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

Abstract

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 α7 nicotinic acetylcholine receptor (α7nAChR) 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 IC(50): 0.2-0.6 nM) or genetic deletion of the α7nAChR 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 α7nAChR (EC(50): 0.2 μM), 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 α7 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.

• Authors: Mathieu Lafargue, Lijun Xu, Michel Carlès, Emilie Serve, Naseem Anjum, Karen E Iles, Xiaoxing Xiong, Rona Giffard, Jean-François Pittet
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 26 Issue 7 Pg. 2919-29 (Jul 2012) ISSN: 1530-6860 [Electronic] United States
• PMID: 22490926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenergic beta-Antagonists
• Benzamides
• Bridged Bicyclo Compounds
• Chrna7 protein, mouse
• Nicotinic Agonists
• Nicotinic Antagonists
• PNU-282987
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• methyllycaconitine
• Aconitine

Topics

• Aconitine (analogs & derivatives, pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Benzamides (pharmacology)
• Bridged Bicyclo Compounds (pharmacology)
• Cell Line
• Disease Models, Animal
• Immune Tolerance
• Infarction, Middle Cerebral Artery (complications, immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (immunology)
• Nicotinic Agonists (pharmacology)
• Nicotinic Antagonists (pharmacology)
• Pneumonia, Bacterial (etiology, immunology, metabolism)
• Pseudomonas Infections (etiology, immunology, metabolism)
• Pseudomonas aeruginosa (immunology)
• Pulmonary Edema (etiology)
• Receptors, Nicotinic (deficiency, genetics, metabolism)
• Signal Transduction
• alpha7 Nicotinic Acetylcholine Receptor