Background & Aims: Endotoxin elicits an inflammatory response within the intestinal muscularis and causes intestinal muscle dysfunction. Our aims were to investigate intestinal muscle recovery after a single or repeated lipopolysaccharide (LPS) injections. We also investigated the ability of LPS to induce cross-tolerance to postoperative ileus. Methods: Motility was measured in vivo and in vitro by transit and organ-bath techniques. Nuclear factor kappa-B, nuclear factor interleukin 6, and signal transducer and activator of transcription were quantified by using electrophoretic mobility shift assay, and tumor necrosis factor alpha, interleukin 6, inducible nitric oxide synthase, and cyclooxygenase 2 were measured with reverse-transcription polymerase chain reaction. Myeloperoxidase histochemistry for neutrophils was performed in jejunal muscularis whole mounts. Results: Endotoxin-induced suppression of in vitro muscle contractility temporally recovered over 7 days with a similar profile whether after a single dose or during the continuous daily injection of LPS. Functional adaptation to continuous LPS was reflected in a significant blunting of transcription factor activation and cytokine messenger RNA up-regulation compared with the naive LPS-stimulated muscularis. Preconditioning of the muscularis showed significant cross-tolerance to the functional, molecular, and leukocytic sequelae of intestinal manipulation. Conclusions: The muscularis externa recovered and developed tolerance to endotoxin over 7 days, which conferred cross-tolerance to intestinal manipulation. Thus, preconditioning induces protective mechanisms to a subsequent insult within the muscularis externa.
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