Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung.
BACKGROUND
Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment.


METHODS
Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue.


RESULTS
PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2.


CONCLUSIONS
These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics.
Groneberg
D A
DA
Department of Pediatric Pneumology and Immunology, Charité Campus Virchow, Humboldt University, Augustenburger Platz 1, D-13353 Berlin, Germany.
Eynott
P R
PR
Döring
F
F
Dinh
Q Thai
QT
Oates
T
T
Barnes
P J
PJ
Chung
K F
KF
Daniel
H
H
Fischer
A
A
D000085:Acetates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D002434:Cefadroxil / Q000494:pharmacology; D002867:Chromones / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D003550:Cystic Fibrosis / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D014132:Trachea / Q000378:metabolism
D000085:Acetates; C400304:Alexa 350; D000806:Angiotensin-Converting Enzyme Inhibitors; D002867:Chromones; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D002434:Cefadroxil; D002216:Captopril