Cytokine and radical inhibition in septic intestinal barrier failure

Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model.

Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups.

After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon.

Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown.