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Inactivation of inducible nitric oxide synthase protects intestinal pacemaker cells from postoperative damage
Hiroe Yanagida1, Kenton M Sanders, Sean M Ward
1Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Abstract:
Abdominal surgery causes postoperative gastrointestinal dysmotility which can progress to paralytic ileus. Surgery causes inflammatory responses leading to loss of interstitial cells of Cajal (ICC), which generate intestinal pacemaker activity. Here, we demonstrate that a deficiency in or pharmacological inhibition of inducible nitric oxide synthase (iNOS) before surgery protects ICC from postoperative damage. Ileal segments from wild-type, iNOS and cyclooxygenase-2 (COX-2) knockout mice were resected and reconstructions were performed by end-to-end anastomoses. Wild-type animals were exposed to iNOS inhibitors before surgery, and electrical activity and ICC were examined 5 h after surgery. Intestinal surgery on wild-type mice caused a significant reduction in ICC and pacemaking at distances up to 5 cm from the anastomosis site. ICC networks and pacemaking were protected in iNOS(-/-) mice. In animals treated preoperatively with iNOS inhibitors, pacemaker activity was depressed only at the anastomosis site. COX-2 deficiency also muted postoperative disruption in pacemaker activity. Postoperative surgical damage consists of a local response and a more widespread response in which ICC and pacemaker activity are disrupted. Damage to ICC and pacemaking was greatly attenuated in the absence of NO derived from iNOS. Thus, management of iNOS expression or activity prior to intestinal surgery protects against postsurgical dysmotility and reduces the severity of postoperative ileus.
Insights
Preoperative inhibition of inducible nitric oxide synthase (iNOS) protects interstitial cells of Cajal (ICC) from surgical damage. This strategy mitigates postoperative gastrointestinal dysmotility and paralytic ileus.
Area of Science:
- Gastroenterology
- Surgical Research
- Neurogastroenterology
Background:
- Abdominal surgery frequently leads to postoperative gastrointestinal dysmotility and paralytic ileus.
- This is attributed to inflammatory responses that damage interstitial cells of Cajal (ICC), essential for intestinal pacemaker activity.
Purpose of the Study:
- To investigate the protective role of inducible nitric oxide synthase (iNOS) deficiency or inhibition against postsurgical damage to ICC and intestinal pacemaker function.
- To explore the impact of iNOS and cyclooxygenase-2 (COX-2) on the widespread disruption of ICC networks and pacemaking post-surgery.
Main Methods:
- Resection and end-to-end anastomosis of ileal segments in wild-type, iNOS knockout, and COX-2 knockout mice.
- Administration of iNOS inhibitors to wild-type mice prior to surgery.
- Assessment of electrical activity and ICC integrity 5 hours post-surgery.
Main Results:
- Intestinal surgery significantly reduced ICC and pacemaking in wild-type mice up to 5 cm from the anastomosis.
- ICC networks and pacemaking were preserved in iNOS knockout mice.
- Preoperative iNOS inhibition protected pacemaker activity, with depression limited to the anastomosis site. COX-2 deficiency also reduced disruption.
Conclusions:
- Absence or inhibition of nitric oxide (NO) derived from iNOS significantly attenuates damage to ICC and pacemaking post-surgery.
- Preoperative management of iNOS activity is a promising strategy to protect against postsurgical dysmotility and reduce paralytic ileus severity.
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