Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers

J Pharmacol Exp Ther. 2003 Jan;304(1):464-76. doi: 10.1124/jpet.102.043182.

Abstract

Ethyl pyruvate (EP) solution ameliorates ileal mucosal hyperpermeability and decreases the expression of several proinflammatory genes in ileal and/or colonic mucosa when it is used instead of Ringer's lactate solution (RLS) to resuscitate mice from hemorrhagic shock. To test the hypothesis that EP can ameliorate gut barrier dysfunction induced by other forms of inflammation, we incubated Caco-2 monolayers for 24 to 48 h with cytomix (a mixture of interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta) in the presence or absence of graded concentrations of EP or sodium pyruvate. Cytomix increased the permeability of Caco-2 monolayers to fluorescein isothiocyanate-labeled dextran (FD4; average molecular mass 4 kDa), but this effect was inhibited by adding 0.1 to 10 mM EP (but not similar concentrations of sodium pyruvate) to the culture medium. EP inhibited several other cytomix-induced phenomena, including nuclear factor-kappaB activation, inducible nitric oxide synthase mRNA expression, and nitric oxide production. Cytomix altered the expression and localization of the tight junctional proteins, ZO-1 and occludin, but this effect was prevented by EP. Delayed treatment with EP solution instead of RLS ameliorated ileal mucosal hyperpermeability to FD4 and bacterial translocation to mesenteric lymph nodes in mice challenged with lipopolysaccharide (LPS). These data support the view that EP ameliorates cytokine- and/or LPS-induced derangements in intestinal epithelial barrier function.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Alanine Transaminase / metabolism
  • Animals
  • Biological Transport, Active
  • Blotting, Western
  • Caco-2 Cells
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cell Survival / drug effects
  • Chemical and Drug Induced Liver Injury / pathology
  • Dose-Response Relationship, Drug
  • Electrophoresis
  • Endotoxemia / drug therapy*
  • Endotoxemia / pathology*
  • Humans
  • Immunohistochemistry
  • Intestinal Absorption
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Liver / pathology
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type II
  • Pyruvates / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism

Substances

  • Adjuvants, Immunologic
  • NF-kappa B
  • Pyruvates
  • ethyl pyruvate
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Alanine Transaminase