Kinetic and Dynamic Effects of Intestinal PEPT1 on the Bacterially-ProducedChemotactic Peptide fMet-Leu-Phe and the Anti-Inflammatory PeptideLys-Pro-Val.

PEPT1;IBD;Inflammatory Bowel Disease;Perfusion;KPV;FMLP;Pharmacy and Pharmacology;Health Sciences;Pharmaceutical Sciences

Wu, Shu-PeiZimmermann, Ellen Mary ;

University of Michigan

关键词: PEPT1;    IBD;    Inflammatory Bowel Disease;    Perfusion;    KPV;    FMLP;    Pharmacy and Pharmacology;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/89738/shupeiwu_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The proton-coupled oligopeptide transporter PEPT1 has recently been linked to intestinal inflammation and inflammatory bowel disease (IBD) because of its ability to transport bacterial peptides (e.g., Tri-DAP, MDP, fMet-Leu-Phe) and its aberrant expression in the colon of IBD patients. Although studies have demonstrated that several bacterial peptides were substrates of PEPT1, the relative importance of this protein (as compared to other transporters and pathways) and its regional permeability have not been addressed. Therefore, the first objective of this dissertation focused on the importance of intestinal PEPT1 in transporting a bacterially-produced chemotactic peptide, fMet-Leu-Phe, using the in situ single-pass intestinal perfusion (SPIP) technique in wild-type and Pept1 knockout mice. The dynamic effect of fMet-Leu-Phe transport was examined by the activity of myeloperoxidase (MPO), a marker for neutrophil migration with a modified intestinal perfusion. These findings suggested that PEPT1 was the major transporter for the transport of fMet-Leu-Phe in the small intestine and could influence the induction of inflammation.Lys-Pro-Val has been suggested as a potential therapeutic agent for IBD due to its anti-inflammatory effects in mouse colitis models. However, some important properties (e.g., intestinal permeability and stability) have not been studied. Therefore, the second objective of this dissertation was to study the transport properties of the anti-inflammatory tripeptide Lys-Pro-Val using the intestinal perfusion technique in wild-type and Pept1 knockout mice. The results suggested that although Lys-Pro-Val may be a good candidate to treat IBD through the aberrant expression of colonic PEPT1, drug stability was a significant concern for oral administration.In conclusion, results from this dissertation suggested that PEPT1 could transport bacterial peptides, implying that aberrant expression of PEPT1 in the colon may contribute to the progression of IBD. Although colonic PEPT1 may also serve as a drug targeting (delivery) opportunity for some bioactive peptides, such as Lys-Pro-Val to treat IBD, intestinal stability of this substrate is a realistic concern.