The inhibitor of semicarbazide‐sensitive amine oxidase, PXS‐4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model

• Published in: British journal of pharmacology 2016-11, Vol.173 (22), p.3161-3175
• Main Authors: Jarnicki, A G, Schilter, H, Liu, G, Wheeldon, K, Essilfie, A‐T, Foot, J S, Yow, T T, Jarolimek, W, Hansbro, P M
• Format: Article
• Language: English
• Subjects: Adhesion; Allylamine - analogs & derivatives; Allylamine - pharmacology; Amine Oxidase (Copper-Containing) - antagonists & inhibitors; Amine Oxidase (Copper-Containing) - metabolism; Animals; Benzamides - pharmacology; Chronic obstructive pulmonary disease; Cigarette smoking; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Exposure; Female; Fibrosis; Inflammation; Leukocyte migration; Lung diseases; Mice; Mice, Inbred C57BL; Obstructive lung disease; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - enzymology; Research Paper; Research Papers; Respiratory function; Respiratory tract; Respiratory tract diseases; Semicarbazide; Smoking
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13573

Background and Purpose Chronic 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 Approach PXS‐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 Results Treatment 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 Implications Treatment 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.