S. Langness1, B. P. Eliceiri1, V. Bansal1, R. Coimbra1, T. W. Costantini1 1University Of California – San Diego,Division Of Trauma, Surgical Critical Care, Burns, And Acute Care Surgery,San Diego, CA, USA
Introduction: Acute lung injury is a frequent complication of severe burns and is responsible for approximately 10-15% of burn-related deaths. Acute lung injury occurs as a result of an unrestrained immune response after injury and is understood to be initiated by gut barrier failure and gut inflammation. We have previously shown that vagus nerve signaling (VNS) limits burn-induced acute lung injury through its ability to prevent gut barrier failure. While the alpha-7 nicotinic acetylcholine receptor (alpha-7 nAChR) is required to mediate the systemic anti-inflammatory effects of VNS in the spleen, the role of the alpha-7 nAChR in limiting acute lung injury via the gut-lung axis is unknown. We hypothesized that the alpha-7 nAChR is required for vagal-mediated lung protection, where the anti-inflammatory effects of VNS would be lost in alpha-7 nAChR KO mice.
Methods: Male alpha-7 nAChR knock-out (KO) and matched control C57BL/6 wild-type (WT) mice were subjected to 30% total body surface area cutaneous burn. A separate cohort of WT and KO animals was treated with cervical VNS following injury. Changes in gut architecture were characterized using histology. Lung injury was evaluated by histology and by measuring changes in inflammatory cell infiltration using florescence-labeled antibodies to myeloperoxidase (MPO) and CD68, surrogate markers for neutrophils and macrophages, respectively.
Results: Severe burn caused histologic gut and lung injury in both alpha-7 nAchR WT and KO mice. Burn-induced lung injury was characterized by increased staining for MPO and CD68 compared to sham. VNS prevented burn-induced gut barrier injury and lung inflammation in alpha-7 nAchR WT mice. The protective effects of VNS on gut barrier failure after injury were lost in alpha-7 nAchR KO mice. VNS also failed to prevent acute lung injury in burn-injured alpha-7 nAchR KO mice, with lung histology similar to alpha-7 nAchR WT and KO mice exposed to burn alone. The ability of VNS to attenuate the mobilization of inflammatory cells to the lung after burn injury was also lost in alpha-7 nAchR KO mice, with MPO and CD68 staining intensity comparable to burn.
Conclusion: The alpha-7 nAChR is required for vagal-mediated protection against burn-induced acute lung injury. Therapies that alter the inflammatory response after injury by either enhancing vagal activity or activating the alpha-7 nAChR may limit acute lung injury and improve outcomes in severely burned patients.