title: Electrical vagus nerve stimulation attenuates systemic inflammation and improves survival in a rat heatstroke model.
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.
authors: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. k.yamakawa0911@gmail.com
authors: Kazuma
authors: K
authors: Yamakawa
authors: Naoya
authors: N
authors: Matsumoto
authors: Yukio
authors: Y
authors: Imamura
authors: Takashi
authors: T
authors: Muroya
authors: Tomoki
authors: T
authors: Yamada
authors: Junichiro
authors: J
authors: Nakagawa
authors: Junya
authors: J
authors: Shimazaki
authors: Hiroshi
authors: H
authors: Ogura
authors: Yasuyuki
authors: Y
authors: Kuwagata
authors: Takeshi
authors: T
authors: Shimazu
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy / Q000379:methods*; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D018883:Heat Stroke / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018869:Heat-Shock Response; D007249:Inflammation / Q000150:complications; D008168:Lung / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D014630:Vagus Nerve; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D039481:CD11b Antigen; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor