title: Targeted delivery of antiprotease to the epithelial surface of human tracheal xenografts.
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 (hpIgR). A fusion protein consisting of a single-chain Fv directed against secretory component, the extracellular portion of the pIgR, 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 hpIgR 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.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. ferkol_t@kids.wustl.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferkol
authors.forename: Leah A
authors.initials: LA
authors.lastname: Cohn
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Phillips
authors.forename: Arnold
authors.initials: A
authors.lastname: Smith
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Davis
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D011480:Protease Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015657:Respiratory Transport / Q000502:physiology; D013045:Species Specificity; D014183:Transplantation, Heterologous; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase