A novel SSAO inhibitor PXS-4728A suppresses inflammation and fibrosis and improves lung function in experimental chronic obstructive pulmonary disease†

Background and Purpose Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death that is often induced by cigarette smoking (CS). It is characterised by pulmonary inflammation and fibrosis that impairs lung function. Existing pharmaceuticals aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A potential new therapeutic target is ectoenzyme semicarbazide-sensitive mono-amine oxidase (SSAO, or vascular adhesion protein-1, VAP-1). SSAO is elevated in smokers serum, and is a pro-inflammatory enzyme that facilitates the adhesion and transmigration of leukocytes from the vasculature to sites of inflammation. Experimental Approach PXS-4728A has been developed as a small molecule inhibitor of SSAO. We tested its ability to suppress SSAO activity and ameliorate inflammation and hallmark features of human disease in a mouse model of CS-induced experimental COPD. The model replicates key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. Key Results PXS-4728A treatment 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 the SSAO small molecule inhibitor, PXS-4728A, suppresses airway inflammation and fibrosis and improves lung function in experimental COPD. This study demonstrates the therapeutic potential of PXS-4728A for this debilitating disease.