Targeted delivery of antiprotease to the epithelial surface of human tracheal xenografts

Thomas Ferkol, Leah A. Cohn, Thomas E. Phillips, Arnold Smith, Pamela B. Davis

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The cystic fibrosis (CF) lung is uniquely susceptible to Pseudomonas aeruginosa, and infection with this organism incites an intense, compartmentalized inflammatory response that leads to chronic airway obstruction and bronchiectasis. Neutrophils migrate into the airway, and released neutrophil elastase contributes to the progression of the lung disease characteristic of CF. We have developed a strategy that permits the delivery of antiproteases to the inaccessible CF airways by targeting the respiratory epithelium via the human polymeric immunoglobulin receptor (hplgR). A fusion protein consisting of a single-chain Fv directed against secretory component, the extracellular portion of the plgR, linked to human α1-antitrypsin is effectively ferried across human tracheal xenografts and delivers the antiprotease to the apical surface to a much greater extent than occurs by passive diffusion of human α1-antitrypsin alone. Targeted antiprotease delivery paralleled hplgR expression in the respiratory epithelium in vivo and was not increased by escalating dose, so airway penetration was receptor-dependent, not dose-dependent. Thus, this approach provides us with the ability to deliver therapeutics, like antiproteases, specifically to the lumenal surface of the respiratory epithelium, within the airway surface fluid, where it will be in highest concentration at this site.

Original languageEnglish
Pages (from-to)1374-1379
Number of pages6
JournalAmerican journal of respiratory and critical care medicine
Volume167
Issue number10
DOIs
StatePublished - May 15 2003
Externally publishedYes

Keywords

  • Airway
  • Antiprotease
  • Epithelium
  • Human tracheal xenograft
  • Polymeric immunoglobulin receptor

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