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(American Journal of Pathology. 2001;158:707-714.)
© 2001 American Society for Investigative Pathology

Regular Article

Localization of the Peptide Transporter PEPT2 in the Lung

Implications for Pulmonary Oligopeptide Uptake

David A. Groneberg*, Monika Nickolaus{dagger}, Jochen Springer*, Frank Döring{dagger}, Hannelore Daniel{dagger} and Axel Fischer*{ddagger}

From the Institute of Anatomy and Cell Biology,*
University of Giessen, Giessen; the Institute of Nutritional Sciences,{dagger}
Technical University of Munich, Freising-Weihenstephan; and the Department of Pediatric Pneumology and Immunology,{ddagger}
Charite-Virchow Klinikum, Humboldt-University, Berlin, Germany

Pulmonary delivery of peptidomimetic antibiotics is frequently used for local drug therapy in pulmonary infections. Identification of transport pathways into airway epithelia can lead to new strategies of therapy. Here we describe the distribution of the {beta}-lactam-transporting high-affinity proton-coupled peptide transporter PEPT2 in mammalian lungs. Using reverse transcriptase-polymerase chain reaction and Northern blot analysis, PEPT2-mRNA was detected in lung extracts. The expression of PEPT2-mRNA and protein was localized to alveolar type II pneumocytes, bronchial epithelium, and endothelium of small arteries of rat lung by nonisotopic in situ hybridization and immunohistochemistry. In addition, transport studies using murine whole-organ preparations revealed transporter-mediated uptake of a fluorophore-conjugated dipeptide derivative into bronchial epithelial cells and type II pneumocytes. This transport was competitively inhibited by cephalosporins and dipeptides that are reported as PEPT2-carried substrates. Cell specificity of the PEPT2-mediated uptake pattern was confirmed by double labeling with Lycopersicon esculentum lectin. Together these data suggest that PEPT2 is the molecular basis for the transport of peptides and peptidomimetics in pulmonary epithelial cells. In conclusion PEPT2 may be an interesting target for pulmonary delivery of peptides and peptidomimetics.




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