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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. GASTROENTEROLOGY 2002;123:586-598

Background & Aims: This study demonstrates a significant role for cyclooxygenase (COX)-2 and prostanoid production as mechanisms for surgically induced postoperative ileus. Methods: Rats, COX-2 +/+ , and COX-2 −/− mice underwent simple intestinal manipulation. Reverse-transcription polymerase chain reaction and immunohistochemistry were used to detect and localize COX-2 expression. Prostaglandin levels were measured from serum, peritoneal lavage fluid, and muscularis culture media. Jejunal circular muscle contractions were measured in an organ bath, and gastrointestinal transit was measured in vivo. Results: The data show that intestinal manipulation induces COX-2 messenger RNA and protein within resident muscularis macrophages, a discrete subpopulation of myenteric neurons and recruited monocytes. The manipulation-induced increase in COX-2 expression resulted in significantly elevated prostaglandin levels within the circulation and peritoneal cavity. The source of these prostanoids could be directly attributed to their release from the inflamed muscularis externa. As a consequence of the molecular up-regulation of COX-2, we observed a decrease in in vitro jejunal circular muscle contractility and gastrointestinal transit, both of which could be alleviated pharmacologically with selective COX-2 inhibition. These studies were corroborated with the use of COX-2 −/− mice. Conclusions: Prostaglandins, through the induction of COX-2, are major participants in rodent postoperative ileus induced by intestinal manipulation. GASTROENTEROLOGY 2001;121:1354-1371

Background & aims: Small bowel manipulation initiates an intense molecular and cellular inflammatory response within the jejunal muscularis, which causes ileus. The current objective was to investigate pan-enteric inflammatory molecular and functional motility alterations of the muscularis from the unmanipulated stomach and colon initiated by selective jejunal manipulation. Methods: Rat jejunum was manipulated, and animals sacrificed between 0–24 hours. In vivo gastric emptying, gastrointestinal transit, and in vitro colonic circular muscle recordings were measured. Reverse-transcriptase polymerase chain reaction (RT-PCR) and electromobility shift assay (EMSA) of gastric, jejunal, and colonic muscularis extracts were performed. Whole mounts were histochemically stained for myeloperoxidase leukocytes. Results: Surgical manipulation suppressed jejunal contractions that were significantly prevented by dexamethasone pretreatment. Selective jejunal manipulation also suppressed in vivo gastric emptying, gastrointestinal transit, and in vitro colonic circular muscle contractility. Nuclear factor interleukin-6 (NF-IL-6) was activated within the gastric and colonic muscularis. RT-PCR showed a 14.9-, 8.1-, and 11.4-fold up-regulation of IL-6 messenger RNA within the jejunal, gastric, and colonic muscularis, respectively. EMSA showed a 30.6-, 14.2-, and 20.8-fold increased activation of signal transducer and activator of transcription (STAT) proteins in jejunal, gastric, and colonic muscularis extracts, respectively. Tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase showed a significant up-regulation in the manipulated jejunum, as well as the unmanipulated gastric and colonic muscularis. Neutrophils were significantly recruited into all gastrointestinal regions. Conclusion: Selective small bowel manipulation leads to a molecular, cellular, and functional pan-enteric "field effect" phenomenon in the unmanipulated gastric and colonic muscularis.

We and others have shown that a single injection of LPS or IM alone triggers an acute molecular and cellular inflammatory response within the intestinal muscularis which results in ileus. We also have shown in unpublished data, that LPS potentiates the inhibitory effects of intestinal manipulation on the small intestine. It is known, that LPS induces adaptational processes. The objective of this study was to investigate the effect of molecular preconditioning of the intestine by continous LPS administration and its potential cross-adaptation towards other insults.