Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

BACKGROUND: The systemic inflammatory response (SIRS) drives late morbidity and mortality after injury. The α7 nicotinic acetylcholine receptor (α7nAchR) expressed on immune cells regulates the vagal anti-inflammatory pathway that prevents an overwhelming SIRS response to injury. Nonspecific pharmacologic stimulation of the vagus nerve has been evaluated as a potential therapeutic to limit SIRS. Unfortunately, the results of clinical trials have been underwhelming. We hypothesized that directly targeting the α7nAchR would more precisely stimulate the vagal anti-inflammatory pathway on immune cells and decrease gut and lung injury after severe burn. METHODS: C57BL/6 mice underwent 30% total body surface area steam burn. Mice were treated with an intraperitoneal injection of a selective agonist of the α7nAchR (AR-R17779) at 30 minutes postburn. Intestinal permeability to 4 kDa FITC-dextran was measured at multiple time points postinjury. Lung vascular permeability was measured 6 hours after burn injury. Serial behavioral assessments were performed to quantify activity levels. RESULTS: Intestinal permeability peaked at 6 hours postburn. AR-R17779 decreased burn-induced intestinal permeability in a dose-dependent fashion (p < 0.001). There was no difference in gut permeability to 4 kDa FITC-dextran between sham and burn-injured animals treated with 5 mg/kg of AR-R17779. While burn injury increased lung permeability 10-fold, AR-R17779 prevented burn-induced lung permeability with no difference compared with sham (p < 0.01). Postinjury activity levels were significantly improved in burned animals treated with AR-R17779. CONCLUSION: Directly stimulating the α7nAchR prevents burn-induced gut and lung injury. Directly targeting the α7nAChR that mediates the cholinergic anti-inflammatory response may be an improved strategy compared with nonspecific vagal agonists.