Site- and Cell-Type- Specific Induction of Intestinal Inducible Nitric Oxide Synthase in a Rat Model of Endotoxemia

T.      Takahashi; H.      Fujii; H.      Shimizu; E.      Omori; K.      Uehara; M.      Takeuchi; M.      Matsumi; M.      Yokoyama; R.      Akagi; K.      Morita

doi:10.2174/157340605774598171

Abstract

The intestine is one of the major organs that are involved in sepsis. The inducible isoform of nitric oxide synthase (iNOS) is known to play a critical role in the pathogenesis of septic tissue injury by generating excess amount of nitric oxide (NO) in response to cytokines and endotoxin. In this study, we examined changes in gene expression of iNOS in various regions of the intestine as well as the distribution of iNOS protein in the intestinal cells in a rat model of endotoxemia produced by intraperitoneal injection of lipopolysaccharide (LPS; 10 mg/kg). While iNOS mRNA was undetectable in the intestine of untreated control animals, it underwent marked induction following LPS treatment. Induction of iNOS mRNA in the ileum was marked and biphasic, while it was also marked but monophasic in the jejunum. The induction of iNOS mRNA was maximal in the ileum. The administration of interleukin-6 (IL-6) upregulated intestinal iNOS gene expression specifically in the ileum. Consistent with enhanced iNOS gene expression, iNOS protein was markedly expressed in the ileum after LPS treatment, exclusively in the mucosal epithelium both at crypt and villus cells, although more prominently in the former. These findings suggested that intestinal iNOS expression was upregulated both at transcriptional and protein levels not only in a site-specific, but also in a cell typespecific manner in a rat model of endotoxemia, possibly through increasing serum IL-6 levels. Differential regulation of iNOS expression along the longitudinal and crypt-villus axes of the gut might be a determinant of the pattern of sepsisinduced intestinal damage.

Keywords: inducible nitric oxide synthase, lipopolysaccharide, intestinal injury, interleukin-6, sepsis, nitric oxide, inflammation

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