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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.
AuthorsDonna M Small, Marie-Louise Zani, Derek J Quinn, Sandrine Dallet-Choisy, Arlene M A Glasgow, Cecilia O'Kane, Danny F McAuley, Paul McNally, Sinéad Weldon, Thierry Moreau, Clifford C Taggart
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 23 Issue 1 Pg. 24-31 (Jan 2015) ISSN: 1525-0024 [Electronic] United States
PMID25189740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • Elafin
  • Fibronectins
  • Lipopolysaccharides
  • Protease Inhibitors
  • Protein Isoforms
  • Recombinant Proteins
  • Transglutaminases
Topics
  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents (chemistry, pharmacology)
  • Bronchoalveolar Lavage Fluid (chemistry)
  • Cystic Fibrosis (metabolism, pathology)
  • Elafin (chemistry, genetics, pharmacology)
  • Fibronectins (antagonists & inhibitors, metabolism)
  • Gene Expression
  • Humans
  • Kinetics
  • Lipopolysaccharides
  • Lung (drug effects, metabolism, pathology)
  • Male
  • Mice
  • Molecular Sequence Data
  • Pneumonia (chemically induced, drug therapy, metabolism, pathology)
  • Protease Inhibitors (chemistry, pharmacology)
  • Protein Engineering
  • Protein Isoforms (chemistry, genetics, pharmacology)
  • Proteolysis (drug effects)
  • Recombinant Proteins (chemistry, genetics, pharmacology)
  • Transglutaminases (antagonists & inhibitors, metabolism)

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