IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.
IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.
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DOI：
10.1371/journal.pone.0121615
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Nishioka Y
中科院分区：
文献类型：
--
作者：
Tezuka T;Ogawa H;Azuma M;Goto H;Uehara H;Aono Y;Hanibuchi M;Yamaguchi Y;Fujikawa T;Itai A;Nishioka Y
纤溶酶原激活剂抑制剂(PAI)-1是纤溶酶原激活剂的主要抑制剂，负责纤维蛋白和细胞外基质的降解。 IMD-4690是一种新合成的PAI-1抑制剂，但其对过敏性气道炎症和重塑的作用尚不清楚。我们通过使用小鼠支气管哮喘的慢性过敏原暴露模型来检查体内效果。该模型是通过使用屋尘螨抗原 Dermatophagoides pteronyssinus (Dp) 进行 8 周的免疫攻击而生成的。在攻击期间腹腔内施用IMD-4690。分析了肺组织病理学、高反应性和肺匀浆中介质的浓度。用 Dp 治疗的小鼠肺部活性 PAI-1 的量增加。 IMD-4690 给药降低了活性 PAI-1 与总 PAI-1 的比率。 IMD-4690 还根据肺匀浆中 Th2 细胞因子表达的减少减少了支气管嗜酸性粒细胞的数量。通过减少上皮下胶原沉积、平滑肌肥大和血管生成来抑制气道重塑。 IMD-4690 的作用部分是通过 TGF-β、HGF 和基质金属蛋白酶的调节介导的。这些结果表明，PAI-1在气道炎症和重塑中发挥着至关重要的作用，而IMD-4690作为一种特异性PAI-1抑制剂，可能对因气道重塑而导致的难治性哮喘患者具有治疗潜力。
Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
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影响因子：
5.8
作者：
Chen, G;Khalil, N
通讯作者：
Khalil, N
影响因子：
5.9
作者：
Cho, Seong;Kang, Joseph;Lyttle, Christopher;Harris, Kathleen;Daley, Brendan;Grammer, Leslie;Avila, Pedro;Kumar, Rajesh;Schleimer, Robert
通讯作者：
Schleimer, Robert
影响因子：
3.1
作者：
Cesari M;Pahor M;Incalzi RA
通讯作者：
Incalzi RA
DOI：
10.1165/ajrcmb.17.5.2562
发表时间：
1997-11-01
影响因子：
6.4
作者：
Mautino, G;Oliver, N;Capony, F
通讯作者：
Capony, F
影响因子：
4.4
作者：
Cho, SH;Tam, SW;Oh, CK
通讯作者：
Oh, CK