrosis.
  
  
  METHODS
  To clarify the detailed mechanism by which α2AP induces TGFβ production, we focused on adipose triglyceride lipase (ATGL)/calcium-independent phospholipase A(2) (iPLA(2)) and examined whether ATGL/ iPLA(2) is associated with α2AP-induced TGFβ production. The mouse model of bleomycin-induced SSc was used to evaluate the role of α2AP 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 TGFβ and prostaglandin F(2α) (PGF(2α)).
  
  
  RESULTS
  We found that α2AP binding to ATGL promoted PGF(2α) synthesis through iPLA(2) in fibroblasts, and the PGF(2α) synthesis that was promoted by α2AP induced TGFβ production in fibroblasts. In addition, the neutralization of α2AP attenuated the production of TGFβ and PGF(2α) in SSc-like fibroblasts from mice. The α2AP deficiency attenuated bleomycin-induced fibrosis and PGF(2α) synthesis, while the administration of PGF(2α) to α2AP-deficient mice facilitated α2AP deficiency-attenuated fibrosis.
  
  
  CONCLUSIONS
  These findings suggest that α2AP regulates the development of fibrosis by PGF(2α) synthesis through ATGL/iPLA(2). The inhibition of α2AP-initiated pathways might provide a novel therapeutic approach to fibrotic diseases.
authors.affiliation: Doshisha Women's College of Liberal Arts, Kyoto, Japan. ykanno@dwc.doshisha.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.forename: Eri
authors.initials: E
authors.lastname: Kawashita
authors.forename: Akiko
authors.initials: A
authors.lastname: Kokado
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ueshima
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuno
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000378:metabolism*; D051379:Mice; D054512:Phospholipases A2, Calcium-Independent / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000378:metabolism* / Q000494:pharmacology; D000217:Acyltransferases
chemical_list: D001761:Bleomycin; D003094:Collagen; D015237:Dinoprost; D015232:Dinoprostone; D008049:Lipase; D054512:Phospholipases A2, Calcium-Independent; D016212:Transforming Growth Factor beta; D000979:alpha-2-Antiplasmin; C494794:PNPLA2 protein, human; D000217:Acyltransferases