Nuclear factor-kappa B (NF-kappa B) regulates nitric oxide (NO) induced intestinal inflammation and stasis following hemorrhagic shock

Background: In hemorrhagic shock (HS) increased cytokine production contrib utes to gut inflammation and impairment of smooth muscle function through t he recruitment of PMN. NO-mediated activation of NF-kappa B can result in t he induction of cytokines that contain NF-kappa B bindings sites. Experimen ts were performed to determine the contribution of induced NO to gut inflam mation and dysmotility in HS. Materials and Methods: Sprague-Dawley rats were subjected to severe HS (40 mmHg MAP for 2.5 hours) followed by resuscitation and sacrifice at 4 hours. The selective iNOS inhibitor L-NIL (50 mg/kg body weight) was administered intravenously during the decompensation phase. We determined IL-6 mRNA lev els using RT-PCR and activation of NF-kappa B and Stat3 using EMSA gel shif t. Jejunal damage was assessed using histology, PMN infiltration, and smoot h muscle contractility. Results: In this study we demonstrate an attenuated inflammatory response i n the jejunum of animals subjected to severe HS and treated with L-NIL. L-N IL-treated animals demonstrated significant reduction in IL-6 mRNA expressi on (57%), reduction in NF-kappa B (57%) and Stat3 activity (38%), reduction in PMN infiltration (58%) and attenuated organ damage. Furthermore, muscle contractility was almost completely restored. Conclusions: We propose that early upregulation of iNOS contributes signifi cantly to the activation of NF-kappa B resulting in proinflammatory cytokin e production in the gut wall ultimately leading to PMN recruitment and impa ired motility. Thus, reducing induced NO bioavailability following severe H S may improve gut function through downmodulation of NF-kappa B.