Involvement of plasminogen activator inhibitor-1 in the pathogenesis of uveitis

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K09924
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Hokkaido University
• Principal Investigator: Iwata Daiju 北海道大学, 大学病院, 講師 (70374402)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: ぶどう膜炎 / PAI－１ / 実験的自己免疫性ぶどう膜網膜炎 / EAU

Outline of Final Research Achievements

Plasminogen activator inhibitor (PAI) -1 has been widely accepted as the major inhibitor of endogenous fibrinolysis pathways. In addition to this role, PAI-1 has a further role in inflammatory diseases. The aim of this study is to evaluate the involvement of PAI-1 in the pathogenesis of ocular inflammation.
Firstly, we measured the protein levels of PAI-1 in vitreous samples from patients with uveitis using a magnetic multiplex bead-based quantitative immunoassay. The protein levels of PAI-1 were significantly higher in the vitreous samples of patients with uveitis than in the controls (P < 0.05). Secondly, the retinochoroidal mRNA level of PAI-1 was significantly upregulated in the EAU mice compared to the control mice (P < 0.05). Furthermore, the clinical severity of EAU was ameliorated by treatment with PAI-1 inhibitor, IMD4482 (P < 0.05). The migration of THP-1 macrophages was significantly suppressed by IMD4482.
Thus, PAI-1 has potential as a novel therapeutic target for uveitis.

Free Research Field

眼科　ぶどう膜炎

Academic Significance and Societal Importance of the Research Achievements

ぶどう膜炎動物モデルEAUの網膜でのPAI-1の発現変化と病態への関与を検討し、炎症増悪とともにPAI-1の発現が亢進すること、またぶどう膜炎患者の眼局所の検体である硝子体液でPAI-1濃度が有意に高値となること、さらにPAI-1阻害薬を用いた治療でEAUの重症度の有意な低下することを初めて明らかとした。またTranswell Assayの結果からはPAI-1阻害薬による炎症抑制の背景にあるメカニズムとしてマクロファージの遊走抑制が関与している可能性を示した。
これらの結果を礎として、眼炎症の治療にこれまでと異なる分子標的からの治療スキームが我が国から誕生し、大きな社会貢献になると予測される。