Plasminogen activator inhibitor-1 is elevated, but not essential, in the development of bleomycin-induced murine scleroderma.
Accumulative data have demonstrated that plasminogen activator inhibitor-1 (PAI-1) plays an important role in the extracellular matrix metabolism; however, the involvement of PAI-1 in scleroderma has not been fully elucidated. In this study, we investigated the role of PAI-1 in bleomycin-induced murine scleroderma. 100 microg of bleomycin was injected subcutaneously to the back skin of C3H/HeJ mice on alternate day for 4 weeks. Histopathological findings revealed that PAI-1 was positive in macrophage-like cells and fibroblastic cells in the dermis, in parallel with the induction of dermal sclerosis. PAI-1 mRNA expression in the whole skin was up-regulated at 1 and 4 weeks. The production of active PAI-1 protein in the lesional skin was significantly increased 3 and 4 weeks after bleomycin treatment. Next, we examined whether dermal sclerosis is induced by bleomycin in PAI-1-deficient (PAI-1-/-) mice. 10 microg of bleomycin was subcutaneously injected to PAI-1-/- and wild type (WT) mice 5 days per week for 4 weeks. Histological examination revealed that dermal sclerosis was similarly induced even in PAI-1-/- as well as WT mice. Dermal thickness and collagen contents in the skin were significantly increased by bleomycin injection in both PAI-1-/- and WT mice, and the rate of increase was similar. These data suggest that PAI-1 plays an important role, possibly via TGF-beta pathway activation. However, the fact that PAI-1 deficiency did not ameliorate skin sclerosis suggest that PAI-1 is not the essential factor in the development of bleomycin-induced scleroderma, and more complex biochemical effects other than PA/plasmin system are greatly suspected.
Matsushita
M
M
Department of Dermatology, Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan. mariko.derm@tmd.ac.jp
Yamamoto
T
T
Nishioka
K
K
D000818:Animals; D001761:Bleomycin; D003094:Collagen / Q000032:analysis; D020405:Dermis / Q000737:chemistry* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000737:chemistry; D006651:Histocytochemistry / Q000379:methods; D008264:Macrophages / Q000737:chemistry; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D023421:Models, Animal; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms
D017395:Plasminogen Activator Inhibitor 1; D001761:Bleomycin; D003094:Collagen
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