Effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel of healthy subjects

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Abstract
Increased permeability and increased luminal concentrations of L-lactate have previously been shown in the large bowel in septic patients. To advance these observations, a human model of colorectal barrier failure in sepsis is desirable. Therefore, we assessed the effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel in healthy subjects. Twelve healthy male subjects received intravenous endotoxin (2 ng/kg body weight) or saline in a paired cross-over design. Colorectal permeability was assessed after 3, 6, 9 and 12 h by the systemic recovery of luminally instilled (99m)Tc-diethylenetriaminepentaacetate. Luminal concentrations of L-lactate were assessed by equilibrium dialysis. Mucosal biopsies from the large bowel were sampled after 6 and 12 h, and the apoptotic ratio of the epithelium was assessed by terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end-labelling (TUNEL) assay and the expression of inducible nitric oxide synthase (iNOS) mRNA by reverse transcriptase-polymerase chain reaction. Systemic effects of endotoxaemia were observed, including fever, tachycardia and strongly increased plasma values of tumour necrosis factor-alpha. By contrast, the colorectal permeability, luminal lactate concentrations, mucosal infiltration of inflammatory cells, epithelial apoptotic ratio and expression of iNOS were all unaffected by endotoxin. No effect of a single intravenous dose of endotoxin was observed on markers of large bowel permeability, metabolism and inflammation in healthy subjects. This suggests that this part of the gut is relatively resistant to the systemic inflammation induced by experimental endotoxaemia in humans.