title: The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases.
abstract: The serine proteases released by activated polymorphonuclear neutrophils [NSPs (neutrophil serine proteases)] contribute to a variety of inflammatory lung diseases, including CF (cystic fibrosis). They are therefore key targets for the development of efficient inhibitors. Although rodent models have contributed to our understanding of several diseases, we have previously shown that they are not appropriate for testing anti-NSP therapeutic strategies [Kalupov, Brillard-Bourdet, Dade, Serrano, Wartelle, Guyot, Juliano, Moreau, Belaaouaj and Gauthier (2009) J. Biol. Chem. 284, 34084-34091). Thus NSPs must be characterized in an animal model that is much more likely to predict how therapies will act in humans in order to develop protease inhibitors as drugs. The recently developed CFTR-/- (CFTR is CF transmembrane conductance regulator) pig model is a promising alternative to the mouse model of CF [Rogers, Stoltz, Meyerholz, Ostedgaard, Rokhlina, Taft, Rogan, Pezzulo, Karp, Itani et al. (2008) Science 321, 1837-1841]. We have isolated blood neutrophils from healthy pigs and determined their responses to the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus, and the biochemical properties of their NSPs. We used confocal microscopy and antibodies directed against their human homologues to show that the three NSPs (elastase, protease 3 and cathepsin G) are enzymatically active and present on the surface of triggered neutrophils and NETs (neutrophil extracellular traps). All of the porcine NSPs are effectively inhibited by human NSP inhibitors. We conclude that there is a close functional resemblance between porcine and human NSPs. The pig is therefore a suitable animal model for testing new NSP inhibitors as anti-inflammatory agents in neutrophil-associated diseases such as CF.
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Bréa
authors.forename: François
authors.initials: F
authors.lastname: Meurens
authors.forename: Alice V
authors.initials: AV
authors.lastname: Dubois
authors.forename: Julien
authors.initials: J
authors.lastname: Gaillard
authors.forename: Claire
authors.initials: C
authors.lastname: Chevaleyre
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jourdan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Winter
authors.forename: Brigitte
authors.initials: B
authors.lastname: Arbeille
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Francis
authors.initials: F
authors.lastname: Gauthier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Attucci
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D015550:Cell Degranulation; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology; D011014:Pneumonia / Q000097:blood / Q000201:enzymology*; D011550:Pseudomonas aeruginosa / Q000502:physiology; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013045:Species Specificity; D013211:Staphylococcus aureus / Q000502:physiology; D013552:Swine
chemical_list: D061207:Calcium Ionophores; D015842:Serine Proteinase Inhibitors; D000001:Calcimycin; D057057:Serine Proteases