Reactive Enteric Glial Cells Participate in Paralytic Ileus by Damaging Nitrergic Neurons During Endotoxemia
Abstract BackgroundParalytic ileus is common in patients with septic shock, which may cause high morbidity and mortality. Enteric neurons and enteric glial cells (EGCs) participate in the regulation of intestinal motility, but little is known about their role. We aimed to prove whether reactive EGCs have harmful effects on enteric neurons during endotoxemia and lead to intestinal motility disorder in mice. MethodsIn this study, lipopolysaccharide (LPS) was used to induce endotoxemia in mice, and intraperitoneal injections of fluorocitrate (FC) twice per day (9 AM and 6 PM) for 7 days before LPS injections to prevent the activation of EGCs. The effects of reactive EGCs on intestinal motility were analyzed by motility assays in vivo and colonic migrating motor complexes (CMMCs) in vitro. The changes of enteric neurons were evaluated by immunofluorescent staining HuCD, nNOS, CHAT, and TUNEL.ResultsThe expression of glial fibrillary acidic protein (GFAP) was significantly upregulated in LPS-injected animals, indicating EGCs were transformed into a reactive state. The administration of FC could significantly prevent it. Meanwhile, inhibition of reactive EGCs can improve intestinal motility and peristaltic reflex. The density of the general neuronal population (HuC/D-immunoreactive) in the colonic myenteric plexus was significantly increased after suppressing reactive EGCs. The population of nNOS neurons was increased significantly, but there was no significant difference in the number of ChAT neurons. Furthermore, the apoptotic rate of enteric neurons significantly increased, when incubated with the conditional medium of reactive EGCs in vitro. At the same time, the dendritic complexity and the number of primary neuritis neurons were significantly reduced.ConclusionReactive enteric glial cells participated in paralytic ileus by damaging nitrergic neurons during endotoxemia. It may provide a novel therapeutic strategy for intestinal motility disorders during endotoxemia or sepsis.