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Published on: March 29, 2017
Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn
Todd W Costantini1, Raul Coimbra, Jessica L Weaver
1From the Department of Surgery (T.W.C., J.L.W., B.P.E.), Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, UC San Diego School of Medicine, San Diego; and Comparative Effectiveness and Clinical Outcomes Research Center (R.C.), Riverside University Health System, Loma Linda University School of Medicine, Riverside, California.
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.
Insights
Targeting the alpha7 nicotinic acetylcholine receptor (α7nAchR) with AR-R17779 significantly reduced gut and lung injury in burn-injured mice. This approach may improve upon nonspecific vagal nerve stimulation for treating severe burns.
Area of Science:
- * Immunology
- * Pharmacology
- * Trauma Research
Background:
- * Systemic inflammatory response (SIRS) significantly contributes to post-injury morbidity and mortality.
- * The alpha7 nicotinic acetylcholine receptor (α7nAchR) on immune cells regulates the vagal anti-inflammatory pathway, crucial for mitigating SIRS.
- * Previous attempts using nonspecific vagal nerve stimulation have yielded underwhelming clinical results.
Purpose of the Study:
- * To investigate if directly targeting the α7nAchR could more precisely stimulate the vagal anti-inflammatory pathway.
- * To assess the efficacy of α7nAchR stimulation in decreasing gut and lung injury following severe burn.
Main Methods:
- * C57BL/6 mice were subjected to a 30% total body surface area steam burn.
- * Mice received intraperitoneal injections of a selective α7nAchR agonist (AR-R17779) 30 minutes postburn.
- * Intestinal and lung permeability, along with activity levels, were measured at various time points.
Main Results:
- * AR-R17779 demonstrated a dose-dependent reduction in burn-induced intestinal permeability (p < 0.001).
- * The agonist effectively prevented a 10-fold increase in lung permeability observed after burn injury (p < 0.01).
- * Treated mice exhibited significantly improved post-injury activity levels.
Conclusions:
- * Direct stimulation of the α7nAchR effectively prevents burn-induced gut and lung injury.
- * Targeting the α7nAchR may represent a more effective strategy than nonspecific vagal agonists for modulating the cholinergic anti-inflammatory response.
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