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

Groneberg, David A.; Eynott, Paul R.; Döring, Frank; Dinh, Q. Thai; Oates, Thomas; Barnes, Peter J.; Chung, Kian Fan; Daniel, Hannelore; Fischer, Axel

doi:10.1136/thorax.57.1.55

Cited by 72 publications

(38 citation statements)

References 44 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous work has shown that MDP is a substrate for PEPT1, a paralogous member of the SLC15A proton oligopeptide transporter family (20). Interestingly, PEPT2 is abundantly expressed throughout the respiratory tract by epithelia and PEPT1 is not (10), whereas the opposite holds true of the gut epithelium. Taken with our findings, we contend that MDP was not immunoreactive due to a lack of cell uptake by lung epithelia.…”

Section: Discussionmentioning

confidence: 79%

“…PEPT2 displays promiscuous ligand affinity and mediates, in addition to its natural di-and tripeptide substrates, the uptake of numerous peptidomimetic drug molecules, such as b-lactam antibiotics and antivirals. Our previous work and that of others characterized PEPT2 expression and function in humans in situ in bronchial, bronchiolar, and alveolar type II epithelial cells (9)(10)(11). We first reported the functional characterization of PEPT2-mediated transport across the apical surface of fully differentiated, polarized, primary human upper airway epithelial cultures (hUAECs, henceforth referred to as human lung epithelial cells [hLECs]).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Bacterial Peptide Recognition and Immune Activation Facilitated by Human Peptide Transporter PEPT2

Swaan¹,

Bensman²,

Bahadduri³

et al. 2008

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Microbial detection requires the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) that are distributed on the cell surface and within the cytosol. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family functions as an intracellular PRR that triggers the innate immune response. The mechanism by which PAMPs enter the cytosol to interact with NLRs, particularly muropeptides derived from the bacterial proteoglycan cell wall, is poorly understood. PEPT2 is a proton-dependent transporter that mediates the active translocation of di-and tripeptides across epithelial tissues, including the lung. Using computational tools, we initially established that bacterial dipeptides, particularly g-D-glutamyl-meso-diaminopimelic acid (g-iE-DAP), are suitable substrates for PEPT2. We then determined in primary cultures of human upper airway epithelia and transiently transfected CHO-PEPT2 cell lines that g-iE-DAP uptake was mediated by PEPT2 with an affinity constant of approximately 193 mM, whereas muramyl dipeptide was not transported. Exposure to g-iE-DAP at the apical surface of differentiated, polarized cultures resulted in activation of the innate immune response in an NOD1-and RIP2-dependent manner, resulting in release of IL-6 and IL-8. Based on these findings we report that PEPT2 plays a vital role in microbial recognition by NLR proteins, particularly with regard to airborne pathogens, thereby participating in host defense in the lung.Keywords: human; lung; bacterial; cell surface molecules; acute phase reactants Pathogen-associated molecular patterns (PAMPs) are recognized by cell surface or cytosolic pattern recognition receptors (PRRs) (1). One family of intracellular PRRs include the nucleotide-binding oligomerization domain (NOD)-containing proteins (NODs or NOD-like receptors [NLRs]) that sense intracellular pathogen invasion and trigger signaling cascades, thereby activating the host immune response (2-4). NOD1 and NOD2 mediate intracellular recognition of bacterial proteoglycan (PGN)-derived molecules through recognition by their carboxy-terminal leucine-rich repeat region (5). This results in recruitment of the downstream kinase protein RIP2 and initiation of NF-kB-mediated transcription and elaboration of newly synthesized cytokines and chemokines (6). Biochemical and functional analyses have identified g-D-glutamyl-mesodiaminopimelic acid (g-iE-DAP) and muramyl dipeptide (MDP) as the minimal bacterial muropeptide epitopes recognized by NOD1 and NOD2, respectively, resulting in immune activation (5, 7).Enzymes that are naturally present in the epithelial lining fluid (e.g., lysozyme) are believed to act in concert to degrade the bacterial cell wall as a front-line defense mechanism, thereby liberating muropeptide fragments that include both g-iE-DAP and MDP. The dipeptides may also be derived as byproducts of bacterial PGN biosynthesis, cell growth, and division; therefore, it is plausible that these particular PAMPs reside in the airway...

show abstract

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Bacterial Peptide Recognition and Immune Activation Facilitated by Human Peptide Transporter PEPT2

Swaan¹,

Bensman²,

Bahadduri³

et al. 2008

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…PEPT would act by decreasing the drug concentration within ELF by uptake into epithelial cells. Yet, the mechanism describing how drugs leave pulmonary cells has not been characterized (41,42). Further studies are necessary to characterize the functions of OCTs and PEPT in the transport of colistin at the air-blood barrier level, since this in vivo study could not address this issue.…”

Section: Discussionmentioning

confidence: 93%

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 2. Colistin

Gontijo

Grégoire

Lamarche

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (V ELF ), a passive diffusion clearance (Q ELF ) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg ؊1 ). The k m was estimated to be 133 g ml ؊1 , and the V max, in -to-K m ratio was equal to 2.5 ؋ 10 ؊3liter h ؊1 kg ؊1 , which was 37 times higher than the Q ELF (6.7 ؋ 10 ؊5 liter h ؊1 kg ؊1 ). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.T reatment of lung infections by administration of antimicrobial agents using the pulmonary route presents potential clinical use, since it may afford higher drug concentrations at the site of infection with a reduction of systemic exposure (1, 2). Consequently, increased use of inhaled antibiotics, such as tobramycin, aztreonam, or colistin methansulfonate (CMS), has been observed to treat lung infections (3, 4).CMS is the inactive prodrug of colistin (5), which is a multicomponent cationic polypeptide that belongs to the class of polymyxins, comprised mainly of colistin A and colistin B (6). It is an old antibiotic that was abandoned in the 1970s due to its adverse effects (7). During the last 15 years, it has occasionally been used as "salvage" therapy for the treatment of infections engendered by multidrug-resistant bacteria, due to the lack of new antibiotics (8). When CMS was developed, controlled clinical trials and determination of pharmacokinetic and pharmacodynamic (PK/PD) properties were not required by drug-regulating agencies (6). However, the understanding of colistin pharmacokinetics after CMS intravenous (i.v.) administration to critically ill patients is progressing (9-13). But CMS is also nebulized for the treatment of pulm...

show abstract

“…221 PEPT 2 and more recently PEPT 1 were detected first in the airway epithelium and then in the bronchial epithelium. 222,223 These two transporters have also been found in animals and cell lines. 224,225 However, how they interact with drug formulations and their activity in respiratory diseases 226 has not been fully investigated.…”

Section: Peptide Transportersmentioning

confidence: 96%

Inhaled chemotherapy in lung cancer: future concept of nanomedicine

Zarogoulidis

Chatzaki²,

Porpodis³

et al. 2012

IJN

166

160

View full text Add to dashboard Cite

Regional chemotherapy was first used for lung cancer 30 years ago. Since then, new methods of drug delivery and pharmaceuticals have been investigated in vitro, and in animals and humans. An extensive review of drug delivery systems, pharmaceuticals, patient monitoring, methods of enhancing inhaled drug deposition, safety and efficacy, and also additional applications of inhaled chemotherapy and its advantages and disadvantages are presented. Regional chemotherapy to the lung parenchyma for lung cancer is feasible and efficient. Safety depends on the chemotherapy agent delivered to the lungs and is dose-dependent and time-dependent. Further evaluation is needed to provide data regarding early lung cancer stages, and whether regional chemotherapy can be used as neoadjuvant or adjuvant treatment. Finally, inhaled chemotherapy could one day be administered at home with fewer systemic adverse effects.

show abstract

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

Cited by 72 publications

References 44 publications

Bacterial Peptide Recognition and Immune Activation Facilitated by Human Peptide Transporter PEPT2

Bacterial Peptide Recognition and Immune Activation Facilitated by Human Peptide Transporter PEPT2

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 2. Colistin

Inhaled chemotherapy in lung cancer: future concept of nanomedicine

Contact Info

Product

Resources

About