A Functional Variant of Elafin With Improved Anti-inflammatory Activity for Pulmonary Inflammation

Donna M. Small*, Marie Louise Zani, Derek J. Quinn, Sandrine Dallet-Choisy, Arlene MA Glasgow, Cecilia O'Kane, Danny F. Mcauley, Paul Mcnally, Sinéad Weldon, Thierry Moreau, Clifford C. Taggart

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)24-31
Number of pages8
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume23
Issue number1
Early online date30 Sep 2014
DOIs
Publication statusPublished - 2015

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