Rolle der selektiv leukozytären iNOS-Expression bei der Genese der septischen Atonie des Gastrointestinaltraktes
Background: Lipopolysaccharide (LPS) induces massive muscularis inflammation in the small intestine that has been associated with iNOS expression and ileus. Aims: The objective of the study was to provide evidence that iNOS specifically expressed in gastrointestinal muscularis leukocytes plays a major role in the development of endotoxemic smooth muscle dysfunction of the entire gastrointestinal tract. Methods: We constructed iNOS knockout mice (iNOS-/-), that generate iNOS only in their leukocytes by lethal irradiation and reconstitution with reciprocal wildtype (iNOS+/+) bone marrow. iNOS-/- and iNOS+/+ mice served as controls. Three hours after LPS challenge (15 mg/kg), iNOS mRNA was determined in jejunal muscularis extracts by RT-PCR. Histochemical and immunohistochemical analyses were performed on gastrointestinal muscularis whole mounts. In vitro smooth muscle function at 24 h was evaluated in a standard organ bath. Results: LPS significantly increased iNOS mRNA expression in iNOS+/+ and iNOS-/- mice with iNOS+/+ bone marrow, but not in iNOS-/- animals. The expression was similar within the stomach, the small intestine and the colon. iNOS protein was immunohistochemically localized in resident and recruited leukocytes. LPS challenged iNOS+/+ mice exhibited a significant (43 – 53%) suppression of bethanechol stimulated contractions of the circular muscularis in vitro. iNOS-deficient mice presented with a significant improvement of postoperative gastrointestinal smooth muscle contractility, whereas replacement with iNOS+/+ completely prevented this improvement. Conclusion: iNOS, selectively expressed in leukocytes within the entire gastrointestinal muscularis plays a key role in the development of LPS-induced smooth muscle dysfunction and endotoxemic ileus.
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