Abstract
This study was performed to gain insights into novel therapeutic approaches for the treatment of heatstroke. The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation (VNS) reportedly suppresses pro-inflammatory cytokine release in several models of inflammatory disease. Here, we evaluated whether electrical VNS attenuates severe heatstroke, which induces a systemic inflammatory response. Anesthetized rats were subjected to heat stress (41.5°C for 30 minutes) with/without electrical VNS. In the VNS-treated group, the cervical vagus nerve was stimulated with constant voltage (10 V, 2 ms, 5 Hz) for 20 minutes immediately after completion of heat stress. Sham-operated animals underwent the same procedure without stimulation under a normothermic condition. Seven-day mortality improved significantly in the VNS-treated group versus control group. Electrical VNS significantly suppressed induction of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in the serum 6 hours after heat stress. Simultaneously, the increase of soluble thrombomodulin and E-selectin following heat stress was also suppressed by VNS treatment, suggesting its protective effect on endothelium. Immunohistochemical analysis using tissue preparations obtained 6 hours after heat stress revealed that VNS treatment attenuated infiltration of inflammatory (CD11b-positive) cells in lung and spleen. Interestingly, most cells with increased CD11b positivity in response to heat stress did not express α7 nicotinic acetylcholine receptor in the spleen. These data indicate that electrical VNS modulated cholinergic anti-inflammatory pathway abnormalities induced by heat stress, and this protective effect was associated with improved mortality. These findings may provide a novel therapeutic strategy to combat severe heatstroke in the critical care setting.
Highlights
During the summer season, heat waves are responsible for a large number of deaths in various parts of the world
Electrical vagus nerve stimulation (VNS) significantly decreased the induction of serum tumor necrosis factor (TNF)-a level at 6 hours after heat stress (p,0.05) (Figure 3A)
We demonstrated for the first time, to our knowledge, that cholinergic activation by electrical VNS attenuated heat stress-related systemic inflammation, resulting in an increased survival rate in a rat model of heatstroke
Summary
Heat waves are responsible for a large number of deaths in various parts of the world. In Japan, there is a growing concern in regard to prevention and treatment of heatstroke because of restrictions placed on power consumption in the aftermath of the Fukushima nuclear disaster, which followed the Great East Japan Earthquake on March 11, 2011 [1]. Heatstroke is a life-threatening disease characterized by hyperthermia associated with a systemic inflammatory response leading to multiple organ dysfunction or failure, including hemorrhage and necrosis in the brain, lungs, heart, gastrointestinal tract, liver, and kidneys [2,3]. Various strategies for the treatment of heatstroke-induced inflammation have been used clinically over the past several decades, the clinical efficacy of therapeutic interventions has been limited. Mortality rate in heatstroke patients over the last 50 years has remained in the 10% to 50% range [4]. A novel therapeutic strategy other than supportive care is required to improve patient outcome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
