Stroke-induced activation of the α7 nicotinic receptor increases Pseudomonas aeruginosa lung injury

Infectious complications, predominantly pneumonia, are the most common cause of death in the postacute phase of stroke, although the mechanisms underlying the corresponding immunosuppression are not fully understood. We tested the hypothesis that activation of the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) pathway is important in the stroke-induced increase in lung injury caused by Pseudomonas aeruginosa pneumonia in mice. Prior stroke increased lung vascular permeability caused by P. aeruginosa pneumonia and was associated with decreased lung neutrophil recruitment and bacterial clearance in mice. Pharmacologic inhibition (methyllycaconitine IC50: 0.2-0.6 nM) or genetic deletion of the alpha 7nAChR significantly (P<0.05) attenuates the effect of prior stroke on lung injury and mortality caused by P. aeruginosa pneumonia in mice. Finally, pretreatment with PNU-282987, a pharmacologic activator of the alpha 7nAChR (EC50: 0.2 mu M), significantly (P<0.05) increased lung injury caused by P. aeruginosa pneumonia, significantly (P<0.05) decreased the release of KC, a major neutrophil chemokine, and significantly (P<0.05) decreased intracellular bacterial killing by a mouse alveolar macrophage cell line and primary mouse neutrophils. In summary, the alpha 7 nicotinic cholinergic pathway plays an important role in mediating the systemic immunosuppression observed after stroke and directly contributes to more severe lung damage induced by P. aeruginosa.-Lafargue, M., Xu, L., Carles, M., Serve, E., Anjum, N., Iles, K. E., Xiong, X., Giffard, R., Pittet, J.-F. Stroke-induced activation of the alpha 7 nicotinic receptor increases Pseudomonas aeruginosa lung injury. FASEB J. 26, 2919-2929 (2012). www.fasebj.org