Stimulation of the Efferent Vagus Nerve Mitigates Acute Lung Injury and Ventilator Induced Lung Injury

Abstract

RationaleVentilator induced lung injury (VILI) significantly contributes to the mortality in patients with acute respiratory distress syndrome.ObjectivesTo determine the role of vagus nerve signaling in VILI.MethodsTo determine whether vagus signaling plays a role in VILI we first demonstrated that disruption of the CAP reflex by bilateral vagotomy results in worsening lung injury in a mouse model of high‐volume‐induced lung injury. In a clinically relevant model of injurious mechanical ventilation following lung injury induced by hemorrhagic shock/resuscitation we then tested the hypothesis that electrical and pharmacological stimulation of the vagus nerve can attenuate lung injury in rats.ResultsVagotomy exacerbates lung injury from high volume ventilation in mice as demonstrated by increased wet‐to‐dry ratio, infiltration of neutrophils in bronchoalveolar lavage fluid and lung tissues, and increased tissue levels of interleukin‐6. Vagotomy exacerbated while vagus stimulation attenuates lung injury in rats after ischemia reperfusion injury ventilated with either high or low volume strategies. Treatment of both mice and rats with the vagus mimetic drug, semapimod, resulted in decreased lung injury. Vagotomy also increased pulmonary apoptosis whilst vagus stimulation attenuated VILI‐induced apoptosis. In‐vitro studies suggest that vagus‐dependent effects on inflammation and apoptosis are mediated via the alpha 7 subunit of the acetylcholine nicotinic receptor effect on cyclic stretch‐dependent singling pathways c‐jun N‐terminal kinase (JNK) and Fas (TNF receptor superfamily, member 6).ConclusionStimulation of the cholinergic anti‐inflammatory reflex may represent a promising alternative for the treatment of VILI.