Plasminogen activator inhibitor-1 is elevated, but not essential, in the development of bleomycin-induced murine scleroderma

Abstract

SummaryAccumulative 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 m m m m g 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 m m m m g 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-b b b b 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.

PAI‐1 in tissue fibrosis

“…Although PAI-1 plays an important role in ECM remodeling through inhibition of proteolytic degradation of matrix proteins, the degree of bleomycin-induced skin fibrosis in PAI-1 deficient mice is comparable with that in wildtype controls suggesting that 1) PAI-1 is not essential for the development of bleomycin-induced skin fibrosis, and 2) PAI-1 deficiency is not protective against the development of bleomycin-induced skin fibrosis (Matsushita et al, 2005). Paradoxically, fibroblast-specific overexpression of a kinase-deficient Type II TGF-β receptor leads to constitutive activation of TGF-β signaling and development of spontaneous skin fibrosis.…”

Update on autoantibodies in systemic sclerosis

“…Abnormalities of tissue plasminogen acitvator (tPA) and tPA inhibitor have been described in SSc and in-vitro and animal model studies also suggest that changes in the tPA receptor or levels of tPA inhibitor may contribute to SSc [155][156][157]. When tPA was bound to its natural ligand, fibrin, anti-tPA antibodies were identified in 25/128 (20%) of unselected SSc patients with increased frequency in lcSSc and pulmonary hypertension [158].…”

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

“…PAI-1 expression is a feature of preeclampsia (19) and scleroderma, although experimental data suggest that PAI-1 is not essential in the latter (20,21). Radiation nephropathy is characterized in its early phase by TMA with PAI-1 generation, and it often progresses to sclerosis.…”