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2001 Abstract: 1811 Effects of Molecular and Functional Intestinal Adaptation to Chronic LPS Administration

2001 Digestive Disease Week

# 1811 Effects of Molecular and Functional Intestinal Adaptation to Chronic LPS Administration
Nicolas T. Schwarz, Joerg C. Kalff, Britta M Engel, Tulu R. Sarkar, Timothy R. Billiar, Anthony J. Bauer, Pittsburgh, PA, Bonn, Germany

Introduction: We and others have shown that a single injection of LPS or intestinal manipulation (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 We also have shown in unpublished data, that LPS potentiates the inhibitory effects of intestinal manipulation on the small intestine.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.

Methods: SD rats were treated daily with an i.p. injection of LPS (1 or 12.5 mg/kg) for 1 or 7 consecutive days (N=4, p<0.05). Gentle IM was performed 24 hrs after the last LPS administration. Jejunal circular muscle strips were functionally evaluated using organ bath recordings 24 hrs after intestinal manipulation. MPO staining was assessed to measure the neutrophil recruitment into the muscularis. RT-PCR and electrophoretic mobility shift assays (EMSA) were performed on isolated jejunal muscularis extracts.

Results: EMSA for NF-kB, NFIL-6 and STAT3 showed a 3.2 -, 3.8- and 8.6 fold increase in activation in the jejunal muscularis 3 hrs after IM compared to controls. This transcriptional response demonstrated significant adaptation when doing the manipulation with the 7th consecutive administration with only a 3.1-, 4.0- and 3.0- fold activation of NF-kB, NF-IL-6 and STAT3 three hrs after manipulation following the 7th LPS injection. RT-PCR showed an acute significant 6.0-fold upregulation in IL-6 mRNA within the muscularis 3 hrs after IM, which was significantly increased after single LPS administration but adapted to a 3.8-fold increase at IM after 7 days of LPS pretreatment. Similar quantitative observations were also made for TNF-a and iNOS. Functionally, IM caused a significant suppression of in vitro contractility (24 hrs after IM = 0.53± 0.047 vs. Control = 1.26± 0.07 g/mm2 /sec at 300µM bethanechol). However, chronically LPS injected animals had contractile responses similar to control (1.28± 0.02 g/mm2 /sec, at 300µM bethanechol). IM following this LPS preconditioning didn't affect the bethanechol stimulated response compared to controls (1.02± 0.08 g/mm2 /sec, at 300µM bethanechol)

Conclusion: We conclude that significant intestinal adaptation occurs in response to chronic LPS through a down-regulation in the inflammatory milieu and a significant recovery in in vitro muscle contractility.

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