title: Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Drug Discovery Department, Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, 2086, Australia. Heidi.Schilter@pharmaxis.com.au.
authors.forename: Heidi C
authors.initials: HC
authors.lastname: Schilter
authors.affiliation: The University of Newcastle & Vaccines, Infection, Viruses & Asthma, Newcastle, Australia. adam.collison@gmail.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.affiliation: Laboratório de Imunologia e Mecânica Pulmonar, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil. russorc@gmail.com.|Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil. russorc@gmail.com.
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.affiliation: Drug Discovery Department, Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, 2086, Australia. Jonathan.Foot@pharmaxis.com.au.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Foot
authors.affiliation: Drug Discovery Department, Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, 2086, Australia. Tin.Yow@pharmaxis.com.au.
authors.forename: Tin T
authors.initials: TT
authors.lastname: Yow
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil. angelicathomaz@gmail.com.
authors.forename: Angelica T
authors.initials: AT
authors.lastname: Vieira
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil. liviadtavares@gmail.com.
authors.forename: Livia D
authors.initials: LD
authors.lastname: Tavares
authors.affiliation: The University of Newcastle & Vaccines, Infection, Viruses & Asthma, Newcastle, Australia. Joerg.Mattes@newcastle.edu.au.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil. mmtex.ufmg@gmail.com.
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Drug Discovery Department, Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, 2086, Australia. Wolfgang.Jarolimek@pharmaxis.com.au.|School of Medical & Molecular Biosciences, University of Technology Sydney, City Campus, PO Box 123 Broadway, 2007, Sydney, NSW, Australia. Wolfgang.Jarolimek@pharmaxis.com.au.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jarolimek
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D036904:Leukocyte Rolling / Q000187:drug effects; D008026:Ligation; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D010850:Picornaviridae Infections / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000276:immunology; D011677:Punctures; D017208:Rats, Wistar; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000276:immunology; D012229:Rhinovirus / Q000472:pathogenicity
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C000606296:PXS-4728A; C482199:lipopolysaccharide, E coli O55-B5; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse