Cholinergic Pathways, the Immune System and Arthritis
In contrast to the case with systemic inflammation, there is good evidence for the involvement of the vagus in modulating inflammation of the gut and abdominal viscera. For example, prior sectioning of the left cervical vagus has been shown to enhance the blood levels of inflammatory cytokines measured in mice 6 hours after the induction of septic peritonitis. Unilateral vagotomy also worsens the severity of cerulean-induced pancreatitis and raises the levels of the associated circulating pro-inflammatory cytokines over a time course of days. These and related findings on the vagal modulation of intestinal inflammation are ably reviewed elsewhere.
In keeping with the idea that there is some abdominal 'local sign' in the vagal anti-inflammatory influence, mild inflammation was detected in the lungs of the same mice that were given pancreatitis, yet the lung inflammation was unaffected by vagotomy. Furthermore, in experiments where the lungs of rats were directly inflamed by exposure to diesel soot, vagotomy was actually found to reduce the lung inflammatory response, suggesting a vagal pro-inflammatory action in this tissue. This pro-inflammatory action was blocked by atropine.
What remains unclear from these findings, however, is whether the protective actions of the vagus are mediated by parasympathetic efferent fibres (as in Figure 1) - that is, the 'cholinergic anti-inflammatory pathway' - or by vagal afferent fibres (or perhaps both). Some 80 to 90% of the nerve fibres that run in each vagus are not parasympathetic but are visceral afferents. Critically, these are generally not cholinergic. They can have anti-inflammatory actions, as shown by the following examples. In animals given colitis (usually induced experimentally by trinitrobenzenesulfonic acid), vagotomy worsens the severity of the disease. Selective destruction of vagal afferents with capsaicin treatment (which blocks traffic in a subset of afferent fibres while sparing autonomic efferents) also worsens disease severity and increases mortality, suggesting that vagal afferents normally have an anti-inflammatory action. In rats subjected to haemorrhagic shock or acute haemolysis, Luyer and colleagues have demonstrated a dramatic protective effect of a high-fat diet. In haemorrhagic shock, the levels of pro-inflammatory cytokines, such as TNF and interleukin-6, were dramatically lower in the fat-fed animals and their intestinal barrier integrity was preserved. This protection disappeared if the vagi were cut or the animals were given antagonists to cholecystokinin, which is released by lipid in the intestine and stimulates vagal afferents. A high-fat diet was also found to reduce the damaging effect of haemolysed blood on kidney, liver and intestinal function. This protection also depended on the vagi and cholecystokinin receptors, indicating that a reflex mediated by vagal afferent fibres was responsible. In all these cases the protective effects of vagal afferents were blocked by systemic administration of nicotinic antagonists such as chlorisondamine or hexamethonium. These data indicate that the efferent pathway of the protective reflex triggered by vagal afferents is probably autonomic, but do not distinguish whether it is sympathetic or parasympathetic.
In summary, in contrast to the case in acute systemic inflammation, the vagi mediate an inhibitory action on abdominal inflammation. It is unclear, however, whether any of this protective action is mediated by vagal efferent fibres of the 'cholinergic anti-inflammatory pathway'. There is strong evidence that vagal afferent fibres are involved, but there is no evidence yet proving that the reflex motor pathway is vagal rather than sympathetic. Indeed in the case of another reflex response to abdominal inflammation - gastroparesis following intestinal manipulation - it has been shown that the afferent pathway is vagal but the efferent pathway is sympathetic.
Where Vagotomy Does Affect Inflammation
In contrast to the case with systemic inflammation, there is good evidence for the involvement of the vagus in modulating inflammation of the gut and abdominal viscera. For example, prior sectioning of the left cervical vagus has been shown to enhance the blood levels of inflammatory cytokines measured in mice 6 hours after the induction of septic peritonitis. Unilateral vagotomy also worsens the severity of cerulean-induced pancreatitis and raises the levels of the associated circulating pro-inflammatory cytokines over a time course of days. These and related findings on the vagal modulation of intestinal inflammation are ably reviewed elsewhere.
In keeping with the idea that there is some abdominal 'local sign' in the vagal anti-inflammatory influence, mild inflammation was detected in the lungs of the same mice that were given pancreatitis, yet the lung inflammation was unaffected by vagotomy. Furthermore, in experiments where the lungs of rats were directly inflamed by exposure to diesel soot, vagotomy was actually found to reduce the lung inflammatory response, suggesting a vagal pro-inflammatory action in this tissue. This pro-inflammatory action was blocked by atropine.
What remains unclear from these findings, however, is whether the protective actions of the vagus are mediated by parasympathetic efferent fibres (as in Figure 1) - that is, the 'cholinergic anti-inflammatory pathway' - or by vagal afferent fibres (or perhaps both). Some 80 to 90% of the nerve fibres that run in each vagus are not parasympathetic but are visceral afferents. Critically, these are generally not cholinergic. They can have anti-inflammatory actions, as shown by the following examples. In animals given colitis (usually induced experimentally by trinitrobenzenesulfonic acid), vagotomy worsens the severity of the disease. Selective destruction of vagal afferents with capsaicin treatment (which blocks traffic in a subset of afferent fibres while sparing autonomic efferents) also worsens disease severity and increases mortality, suggesting that vagal afferents normally have an anti-inflammatory action. In rats subjected to haemorrhagic shock or acute haemolysis, Luyer and colleagues have demonstrated a dramatic protective effect of a high-fat diet. In haemorrhagic shock, the levels of pro-inflammatory cytokines, such as TNF and interleukin-6, were dramatically lower in the fat-fed animals and their intestinal barrier integrity was preserved. This protection disappeared if the vagi were cut or the animals were given antagonists to cholecystokinin, which is released by lipid in the intestine and stimulates vagal afferents. A high-fat diet was also found to reduce the damaging effect of haemolysed blood on kidney, liver and intestinal function. This protection also depended on the vagi and cholecystokinin receptors, indicating that a reflex mediated by vagal afferent fibres was responsible. In all these cases the protective effects of vagal afferents were blocked by systemic administration of nicotinic antagonists such as chlorisondamine or hexamethonium. These data indicate that the efferent pathway of the protective reflex triggered by vagal afferents is probably autonomic, but do not distinguish whether it is sympathetic or parasympathetic.
In summary, in contrast to the case in acute systemic inflammation, the vagi mediate an inhibitory action on abdominal inflammation. It is unclear, however, whether any of this protective action is mediated by vagal efferent fibres of the 'cholinergic anti-inflammatory pathway'. There is strong evidence that vagal afferent fibres are involved, but there is no evidence yet proving that the reflex motor pathway is vagal rather than sympathetic. Indeed in the case of another reflex response to abdominal inflammation - gastroparesis following intestinal manipulation - it has been shown that the afferent pathway is vagal but the efferent pathway is sympathetic.