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

Abstract

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, semicarbazidesensitive 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.Abbreviations BALF, bronchoalveolar lavage fluid; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; EM, extracellular matrix; G-CSF, granulocyte-colony stimulating factor; MLI, mean linear intercept; SSAO, semicarbazide-sensitive amine oxidase IntroductionChronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and death worldwide, and its prevalence is increasing (Lozano et al., 2012). It is a heterogeneous disease variously comprising debilitating and complex pathological features including chronic pulmonary inflammation (bronchitis), fibrosis and emphysema (Keely et al., 2011;Fricker et al., 2014). These features combine to impair lung function and result in reduced oxygen transfer leading to breathlessness. Cigarette smoke (CS) exposure is the primary etiological agent in Western countries, accounting for more than 90% of cases. Once induced, the patients' condition often continues to deteriorate, even after cessation of smoking. Wood and cooking smoke and pollution are also important risk factors particularly in developing nations (Fabbri et al., 2004;Eisner et al., 2010;Ko and Hui, 2012).There are no cures for COPD, and current treatments have substantial limitations. High doses of corticosteroids, long-acting β-adrenoceptor agonists, ...

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

“…The multiplicity of roles for PrAO in diverse processes has made it an important therapeutic target (O'Sullivan et al, ). Inhibitors of PrAO have been reported and its inhibition is known to have anti‐inflammatory effects and to positively influence vascular health, neurodegenerative disease progress and lung fibrosis, among other conditions (Horváth et al, , Jarnicki et al, ).…”

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

“…Mice deficient in TTP develop severe inflammation and have a high mortality rate in the absence of exogenous inflammatory stimuli, and therefore, using these mice to study inflammatory diseases is not appropriate. 18,21,[29][30][31] CSexposed Zfp36 aa/aa mice had significantly reduced influx of neutrophils in the airway lumen after four days and eight weeks of CS exposure compared to CS-exposed wild-type controls. Notably, as in humans, the hallmark features of COPD do not respond well to corticosteroid treatment, so the induction of TTP is an alternative approach.…”

“…[18][19][20][21][22][23][24]30,50,51,[68][69][70] Exposures are equivalent to a pack-aday smoker. [18][19][20][21][22][23][24]30,50,51,[68][69][70] Exposures are equivalent to a pack-aday smoker.…”

Amine oxidase activity regulates the development of pulmonary fibrosis

“…The liver model also showed that AOC3 mainly supports fibrogenesis by contributing to the recruitment of inflammatory cells into the damaged liver and that blocking of AOC3 with antibodies that do not inhibit the oxidase activity of the molecule alleviated the development of fibrosis. In addition, the SSAO inhibitor PXS4728A inhibits renal fibrosis and inflammatory cell infiltration (61, 62), and very recently it has been shown to alleviate chronic obstructive pulmonary disease (63). In this chronic lung model, the inhibitor reduced leukocyte infiltration and histologic collagen deposition, although no genetic tools or quantitative analyses were used to confirm the specificity and magnitude of the effects.…”