Impact of Intestinal PepT1 on the Kinetics and Dynamics of N-Formyl-Methionyl-Leucyl-Phenylalanine, a Bacterially-Produced Chemotactic Peptide

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• 作者：Shu-Pei Wu ; David E. Smith
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：February 4, 2013
• 年：2013
• 卷：10
• 期：2
• 页码：677-684
• 全文大小：305K
• 年卷期：v.10,no.2(February 4, 2013)
• ISSN：1543-8392

文摘

The primary purpose of this study was to evaluate the intestinal permeability (P_eff) of N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe), a bacterially derived chemotactic tripeptide, in the duodenum, jejunum, ileum, and colon of wild-type and PepT1 knockout mice. A secondary purpose was to determine if the presence of intestinal PepT1 translated into fMet-Leu-Phe directed neutrophil migration in these animals. Using an in situ single pass perfusion technique, the P_eff of [³H]fMet-Leu-Phe was substantially reduced in the duodenum, jejunum, and ileum of PepT1 knockout mice as compared to wild-type animals. In contrast, the P_eff of [³H]fMet-Leu-Phe in colon was unchanged between genotypes and about 5% of that in small intestine. Jejunal uptake of [³H]fMet-Leu-Phe was specific for PepT1 and saturable with an intrinsic K_0.5 of 1.6 mM. The peptide/histidine transporters PhT1 and PhT2 were not involved in [³H]fMet-Leu-Phe uptake. Myeloperoxidase activity (a measure of neutrophil migration) was significantly increased following 4 h perfusions of 10 渭M fMet-Leu-Phe in the jejunum of wild-type mice and was abolished by 50 mM glycylglycine; no change was observed in the jejunum of PepT1 knockout mice. Likewise, fMet-Leu-Phe perfusions had no effect on myeloperoxidase activity in the colon of either genotype. In conclusion, these findings demonstrated that PepT1 had a major influence on the permeability of fMet-Leu-Phe in duodenum, jejunum, and ileum in wild-type mice and on inflammatory response in intestinal regions that expressed PepT1.

Keywords:

PepT1; fMet-Leu-Phe; regional permeability; myeloperoxidase activity