Claudia C. dos Santos1,2, Yuexin Shan1,2, Ali Akram1,2, Arthur S. Slutsky1,2 and Jack J. Haitsma1,2 Published ahead of print on September 24, 2010.American Journal of Respiratory and Critical Care Medicine Vol 183. pp. 471-482, (2011)
Rationale: Ventilator-induced lung injury (VILI) contributes to the mortality in patients with acute lung injury by increasing inflammation. Recent evidence suggests that stimulation of the cholinergic antiinflammatory pathway may be an attractive way to attenuate inflammatory injury.

Objectives: To determine the role of vagus nerve signaling in VILI and establish whether stimulation of the vagus reflex can mitigate VILI.

Methods: We performed bilateral vagotomy in a mouse model of high-tidal volume–induced lung injury. We performed pharmacological and electrical vagus nerve stimulation in a rat model of VILI following ischemia/reperfusion injury. To determine the contribution of the alpha 7 acetylcholine nicotinic receptor to pulmonary cell injury, we exposed human bronchial epithelial cells to cyclic stretch in the presence of specific agonist or antagonist of the alpha 7 receptor.

Measurements and Main Results: Vagotomy exacerbates lung injury from VILI in mice as demonstrated by increased wet-to-dry ratio, infiltration of neutrophils, and increased IL-6. Vagal stimulation attenuates lung injury in rats after ischemia/reperfusion injury ventilated with high-volume strategies. Treatment of both mice and rats with the vagus mimetic drug semapimod resulted in decreased lung injury. Vagotomy also increased pulmonary apoptosis, whereas vagus stimulation (electrical and pharmacological) attenuated VILI-induced apoptosis. In vitro studies suggest that vagus-dependent effects on inflammation and apoptosis are mediated via the 7 nicotinc acetylcholine receptor–dependent effects on cyclic stretch–dependent signaling pathways c-jun N-terminal kinase and tumor necrosis factor receptor superfamily, member 6.

Conclusions: Stimulation of the cholinergic antiinflammatory reflex may represent a promising alternative for the treatment of VILI.

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