Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration

© Schilter et al. Background and purpose: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Methods: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Results: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. Conclusions and implications: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation

Excimer laser radiation for endarterectomy of experimental atheromas.

Open laser endarterectomy produces a smooth arterial surface with welded distal end points. This report evaluates 308-nm excimer laser radiation for the laser endarterectomy operation. Arteriosclerotic New Zealand white rabbits (N = 15) were studied. A thoraco-abdominal exploration was performed, the aorta was isolated, heparin was administered, and multiple endarterectomies were performed in each rabbit. A line of laser craters was created at the proximal and distal ends of an atheroma. Laser radiation was used to connect the craters to form the proximal and distal end points. The atheromas were dissected from the aorta with laser light and the end points were fused. The aortas were removed for light and electron microscopy and the animals were sacrificed. Excimer radiation was delivered by a 600-microns fiber at 50 mJ/pulse, 120-ns pulses and either 15- or 20-Hz frequency. At 15 Hz excimer laser endarterectomies showed no perforations along the surface or at the end points. The surfaces were smooth but the end points were not welded in place. At 20 Hz, perforations were seen along 7/11 surfaces and at 5/11 end points. Excimer laser endarterectomy is best performed at 15 Hz. The end points, however, cannot be welded with excimer laser radiation

Excimer laser radiation for endarterectomy of experimental atheromas.

Open laser endarterectomy produces a smooth arterial surface with welded distal end points. This report evaluates 308-nm excimer laser radiation for the laser endarterectomy operation. Arteriosclerotic New Zealand white rabbits (N = 15) were studied. A thoraco-abdominal exploration was performed, the aorta was isolated, heparin was administered, and multiple endarterectomies were performed in each rabbit. A line of laser craters was created at the proximal and distal ends of an atheroma. Laser radiation was used to connect the craters to form the proximal and distal end points. The atheromas were dissected from the aorta with laser light and the end points were fused. The aortas were removed for light and electron microscopy and the animals were sacrificed. Excimer radiation was delivered by a 600-microns fiber at 50 mJ/pulse, 120-ns pulses and either 15- or 20-Hz frequency. At 15 Hz excimer laser endarterectomies showed no perforations along the surface or at the end points. The surfaces were smooth but the end points were not welded in place. At 20 Hz, perforations were seen along 7/11 surfaces and at 5/11 end points. Excimer laser endarterectomy is best performed at 15 Hz. The end points, however, cannot be welded with excimer laser radiation

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

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