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Colitis reduces short-circuit current response to inflammatory mediators in rat colonic mucosa
J F Kachur1, A Keshavarzian, R Sundaresan
1Immunoinflammatory Diseases Research, Searle Research and Development, Skokie, Illinois 60088, USA.
Abstract:
Inflammatory mediators may contribute to the diarrhea associated with colitis. Although the secretory action of such mediators is reported in normal tissue, there is little information regarding their effects on inflamed tissue. We examined the short-circuit current response (Isc) to these mediators, in mitomycin-C (MC)-induced colitis, a model with histological similarities to colitis in man. Rats were injected once with MC (3.25 mg/kg, intraperitoneally) or vehicle. The colons were removed three and seven days later and mounted, devoid of muscularis, in Ussing chambers for measurement of Isc, potential difference (PD), and resistance (Rt). MC-treated rats had diarrhea after three days, and microscopic studies revealed colonic inflammation. There were no significant differences in Rt, PD, and Isc between control and MC-treated tissues at three and seven days. Maximal increases in Isc to bradykinin, prostaglandin E1, carbachol, substance P, and serotonin were depressed at three and/or seven days after MC. The Isc response to theophylline was not affected. Theophylline activates secretion through an intracellular mechanism; the other agonists act by interaction with epithelial cell membranes. Therefore, the mechanism for the decreased Isc may result from uncoupling of receptors to second-messenger systems or desensitization of receptor-linked secretory mechanisms.
Insights
Inflammatory mediators do not alter baseline colonic function in a colitis model. However, their ability to stimulate short-circuit current (Isc) is significantly reduced in inflamed tissue.
Area of Science:
- Gastroenterology
- Inflammation Research
- Cellular Physiology
Background:
- Inflammatory mediators are implicated in colitis-associated diarrhea.
- Limited data exist on mediator effects on inflamed colonic tissue.
Purpose of the Study:
- To investigate the impact of inflammatory mediators on colonic secretory responses in a rat model of colitis.
- To explore potential mechanisms underlying altered responses in inflamed tissue.
Main Methods:
- Mitomycin-C (MC) induced colitis in rats.
- Ex vivo Ussing chamber experiments to measure short-circuit current (Isc), potential difference (PD), and resistance (Rt).
- Assessment of responses to bradykinin, prostaglandin E1, carbachol, substance P, serotonin, and theophylline.
Main Results:
- MC-induced colitis caused diarrhea and microscopic inflammation.
- No significant differences in baseline Rt, PD, or Isc between control and MC-treated rats.
- Maximal Isc responses to bradykinin, prostaglandin E1, carbachol, substance P, and serotonin were significantly blunted in MC-treated rats.
- The Isc response to theophylline remained unaffected.
Conclusions:
- Colonic inflammation in this model does not alter baseline ion transport but impairs secretory responses to specific inflammatory mediators.
- The findings suggest a potential uncoupling of receptors from second-messenger systems or desensitization of receptor-linked secretory pathways.
- Theophylline's preserved response indicates that intracellular secretory mechanisms may remain intact.