Deficiency of alpha7 cholinergic receptors facilitates bacterial clearance in Escherichia coli peritonitis.

BACKGROUND: The efferent vagus nerve can inhibit inflammation via interaction between acetylcholine and alpha7 cholinergic receptors. METHODS: To determine the role played by alpha7 receptors in antibacterial defense, peritonitis was induced in alpha7 receptor-deficient (alpha7(-/-)) and wild-type (WT) mice by intraperitoneal injection with Escherichia coli. RESULTS: At 20 h after infection, virtually all alpha7(-/-) mice had cleared the infection from their peritoneal cavities and had sterile blood cultures, whereas WT mice had high bacterial loads at the primary site of infection and were bacteremic. In addition, bacterial burdens in liver, spleen, kidneys, and lungs were much lower in alpha7(-/-) mice, and these animals displayed a diminished inflammatory response, as reflected by a reduced number of infiltrating neutrophils in peritoneal lavage fluid and lower circulating cytokine levels. At 2 h after infection, however, when bacterial loads were still similar in alpha7(-/-) and WT mice, the former mouse strain showed a more robust influx of neutrophils into the peritoneal cavity. CONCLUSIONS: Deficiency of the alpha7 receptor is associated with an accelerated clearance of E. coli after intraperitoneal infection, preceded by a faster recruitment of neutrophils. These data provide the first evidence for a detrimental role of alpha7 receptors in the host defense against bacteria.

The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice.

BACKGROUND & AIMS: The nervous system, through the vagus nerve, controls inflammation by decreasing the release of tumor necrosis factor-alpha from endotoxin stimulated macrophages. This anti-inflammatory effect is mediated by an interaction of acetylcholine, the principal neurotransmitter of the vagus nerve, with macrophage cholinergic nicotinic receptors expressing the alpha7 subunit. METHODS: To determine the role of this "nicotinic anti-inflammatory pathway" in experimental pancreatitis, we induced pancreatitis in mice by 12 hourly intraperitoneal injections of cerulein. Pancreatitis was preceded by unilateral left cervical vagotomy or pretreatment with the nicotinic receptor antagonist mecamylamine or by pretreatment with the selective alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21). RESULTS: Vagotomy or pretreatment with mecamylamine resulted in an enhanced severity of pancreatitis, as reflected by histology, edema, plasma hydrolases, and interleukin-6 levels. Furthermore, the number of neutrophils migrated to the pancreas was increased in these mice, as shown by myeloperoxidase content and intrapancreatic staining of neutrophils. Conversely, GTS-21 pretreatment strongly decreased the severity of pancreatitis. Pancreatitis-associated pulmonary inflammation was independent of the integrity of the vagus nerve and nicotinic receptors. CONCLUSIONS: This study provides the first evidence for a therapeutic potential of the vagus nerve and the "nicotinic anti-inflammatory pathway" in attenuating inflammation and injury during experimental pancreatitis.

The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis.

BACKGROUND: The nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of tumor necrosis factor- alpha by endotoxin-stimulated macrophages. This anti-inflammatory effect is mediated by an interaction between acetylcholine, the principal neurotransmitter of the vagus nerve, and cholinergic nicotinic acetylcholine receptors on macrophages. METHODS: We determined the role of this "cholinergic anti-inflammatory pathway" during septic peritonitis induced in mice by intraperitoneal injection of live Escherichia coli. Septic peritonitis was preceded by inhibition of the cholinergic anti-inflammatory pathway by unilateral cervical vagotomy, by stimulation of this pathway by pretreatment of mice with nicotine, or by a combination of both interventions. RESULTS: Initial cytokine release during septic peritonitis was enhanced after previous vagotomy and was decreased after nicotine pretreatment, independently of the integrity of the vagus nerve. Further study established that vagotomy before septic peritonitis resulted in an enhanced influx of neutrophils and a marked increase in proinflammatory cytokine levels and liver damage. Conversely, nicotine pretreatment strongly decreased cell influx, proinflammatory cytokine levels, and liver damage, whereas bacterial clearance and survival were impaired. DISCUSSION: These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.