一种口服的有效的小分子纤溶酶原激活物抑制剂对哮喘的治疗潜能

2016/03/21

   摘要
   哮喘是最常见的呼吸道疾病之一。尽管我们对气道病理的认识已经有了很大的进展,且许多药物已经可用于缓解哮喘症状,但是慢性哮喘仍不能治愈。纤溶酶原激活物抑制剂1(PAI-1)是一种主要的组织型纤溶酶原激活物(tPA)和尿激酶型纤溶酶原激活物(uPA)的抑制剂,除了抑制纤维蛋白溶解之外,还有多种功能。在本项研究中,我们发现:卵白蛋白(OVA)致敏25天以后,使用TM5275(一种口服的有效的小分子PAI-1)能够显著改善卵白蛋白诱导的慢性哮喘模型的气道高反应性。此外,我们发现:使用TM5275能够显著减轻卵白蛋白诱导的炎性细胞(中性粒细胞、嗜酸性粒细胞和单核细胞)浸润,减少OVA-特异性IgE和Th2细胞因子(IL-4和IL-5)的增加,减少气道黏蛋白的生成,减轻气道上皮下的纤维化。总之,这些结果表明:TM5275(PAI-1抑制剂)可能拥有哮喘治疗潜能,这是通过抑制嗜酸性变态反应和改善气道重塑实现的。

 


 

(杨冬 审校)
Am J Physiol Lung Cell Mol Physiol. 2015 Dec 23:ajplung.00217.2015. doi: 10.1152/ajplung.00217.2015. [Epub ahead of print]

 

 

Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.
 

Liu RM1, Eldridge S2, Watanabe N3, Deshane JS2, Kuo HC2, Jiang C2, Wang Y2, Liu G2, Schwiebert LM2, Miyata T3, Thannickal VJ2.

 

Abstract
Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA, respectively), has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyper-responsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor, TM5275, may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.

 


Am J Physiol Lung Cell Mol Physiol. 2015 Dec 23:ajplung.00217.2015. doi: 10.1152/ajplung.00217.2015. [Epub ahead of print]

 


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