Published ahead of print on February 25, 2003, doi:10.1164/rccm.200209-1119OC Am. J. Respir. Crit. Care Med., Volume 167, Number 10, May 2003, 1374-1379 A more recent version of this article appeared on May 15, 2003
Submitted on September 30, 2002 Targeted delivery of antiprotease to the epithelial surface of human tracheal xenograftsThomas Ferkol1*,1 Pediatrics, Washington University School of Medicine, St. Louis, MO, USA, 2 Veterinary Medicine and Surgery, University of Missouri, College of Veterinary Medicine, Columbia, MO, USA, 3 Division of Biological Sciences, University of Missouri, Columbia, MO, USA, 4 Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA, 5 Pediatrics, Case Western Reserve University, Cleveland, OH, USA * To whom correspondence should be addressed. E-mail: ferkol_t{at}kids.wustl.edu.
The cystic fibrosis 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 cystic fibrosis. We have developed a strategy that permits the delivery of antiproteases to the inaccessible cystic fibrosis airways by targeting the respiratory epithelium via the human polymeric immunoglobulin receptor. A fusion protein consisting of a single-chain Fv directed against secretory component, the extracellular portion of the polymeric immunoglobulin receptor, linked to human alpha1-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 alpha1-antitrypsin alone. Targeted antiprotease delivery paralleled human polymeric immunoglobulin receptor 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. Key words: polymeric immunoglobulin receptor, antiprotease, human tracheal xenograft, airway, epithelium
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