Abstract
Background and purposeThe 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.MethodsMice 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.ResultsSelective 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 implicationsThis 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.
Highlights
Background and purposeThe persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of chronic obstructive pulmonary disease (COPD), cystic fibrosis and acute lung inflammation
Several inflammatory diseases of the lung including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute lung injury and bronchiolitis obliterans syndrome are predominantly characterized by neutrophilic infiltration [1,2,3,4]
PXS-4728A compound profile PXS-4728A exhibited an Half maximal inhibitory concentration (IC50) of
Summary
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. Integral to the proper functioning of neutrophils in lung defense is their ability to egress from the microvasculature and migrate through tissues to the targeted site. Given the potential of targeting neutrophil migration via their adhesion process, a number of small molecules have been developed against neutrophil inflammation. Targeting P-selectin glycoprotein ligand 1 (PSGL-1/CD162) and Mac-1 (CD11b/CD18), inhibits pulmonary recruitment of neutrophils and reduces lung damage in sepsis (29, 30). Administration of the CXCR2 antagonists SCH527123 and SB-656933 has been shown to inhibit the increased neutrophil content in sputum as a result of ozone challenge in normal volunteers, while AZD8309 was shown to be efficacious during inhaled LPS challenge in normal volunteers [19,20,21]
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