Neuropeptide Y may mediate psychological stress and enhance TH2 inflammatory response in asthma.

To the Editor: A strong link between psychological stress and asthma onset and exacerbation is well documented. Stress alters the immune response features of asthma, which involve a bias away from cellular (TH1) immunity and toward humoral (TH2) immunity, which is typically manifested by overexpression of TH2 cytokines, such as IL-4, and asthma exacerbations. Although a disruption in neuroendocrine system–immune system communication involving the hypothalamic-pituitary-adrenocortical (HPA) axis is a crucial part of the adverse effects of psychological stress, the precise role of neuroendocrinemediators is not well elucidated. Neuropeptide Y (NPY), a conserved peptide abundantly produced by the central nervous system and peripheral nerves innervating organs, as well as by immune cells, is an endogenous anxiolytic agent and also a potent immunomodulator in asthmatic patients. The data we present here suggest that perceived stress has a persistent precipitating effect in heightening TH2 responses in asthmatic patients, and this effect might be mediated by peripheral blood levels of NPY. This extends previous findings by identifying a plausible neuroendocrine mediator for the influence of perceived stress on the immune-inflammatory profile in asthmatic patients. We recruited young adults (aged 21-35 years) with stable (n 5 51) and acutely exacerbated (n 5 19) chronic asthma and ageand sex-matched healthy control subjects (n 5 69) and collected venous samples during a 4-hour midday period (10 AM2 PM). We used the Perceived Stress Scale (PSS) to measure psychological stress and an index of HPA biological stress response derived from measured levels of adrenocorticotropic hormone (ACTH), noradrenaline, adrenaline, and cortisol in plasma. At a 12-month follow-up point, 63 asthmatic patients were successfully recontacted and provided blood samples. All participants signed written informed consent forms for the study, which was approved by the hospital’s domain-specific review board. Detailed information can be found in the Methods section in this article’s Online Repository at www.jacionline.org. The baseline demographic, clinical, and psychological profiles of study participants are summarized in Table E1 in this article’s Online Repository at www.jacionline.org. We first evaluated differences in the levels of psychological stress, HPA-related biological stress indices, and NPY levels among patients with acute asthma, patients with stable asthma, and healthy control subjects. Although the number of life events did not differ among groups, asthmatic patients, especially those with acute asthma, experienced higher levels of perceived stress than their healthy counterparts, as corroborated by increased levels of ACTH, noradrenaline, and adrenaline and HPA stress index scores and decreased levels of cortisol and NPY, reflecting dysregulated HPA axis responsiveness to chronic stress in asthmatic patients (Table I). Although we could not rule out the possibility that high stress in the emergency medicine department might skew the results, an intimate association between stress and acute asthma exacerbation is frequently reported. Partial correlations between IL-4 levels and psychological and biological stress variables were assessed in the whole sample and the asthma and control groups, controlling for age (see Table E2 in this article’s Online Repository at www.jacionline.org). Although asthmatic patients were included in this study only if they had been free from oral steroid treatment for at least 2 weeks, given that cortisol levels in asthmatic patients might be affected by past steroid treatment (54/70 patients at baseline), the dosage of inhaled corticosteroids was further controlled in the correlation between IL-4 and cortisol levels. We further investigated the association of psychological and biological stress with IL-4 levels and the mediating role of NPY in this association in generalized linear models (Table II). A prior study found that children with asthma who had higher levels of chronic stress showed increased production of IL-4 in response to acute stress. We replicated this finding among the patient groups with nonexacerbated and acutely exacerbated chronic asthma in this study. We further found that perceived stress among asthmatic patients was a significant predictor of IL-4 levels measured concurrently at baseline and 1 year later, controlling for potential confounders, suggesting that perceived stress might have a persistent effect in heightening TH2 inflammatory responses in asthmatic patients. Our data further suggest that the peripheral NPY level is a mediating factor in the association between high perceived stress levels and IL-4 overexpression in asthmatic patients (Sobel test: baseline, z 5 2.134, P < .05; 1 year: z 5 2.134, P < .05). We also explored theHPA stress index as an integratedmeasure of the body’s HPAand sympathetic-adrenomedullary (SAM)-related response to the totality of internal biological stress and its association with IL-4 expression in asthmatic patients. In like manner, the results indicated that increased HPA activity was associated with increased IL-4 levels in asthmatic patients. In keeping with its temporal measurement of acute stress response, the HPA stress index did not predict IL-4 levels at the 1-year follow-up visit. The NPY level did not appear to mediate this relationship (Table II). Our data suggest that NPY concentration is a steady-statemeasure of neuroendocrine activity and consistently and independently predicts a long-lasting TH2-associated hyperimmune and inflammatory response in asthmatic patients. Thus our study showed that NPY levels consistent with a dampened response associated with chronic psychological stress were lower among young patients with chronic asthma, both acutely exacerbated and nonexacerbated asthma, compared with those seen in healthy control subjects. Among asthmatic patients, NPYappeared to play a role in the association between perceived stress and persistently increased IL-4 marker levels of TH2-biased immune and inflammatory profiles. However, the underlying neuroimmunologic mechanisms remain poorly understood. NPY activation of NPY receptor 1 on antigenpresenting cells is essential for T-cell priming, but paradoxically, it acts as a negative regulator for T cells and modulates T-cell hyperresponsiveness, thus suggesting a bimodal role in antigen-presenting cells and T cells in the immune system. Mousemodels of asthma suggest that NPY levels were increased at the late (chronic) stage of the airway inflammatory process and were inversely correlated with IL-4 levels, suggesting an effect in attenuating TH2 cytokine production and release. 9 It is unclear whether the increase in NPY levels is a defensive or compensatory mechanism to modulate the effects of