Changes Of Sympathovagal Balance Induced By Lipopolysaccharide And Its Effect On Systemic Inflammatory Response

Infection associated with systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality in patients with major surgery, polytrauma, and severe bum injury. Some dataes have indicated that activities of sympathetic nerves and vagus nerves showed anti-inflammatory effects respectively. However, little attention has been paid to the effect of maintenance sympathovagal balance on systemic inflammatory response. Considering that sympathovagal balance plays a key role in homeostasis, we hypothesized that systemic inflammatory response was regulated by sympathovagal balance to some extent. Based on current research, the present study was designed to investigate the changes of sympathovagal balance induced by lipopolysaccharide (LPS) and its regulatory effect on systemic inflammatory response through following aspects: 1) To observe the activity of vagal nerve reflex pathway induced by LPS with electrophysiologic analysis; 2) To analysize the influence of total vagal nerve stimulation (VNS) on sympathovagal balance induced by LPS with heart rate varibility (HRV). 3) To examine the effects of VNS on serum TNF α and IL-10 level and expression of liver supressors of cytokoine signaling (SOCS) mRNA in rats; 4) To further explore the mechanism of anti-inflammation mediated by sympathovagal balance, the effect of ACh and NE on TNF α , IL-10 protein and SOCS3 mRNA expression was respectively determined in rat peritoneal macrophage cultures in vivo. The purpose of this study is to elucidate the significance of maintaining sympathovagal balance in SIRS, and to find potential effective anti-inflammatory measures for clinic treatment of SIRS, sepsis and MODS. The main results and conclusions are shown as follows:1. Intravenous injection of LPS enhanced unit discharges of NTS, cervical afferent and efferent vagal nerve fiber discharges in rats, showing that vagual nerve reflex pathway was excited during SIRS, and that periphery inflammatory signals can communicate with central nerve system by a way of vagal nerve discharge. As a stressorLPS is. the results also show that vagal nerve was functioned during stress response.2. Analysis of HRV indicated that LFnm, HFnm and VLF were increased, which means that both the tone of sympathetic nerve and vagal nerve were increased after LPS systemic administration. However, increased value of LF/HF demonstrates that the sympathetic activity was more excitable than that of vagal nerves. Using VNS increased the tone of vagus nerve and decrease sympathetic tone. As a result, the sympathovagal balance was restored to some extent, which implies that VNS acted as a regulator of sympathovagal balance.3. It was fond that VNS suppressed mean aortic pressure (MAP) at lOmin after LPS intravenous injection and elevated depression of MAP at 30min. lh, 2h, 4h and 6h in rats, which means that VNS displaied a dural regulation of MAP. Serum concentration of TNF ci was decreased and IL-10 protein was increased at 4h and 6h after LPS administrated when using VNS, suggesting that VNS regulates the pro- and anti-inflammatory balance. It was SOCS3, not SOCS1 mRNA that was upregulated in liver after VNS induced by LPS. Therefore, the result also showed that the anti-inflammatory effect of VNS involved in cellular JAK/STAT (janus kinase/signal transducers and activators of transcription) signal transduction pathway.4. ACh inhibited TNF a release in rat peritoneal macrophage cultures conditioned by exposure LPS for 4h, but failed to prevent the constitutive release of IL-10. NE not only inhibited TNF a release but also increased IL-10 levels. Administration of ACh decreased the release of IL-10 caused by NE. but TNF a level was unchanged. Both ACh and NE increased the mRNA amounts of SOCS3 detected with real time PCR assay, which means cellular JAK/STAT signal transduction pathway was involved. Coadministration of ACh and NE enhanced the amounts of SOCS3 mRNA expression, however, there was no significant variation as compared with administration of ACh or NE alone. The results suggested that the anti-inflammatory effect of ACh and NE was interacted in immunologic cell, which is the presentation that sympathovagal balance regulates the systemic inflammatory response in vivo.