title: A functional variant of elafin with improved anti-inflammatory activity for pulmonary inflammation.
abstract: Elafin is a serine protease inhibitor produced by epithelial and immune cells with anti-inflammatory properties. Research has shown that dysregulated protease activity may elicit proteolytic cleavage of elafin, thereby impairing the innate immune function of the protein. The aim of this study was to generate variants of elafin (GG- and QQ-elafin) that exhibit increased protease resistance while retaining the biological properties of wild-type (WT) elafin. Similar to WT-elafin, GG- and QQ-elafin variants retained antiprotease activity and susceptibility to transglutaminase-mediated fibronectin cross-linking. However, in contrast to WT-elafin, GG- and QQ-elafin displayed significantly enhanced resistance to degradation when incubated with bronchoalveolar lavage fluid from patients with cystic fibrosis. Intriguingly, both variants, particularly GG-elafin, demonstrated improved lipopolysaccharide (LPS) neutralization properties in vitro. In addition, GG-elafin showed improved anti-inflammatory activity in a mouse model of LPS-induced acute lung inflammation. Inflammatory cell infiltration into the lung was reduced in lungs of mice treated with GG-elafin, predominantly neutrophilic infiltration. A reduction in MCP-1 levels in GG-elafin treated mice compared to the LPS alone treatment group was also demonstrated. GG-elafin showed increased functionality when compared to WT-elafin and may be of future therapeutic relevance in the treatment of lung diseases characterized by a protease burden.
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Small
authors.affiliation: CEPR, INSERM U1100/EA6305, University of Tours, Tours, France.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Zani
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Quinn
authors.affiliation: CEPR, INSERM U1100/EA6305, University of Tours, Tours, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dallet-Choisy
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Arlene M A
authors.initials: AM
authors.lastname: Glasgow
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: O'Kane
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Danny F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: 1] Our Lady's Hospital for Sick Children, Dublin, Ireland [2] National Children's Research Centre, Crumlin, Dublin, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: McNally
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Sinéad
authors.initials: S
authors.lastname: Weldon
authors.affiliation: CEPR, INSERM U1100/EA6305, University of Tours, Tours, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Moreau
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Taggart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D053492:Elafin / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015202:Protein Engineering; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D053492:Elafin; D005353:Fibronectins; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D011503:Transglutaminases