Sepsis is a leading cause of death in patients with critical illness. However, there is no effective therapy available. Recent studies have suggested that ventilation with 100% oxygen (Oxy) can improve the survival rate and organ function in several shock models. However, a lot of work is necessary to be done before its clinical application, and its detailed mechanism remains to be clarified. In the present study, we showed that 100% Oxy inhalation for 2 or 3 h starting at 4 and 12 h after zymosan (ZY) injection, respectively, prevented the abnormal changes of serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate from 10% to 60% to 80% in mice. However, 100% Oxy inhalation for 1 or 4 h starting at the same time points has little preventive effects. We also showed that twice 100% Oxy inhalation for 2 or 3 h attenuated the increase of inflammatory cytokines and precluded the downregulation of antioxidant enzymatic activities. We further showed that the therapeutic time window of Oxy treatment against sterile sepsis was less than 12 h after ZY injection. We conclude that 100% Oxy inhalation for 2 or 3 h starting 4 and 12 h after ZY injection, respectively, protects against ZY-induced sterile sepsis via regulating inflammatory cytokines and antioxidant system in mice. The present results may provide a potential cue for developing more effective therapeutic strategies for patients with sepsis.
Sepsis/multiple organ dysfunction syndrome (MODS) is a major cause of high mortality in the intensive care unit. We have recently reported that 100% oxygen treatment is beneficial to mice with zymosan-induced sterile inflammation by increasing antioxidant enzymatic activities. Yet, the use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. It is believed that systemic inflammation and overproduction of reactive oxygen species (ROS) contribute to the mechanism underlying sepsis/MODS. A ROS scavenger has been proven to protect against sepsis/MODS in some animal models. Therefore, we hypothesized that ROS scavenger pretreatment might enhance the protective action of 100% oxygen treatment against zymosan-induced sterile inflammation in mice. In the present study, we showed that 100% oxygen treatment prevented the abnormal changes in serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate in zymosan-stimulated mice, indicating that 100% oxygen treatment had a protective action on sterile inflammation. We found that pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea) abolished this protective action of 100% oxygen treatment. We also showed that 100% oxygen treatment decreased the levels of serum proinflammatory cytokines (TNF-alpha, IL-6, and high-mobility group box 1), increased the level of serum anti-inflammatory cytokine (IL-10), and upregulated the activities of serum and tissue antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in zymosan-stimulated mice, which were reversed by the pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea). We thus conclude that ROS scavenger pretreatment partly abolishes the protective effects of 100% oxygen treatment on sterile inflammation in mice by regulating inflammatory cytokines as well as antioxidant enzymes.
BackgroundAcute lung injury (ALI) is a common complication after THS/R, and vagus nerve stimulation (VNS) could alleviate lung injury by activating cholinergic anti-inflammatory pathway (CAP) during traumatic hemorrhagic shock/resuscitation (THS/R). The purpose of this study was to explore the effects of VNS on intestinal epithelial glycocalyx and acute lung injury associated with THS/R.MethodsSprague-Dawley rats were subjected to traumatic hemorrhagic shock/ resuscitation to induce ALI. The measurements of intestinal barrier permeability, intestinal epithelial glycocalyx, and the level of inflammation factors and histology of lung and gut tissue were made in each group.ResultsThe level of TNF-α,IL-6 and MPO in lung and gut tissue were significantly decreased in the VNS-treated group. In addition, the shedding of intestinal epithelial glycocalyx and increased gut barrier permeability were alleviated in the VNS-treated group, and the gut tissue and lung tissue injury were mitigated in the VNS-treated group. However, pretreated with methyllycaconitine could reverse the protective effect of VNS.ConclusionsVNS could relieve lung injury associated with THS/R by alleviating the damage of intestinal epithelial glycocalyx, which might be achieved by activating CAP.
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