Skip to main content
PMC home page
Thorax logoLink to Thorax
. 2002 Jan;57(1):55–60. doi: 10.1136/thorax.57.1.55

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung

D Groneberg 1, P Eynott 1, F Doring 1, D Thai 1, T Oates 1, P Barnes 1, K Chung 1, H Daniel 1, A Fischer 1
PMCID: PMC1746169  PMID: 11809991

Abstract

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 ß-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.

Full Text

The Full Text of this article is available as a PDF (188.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berger U. V., Hediger M. A. Distribution of peptide transporter PEPT2 mRNA in the rat nervous system. Anat Embryol (Berl) 1999 May;199(5):439–449. doi: 10.1007/s004290050242. [DOI] [PubMed] [Google Scholar]
  2. Boichot E., Richard M. P., Paubert-Braquet M. Effect of cefadroxil on antigen-induced bronchial hyperresponsiveness and eosinophil accumulation in lung from sensitized guinea pigs. Int Arch Allergy Immunol. 1993;102(1):87–93. doi: 10.1159/000236555. [DOI] [PubMed] [Google Scholar]
  3. Boll M., Herget M., Wagener M., Weber W. M., Markovich D., Biber J., Clauss W., Murer H., Daniel H. Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):284–289. doi: 10.1073/pnas.93.1.284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boll M., Markovich D., Weber W. M., Korte H., Daniel H., Murer H. Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, beta-lactam antibiotics and ACE-inhibitors. Pflugers Arch. 1994 Nov;429(1):146–149. doi: 10.1007/BF02584043. [DOI] [PubMed] [Google Scholar]
  5. Bressolle F., de la Coussaye J. E., Ayoub R., Fabre D., Gomeni R., Saissi G., Eledjam J. J., Galtier M. Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability. Antimicrob Agents Chemother. 1992 Jul;36(7):1404–1411. doi: 10.1128/aac.36.7.1404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chisholm D. R., DeRegis R. G., Behr D. A. Therapeutic efficacy of cefadroxil and cephalexin for pneumonia in a rat test model. Antimicrob Agents Chemother. 1986 Jul;30(1):105–109. doi: 10.1128/aac.30.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Daniel H. Function and molecular structure of brush border membrane peptide/H+ symporters. J Membr Biol. 1996 Dec;154(3):197–203. doi: 10.1007/s002329900144. [DOI] [PubMed] [Google Scholar]
  8. Daniel H., Herget M. Cellular and molecular mechanisms of renal peptide transport. Am J Physiol. 1997 Jul;273(1 Pt 2):F1–F8. doi: 10.1152/ajprenal.1997.273.1.F1. [DOI] [PubMed] [Google Scholar]
  9. Dieck S. T., Heuer H., Ehrchen J., Otto C., Bauer K. The peptide transporter PepT2 is expressed in rat brain and mediates the accumulation of the fluorescent dipeptide derivative beta-Ala-Lys-Nepsilon-AMCA in astrocytes. Glia. 1999 Jan;25(1):10–20. doi: 10.1002/(sici)1098-1136(19990101)25:1<10::aid-glia2>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  10. Döring F., Michel T., Rösel A., Nickolaus M., Daniel H. Expression of the mammalian renal peptide transporter PEPT2 in the yeast Pichia pastoris and applications of the yeast system for functional analysis. Mol Membr Biol. 1998 Apr-Jun;15(2):79–88. doi: 10.3109/09687689809027522. [DOI] [PubMed] [Google Scholar]
  11. Döring F., Walter J., Will J., Föcking M., Boll M., Amasheh S., Clauss W., Daniel H. Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications. J Clin Invest. 1998 Jun 15;101(12):2761–2767. doi: 10.1172/JCI1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Döring F., Will J., Amasheh S., Clauss W., Ahlbrecht H., Daniel H. Minimal molecular determinants of substrates for recognition by the intestinal peptide transporter. J Biol Chem. 1998 Sep 4;273(36):23211–23218. doi: 10.1074/jbc.273.36.23211. [DOI] [PubMed] [Google Scholar]
  13. Fei Y. J., Kanai Y., Nussberger S., Ganapathy V., Leibach F. H., Romero M. F., Singh S. K., Boron W. F., Hediger M. A. Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature. 1994 Apr 7;368(6471):563–566. doi: 10.1038/368563a0. [DOI] [PubMed] [Google Scholar]
  14. Freeman T. C., Bentsen B. S., Thwaites D. T., Simmons N. L. H+/di-tripeptide transporter (PepT1) expression in the rabbit intestine. Pflugers Arch. 1995 Jul;430(3):394–400. doi: 10.1007/BF00373915. [DOI] [PubMed] [Google Scholar]
  15. Groneberg D. A., Döring F., Nickolaus M., Daniel H., Fischer A. Expression of PEPT2 peptide transporter mRNA and protein in glial cells of rat dorsal root ganglia. Neurosci Lett. 2001 May 25;304(3):181–184. doi: 10.1016/s0304-3940(01)01794-3. [DOI] [PubMed] [Google Scholar]
  16. Groneberg D. A., Nickolaus M., Springer J., Döring F., Daniel H., Fischer A. Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake. Am J Pathol. 2001 Feb;158(2):707–714. doi: 10.1016/S0002-9440(10)64013-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Helliwell P. A., Meredith D., Boyd C. A., Bronk J. R., Lister N., Bailey P. D. Tripeptide transport in rat lung. Biochim Biophys Acta. 1994 Mar 23;1190(2):430–434. doi: 10.1016/0005-2736(94)90104-x. [DOI] [PubMed] [Google Scholar]
  18. Hodson M. E., Penketh A. R., Batten J. C. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet. 1981 Nov 21;2(8256):1137–1139. doi: 10.1016/s0140-6736(81)90588-2. [DOI] [PubMed] [Google Scholar]
  19. Honeybourne D. Antibiotic penetration into lung tissues. Thorax. 1994 Feb;49(2):104–106. doi: 10.1136/thx.49.2.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Koch C., Høiby N. Pathogenesis of cystic fibrosis. Lancet. 1993 Apr 24;341(8852):1065–1069. doi: 10.1016/0140-6736(93)92422-p. [DOI] [PubMed] [Google Scholar]
  21. Kramer W., Girbig F., Petzoldt E., Leipe I. Inactivation of the intestinal uptake system for beta-lactam antibiotics by diethylpyrocarbonate. Biochim Biophys Acta. 1988 Aug 18;943(2):288–296. doi: 10.1016/0005-2736(88)90560-3. [DOI] [PubMed] [Google Scholar]
  22. Liang R., Fei Y. J., Prasad P. D., Ramamoorthy S., Han H., Yang-Feng T. L., Hediger M. A., Ganapathy V., Leibach F. H. Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. J Biol Chem. 1995 Mar 24;270(12):6456–6463. doi: 10.1074/jbc.270.12.6456. [DOI] [PubMed] [Google Scholar]
  23. Liu W., Liang R., Ramamoorthy S., Fei Y. J., Ganapathy M. E., Hediger M. A., Ganapathy V., Leibach F. H. Molecular cloning of PEPT 2, a new member of the H+/peptide cotransporter family, from human kidney. Biochim Biophys Acta. 1995 May 4;1235(2):461–466. doi: 10.1016/0005-2736(95)80036-f. [DOI] [PubMed] [Google Scholar]
  24. Nolan G., Moivor P., Levison H., Fleming P. C., Corey M., Gold R. Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin. J Pediatr. 1982 Oct;101(4):626–630. doi: 10.1016/s0022-3476(82)80726-9. [DOI] [PubMed] [Google Scholar]
  25. Ogihara H., Saito H., Shin B. C., Terado T., Takenoshita S., Nagamachi Y., Inui K., Takata K. Immuno-localization of H+/peptide cotransporter in rat digestive tract. Biochem Biophys Res Commun. 1996 Mar 27;220(3):848–852. doi: 10.1006/bbrc.1996.0493. [DOI] [PubMed] [Google Scholar]
  26. Ogihara H., Suzuki T., Nagamachi Y., Inui K., Takata K. Peptide transporter in the rat small intestine: ultrastructural localization and the effect of starvation and administration of amino acids. Histochem J. 1999 Mar;31(3):169–174. doi: 10.1023/a:1003515413550. [DOI] [PubMed] [Google Scholar]
  27. Otto C., Bauer K. Dipeptide uptake: a novel marker for testicular and ovarian macrophages. Anat Rec. 1996 Aug;245(4):662–667. doi: 10.1002/(SICI)1097-0185(199608)245:4<662::AID-AR6>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  28. Otto C., tom Dieck S., Bauer K. Dipeptide uptake by adenohypophysial folliculostellate cells. Am J Physiol. 1996 Jul;271(1 Pt 1):C210–C217. doi: 10.1152/ajpcell.1996.271.1.C210. [DOI] [PubMed] [Google Scholar]
  29. Peng Q., Moan J., Ma L. W., Nesland J. M. Uptake, localization, and photodynamic effect of meso-tetra(hydroxyphenyl)porphine and its corresponding chlorin in normal and tumor tissues of mice bearing mammary carcinoma. Cancer Res. 1995 Jun 15;55(12):2620–2626. [PubMed] [Google Scholar]
  30. Ramsey B. W. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med. 1996 Jul 18;335(3):179–188. doi: 10.1056/NEJM199607183350307. [DOI] [PubMed] [Google Scholar]
  31. Retsema J. A., Girard A. E., Girard D., Milisen W. B. Relationship of high tissue concentrations of azithromycin to bactericidal activity and efficacy in vivo. J Antimicrob Chemother. 1990 Jan;25 (Suppl A):83–89. doi: 10.1093/jac/25.suppl_a.83. [DOI] [PubMed] [Google Scholar]
  32. Ries M., Wenzel U., Daniel H. Transport of cefadroxil in rat kidney brush-border membranes is mediated by two electrogenic H+-coupled systems. J Pharmacol Exp Ther. 1994 Dec;271(3):1327–1333. [PubMed] [Google Scholar]
  33. Rosenstein B. J., Zeitlin P. L. Prognosis in cystic fibrosis. Curr Opin Pulm Med. 1995 Nov;1(6):444–449. doi: 10.1097/00063198-199511000-00003. [DOI] [PubMed] [Google Scholar]
  34. Rowe P. M. Photodynamic therapy begins to shine. Lancet. 1998 May 16;351(9114):1496–1496. doi: 10.1016/S0140-6736(05)78884-X. [DOI] [PubMed] [Google Scholar]
  35. Saito H., Okuda M., Terada T., Sasaki S., Inui K. Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of beta-lactam antibiotics in the intestine and kidney. J Pharmacol Exp Ther. 1995 Dec;275(3):1631–1637. [PubMed] [Google Scholar]
  36. Saito H., Terada T., Okuda M., Sasaki S., Inui K. Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim Biophys Acta. 1996 Apr 26;1280(2):173–177. doi: 10.1016/0005-2736(96)00024-7. [DOI] [PubMed] [Google Scholar]
  37. Shen H., Smith D. E., Yang T., Huang Y. G., Schnermann J. B., Brosius F. C., 3rd Localization of PEPT1 and PEPT2 proton-coupled oligopeptide transporter mRNA and protein in rat kidney. Am J Physiol. 1999 May;276(5 Pt 2):F658–F665. doi: 10.1152/ajprenal.1999.276.5.F658. [DOI] [PubMed] [Google Scholar]
  38. Smith D. E., Pavlova A., Berger U. V., Hediger M. A., Yang T., Huang Y. G., Schnermann J. B. Tubular localization and tissue distribution of peptide transporters in rat kidney. Pharm Res. 1998 Aug;15(8):1244–1249. doi: 10.1023/a:1011996009332. [DOI] [PubMed] [Google Scholar]
  39. Sustronck B., Deprez P., Muylle E., Vermeersch H., Vandenbossche G., Remon J. P. Evaluation of the nebulisation of sodium ceftiofur in the treatment of experimental Pasteurella haemolytica bronchopneumonia in calves. Res Vet Sci. 1995 Nov;59(3):267–271. doi: 10.1016/0034-5288(95)90015-2. [DOI] [PubMed] [Google Scholar]
  40. Terada T., Saito H., Inui K. Interaction of beta-lactam antibiotics with histidine residue of rat H+/peptide cotransporters, PEPT1 and PEPT2. J Biol Chem. 1998 Mar 6;273(10):5582–5585. doi: 10.1074/jbc.273.10.5582. [DOI] [PubMed] [Google Scholar]
  41. Wang H., Fei Y. J., Ganapathy V., Leibach F. H. Electrophysiological characteristics of the proton-coupled peptide transporter PEPT2 cloned from rat brain. Am J Physiol. 1998 Oct;275(4 Pt 1):C967–C975. doi: 10.1152/ajpcell.1998.275.4.C967. [DOI] [PubMed] [Google Scholar]
  42. Wenzel U., Diehl D., Herget M., Kuntz S., Daniel H. Regulation of the high-affinity H+/peptide cotransporter in renal LLC-PK1 cells. J Cell Physiol. 1999 Mar;178(3):341–348. doi: 10.1002/(SICI)1097-4652(199903)178:3<341::AID-JCP8>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  43. Yamashita F., Kim K. J., Lee V. H. Dipeptide uptake and transport characteristics in rabbit tracheal epithelial cell layers cultured at an air interface. Pharm Res. 1998 Jul;15(7):979–983. doi: 10.1023/a:1011957506181. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES