The inhibitor of semicarbazide-sensitive amine oxidase, PXS-4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model
The inhibitor of semicarbazide-sensitive amine oxidase, PXS-4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model
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DOI：
10.1111/bph.13573
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发表时间：
2016-11-01
影响因子：
7.3
通讯作者：
Hansbro, P. M.
中科院分区：
文献类型：
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作者：
Jarnicki, A. G.;Schilter, H.;Hansbro, P. M.
背景和目的慢性阻塞性肺疾病（COPD）是疾病和死亡的主要原因，通常由吸烟引起（CS）。它的特点是肺部炎症和纤维化，损害肺功能。现有的治疗方法旨在控制症状，但疗效低，而且没有广泛有效的治疗方法。一个新的潜在靶标是外酶，氨基脲敏感单胺氧化酶（SSAO，也称为血管粘附蛋白-1）。SSAO在吸烟者的血清中升高，是一种促炎酶，促进白细胞从血管到炎症部位的粘附和转运。实验方法：pxs - 4728a是一种低分子量SSAO抑制剂。CS在小鼠中诱导的COPD模型再现了人类COPD的关键方面，包括慢性气道炎症、纤维化和肺功能受损。该模型用于评估SSAO活性的抑制以及炎症和其他COPD特征的改善。关键结果：PXS-4728A治疗完全抑制急性和慢性cs暴露引起的肺部和全身SSAO活性。每日口服治疗可抑制急性cs暴露引起的气道炎症（免疫细胞内流和炎症因子）。在慢性cs暴露期间，当实验性COPD的主要特征发生和进展时，治疗性治疗可显著抑制气道中的炎症细胞内流和纤维化，并改善肺功能。结论和意义：低MW SSAO抑制剂PXS-4728A治疗实验性COPD，可抑制气道炎症和纤维化，改善肺功能，显示PXS-4728A治疗这种衰弱性疾病的潜力。
BACKGROUND AND PURPOSEChronic obstructive pulmonary disease (COPD) is a major cause of illness and death, often induced by cigarette smoking (CS). It is characterized by pulmonary inflammation and fibrosis that impairs lung function. Existing treatments aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A new potential target is the ectoenzyme, semicarbazide-sensitive mono-amine oxidase (SSAO; also known as vascular adhesion protein-1). SSAO is elevated in smokers' serum and is a pro-inflammatory enzyme facilitating adhesion and transmigration of leukocytes from the vasculature to sites of inflammation.EXPERIMENTAL APPROACHPXS-4728A was developed as a low MW inhibitor of SSAO. A model of COPD induced by CS in mice reproduces key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. This model was used to assess suppression of SSAO activity and amelioration of inflammation and other characteristic features of COPD.KEY RESULTSTreatment with PXS-4728A completely inhibited lung and systemic SSAO activity induced by acute and chronic CS-exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS-exposure. Therapeutic treatment during chronic CS-exposure, when the key features of experimental COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function.CONCLUSIONS AND IMPLICATIONSTreatment with a low MW inhibitor of SSAO, PXS-4728A, suppressed airway inflammation and fibrosis and improved lung function in experimental COPD, demonstrating the therapeutic potential of PXS-4728A for this debilitating disease.