Hamamatsu, Japan
Hamamatsu, Japan

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Yasui H.,Hamamatsu University School of Medicine | Suzuki Y.,Hamamatsu University School of Medicine | Sano H.,Hamamatsu University School of Medicine | Suda T.,Second Division | And 4 more authors.
Thrombosis Research | Year: 2013

Introduction Elevated plasminogen activator inhibitor-1 (PAI-1) reduces fibrinolytic potential in plasma, contributing to thrombotic disease. Thus, inhibiting PAI-1 activity is clinically desirable. We recently demonstrated that tissue plasminogen activator (tPA) remains on the surface of vascular endothelial cells (VECs) after secretion in a heavy-chain dependent manner, which is essential for high fibrinolytic activity on the surface of VECs, and that PAI-1 dissociates retained tPA from the cell surface as a result of high-molecular weight complex formation. Based on the model whereby amounts of tPA and its equilibrium with PAI-1 dynamically change after exocytosis, we examined how TM5275, a newly synthesized small molecule PAI-1 inhibitor, modulated tPA retention and VEC surface-derived fibrinolytic activity using microscopic techniques. Materials and methods The effects of TM5275 on the kinetics of the secretion and retention of green fluorescent protein (GFP)-tagged tPA (tPA-GFP) on VECs were analyzed using total internal reflection fluorescence microscopy. The effects of TM5275 on the generation of plasmin activity were evaluated by both plasminogen accumulation and fibrin clot lysis on tPA-GFP-expressing VECs using confocal laser scanning microscopy. Results TM5275 at concentrations of 20 and 100 μM significantly prolonged the retention of tPA-GFP on VECs by inhibiting tPA-GFP-PAI-1 high-molecular-weight complex formation. TM5275 enhanced the time-dependent accumulation of plasminogen as well as the dissolution of fibrin clots on and around the tPA-GFP-expressing cells. Conclusions The profibrinolytic effects of TM5275 were clearly demonstrated by the prolongation of tPA retention and enhancement of plasmin generation on the VEC surface as a result of PAI-1 inhibition. © 2013 Elsevier Ltd. All rights reserved.

Kono M.,Second Division | Suda T.,Second Division | Enomoto N.,Second Division | Nakamura Y.,Second Division | And 8 more authors.
Blood Purification | Year: 2011

Background: Recently, the potential therapeutic effect of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been reported for acute exacerbation of interstitial pneumonia (AE-IP), a highly morbid clinical event; however, there is no consensus on the appropriate procedure for PMX-DHP. We examined the appropriate perfusion duration of PMX-DHP for AE-IP. Methods: AE-IP patients receiving PMX-DHP were divided into two groups: short-duration group (≤6 h) (n = 5) and long-duration group (12 h) (n = 12). Results: ThePaO 2/FiO 2 (P/F) ratio increased immediately after PMX-DHP in the two groups. In the long-duration group, the P/F ratio continued to increase over the following 7 days, while, in the short-duration group, the P/F ratio declined again 3 days after therapy. The survival rate 30 days after PMX-DHP was significantly higher in the long-duration group than in the short-duration group. Conclusions: A long perfusion duration of PMX-DHP is more efficacious for AE-IP than a short perfusion duration. Copyright © 2011 S. Karger AG, Basel.

Inui N.,Second Division | Inui N.,Hamamatsu University School of Medicine | Hasegawa H.,Second Division | Suda T.,Second Division | And 3 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

Multidrug resistance protein 1 and multidrug resistance-associated protein 1 are transporters that efflux diverse xenobiotics from cells. We investigated changes in the expression and activity of multidrug resistance protein 1 and multidrug resistance-associated protein 1 in highly purified lung dendritic cells (LDCs) during aging using magnetic and flow cytometric cell sorting. Multidrug resistance protein 1 blockade by the specific inhibitor reduced the percentage of rhodamine 123low cells in LDCs from aged mice (54.8% ± 2.6% to 13.2% ± 2.5%, p <. 01). The difference in the proportions of rhodamine 123low cells in aged LDCs was more apparent than that in LDCs from young mice (p <. 05). The multidrug resistance-associated protein 1-specific inhibitor reduced the percentage of Fluo-3low cells in aged LDCs (60.8% ± 5.3% to 25.8% ± 7.5%, p <. 01). The difference in the proportions of Fluo-3low cells in aged LDCs was smaller than that in young LDCs (p <. 05). These data showed that LDCs from aged mice exhibited multidrug resistance protein 1- and multidrug resistance-associated protein 1-mediated efflux and that the age-associated changes differed according to transporters. © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

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