Recent data support the role of efferent, vagus nerve outflow as a regulator of systemic proinflammatory mediator activity during inflammation and infection (42). As an effector arm of the parasympathetic nervous system, vagal activity may regulate inflammation through several mechanisms. Vagus nerve efferent signals have been shown to reduce production of the proinflammatory cytokine TNF-α via acetylcholine binding to the α-7 subunits of nicotinic receptors on mononuclear phagocytes of the reticuloendothelial system (28, 42, 43). Vagotomy has been demonstrated experimentally to enhance proinflammatory cytokine release in a murine model of i.p. sepsis (44). Pharmacologic activation of nicotinic receptors has also been shown to reduce TNF-α release from alveolar macrophages exposed to LPS (45). We have also recently confirmed that antecedent transcutaneous administration of the known α-7 agonist, nicotine, reduced systemic phenotype and proinflammatory mediator responses to endotoxin in humans (37).
Both parasympathetic and sympathetic nervous system activity contribute to protective host responses during systemic inflammation and sepsis. Although parasympathetic activity may exert anti-inflammatory effects through vagally mediated anti-inflammatory pathways (28), sympathetic activity is also of importance in regulating vascular tone during sepsis (46). The influence of both of these systems can be estimated by parameters of HRV (15). Observations in the literature are divided as to whether relative parasympathetic (28) or sympathetic predominance (22) is beneficial during stress. Interestingly in critically ill patients, increased parasympathetic tone and decreased sympathetic tone have been associated with mortality (22), and specific parameters of HRV measuring parasympathetic tone (HF, pNN50) have been identified as independent predictors of mortality (22) and development of septic shock (23). Other measures of the complex interaction between sympathovagal balance and other regulatory systems, such as those reflected in very low frequency variability, have also been suggested to associate with outcome (47).
Previous studies have suggested that relative enhancement of parasympathetic activity assessed by high-frequency power spectral analysis and time domain components of HRV is inversely correlated with ex vivo blood production of the proinflammatory mediators TNF-α and IL-6 (29). To study this correlation in vivo, we measured the parameters of HRV at time point 0 h (immediately before endotoxin exposure) and sought correlates to maximal in vivo TNF-α and IL-6 production. We detected a correlation between parasympathetic/vagal parameters of HRV (HF and pNN50) and maximal TNF-α level but not for IL-6 response after endotoxin exposure. However, our finding is in contrast to what might be anticipated from the results of prior studies which suggest that greater basal parasympathetic/vagal activity would lead to a lesser proinflammatory mediator response via vagally mediated cholinergic anti-inflammatory pathways (28). Several factors may account for this difference, including the younger age of our subjects compared with the generally older subjects evaluated in prior studies. In addition, prior studies used in vitro incubation to assess peak cytokine production, whereas the current study determined peak in vivo responses with a serial sampling protocol. Interestingly enough, gender differences have been observed in ex vivo studies wherein higher TNF-α and IL-6 levels were detected in male subjects (29). This is consistent with prior ex vivo-stimulated blood observations based on gender (48). By contrast, in a previous report, higher IL-6 monocyte expression was observed among females throughout the circadian cycle (49). These results underscore the blurring of lines that separate proinflammatory and anti-inflammatory signaling mechanisms based on discrete sympathetic and parasympathetic components (33).
It remains to be determined what influence the autonomic nervous system exerts over the dynamic processes that result from stress. A previous study measuring the influence of antecedent epinephrine on endotoxin-induced systemic inflammation in healthy subjects suggests that this catecholamine is associated with a modest reduction in vagally mediated HRV (27). This is consistent with previous studies of this α- and β-agonist in humans (50, 51). However, epinephrine excess was associated with decreased TNF-α levels after endotoxin challenge, and this result seems to contrast to an enhanced production that might result from decreased activity of cholinergic anti-inflammatory pathways. This suggests that autonomic signals regulating cytokine release have a more complex interface with the hormonal and nervous systems than previously appreciated (27).
Gender did not significantly influence parameters of HRV after endotoxin exposure. Because the recruitment process for these studies sought to exclude females that might be in a peri-ovulatory phase of the menstrual cycle, only 1 female subject demonstrated an estradiol level more than 100 pg/mL. This precluded a detailed analysis of the influence of increased estrogen on the systemic response after endotoxin administration. Interestingly, during recovery at 6 h after endotoxin, female subjects exhibited a relative decrease in sympathetic activity, as measured by LF/HF ratio, as well as a trend toward increased vagal tone reflected by increased HF and pNN50. These findings may suggest that females may undergo more rapid autonomic recovery after a limited acute systemic stressor. To further analyze gender-related differences in the time to recovery of autonomic balance, we undertook entropy analysis (12) in these subjects. By this analysis, male subjects returned to baseline physiologic complexity at 24 h, whereas female subjects seemed to exhibit greater entropy values than at baseline. The enhanced autonomic recovery in females at 24 h may be influential in modulating the response to subsequent stressors.
This study was specifically limited to subjects younger than 30 years, and hence it is unlikely that age influenced the parameters of HRV. Adiposity did not influence either time domain or frequency domain parameters of HRV after endotoxin exposure. Physical fitness, based on nonexercise oximetric testing (52), has been associated with increased baseline vagal/parasympathetic profile as determined by increased pNN50 and HF after mental stress versus a nonfit cohort (53). In this study, physical fitness, estimated by a resting HR less than 70 beats/min, did not seem to influence parameters of HRV after endotoxin challenge. Other reports suggest that improved fitness increases both time and frequency domain parameters of parasympathetic activity (54). A recent study has confirmed that an extended period of submaximal exercise training is associated with reduced ex vivo TNF-α production in response to endotoxin (55). Further studies are needed to determine how mechanisms of physical fitness-induced autonomic activity might interact with other humoral modulators of innate immunity to derive these potential benefits.
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