The Involvement of Glucocorticoids in Psychological Stress-Induced Exacerbations of Experimental Allergic Asthma

Abstract

Background: Psychological stress is associated with the aggravation of asthma symptoms. Glucocorticoids (GC), which are stress hormones released upon exposure to stress, have the potential to shift immune responses towards a predominant Th2 response by priming antigen-presenting cells to produce lower levels of IL-12 as well as reducing the development of regulatory T cells. However, the involvement of GC in psychological stress-induced exacerbations of allergic asthma has not yet been clarified. Methods: Sensitized mice were exposed to restraint stress followed by forced swimming stress, during which a GC receptor antagonist or a GC synthesis inhibitor was administered, and then antigen was inhaled. Corticosterone levels in the blood were measured in stressed and nonstressed mice. After antigen inhalation, the airway responses to aerosolized methacholine, epithelial mucus secretion and airway inflammation were evaluated, and the IL-13 contents in bronchoalveolar lavage fluid were measured. Results: The exposure to stress significantly increased corticosterone levels. Allergic airway responses and the increase of IL-13 contents evoked by antigen inhalation were significantly higher in stressed mice than in nonstressed mice. The administration of a GC receptor antagonist and a GC synthesis inhibitor during stress exposure significantly reduced the exacerbation of the airway responses and the increase of IL-13 contents in stressed mice challenged with antigen. Conclusions: These results indicate that the increased release of GC upon exposure to stress has a priming effect on the aggravation of allergic airway responses following the exposure, suggesting a pathophysiological role for the neuroendocrine axis in linking psychological stress to asthma exacerbations.

Psychological Stress and Asthma: A New Enemy Within

“…This early decrease in corticosteroid response in the females may have accounted for their increased susceptibility to disease. A similar mechanism may be active in the case of stress and asthma, but this was not investigated in the study by Okuyama et al [6] . The sex of the animals used may also explain, at least in part, the difference in the results between their study and that of Forsythe et al [8] .…”

“…Identification of the exact mechanisms linking psychological stress to asthma development and/ or exacerbations requires better and more comprehensive animal models. One such model, building on previous knowledge regarding the interactions between stress and asthma appeared in a recent issue of International Archives of Allergy and Immunology [6] .…”

“…A previous study on stress and asthma showed that social disruption stress induces a decreased responsiveness of spleen cells to corticosteroids and at the same time decreased GR expression in the lungs [7] . The study by Okuyama et al [6] used a more crude method of identifying responsiveness to glucocorticoids which may not have been as sensitive for detecting a minor decrease in responsiveness. The model used was similar to that of the study by Forsythe et al [8] ; the results differ, however, in that the current study suggests that endogenous glucocorticoids released as a result of stressful stimuli are responsible for the exacerbation of inflammation but may also play a role in the exacerbation of airway hyperresponsiveness.…”

“…The conclusion of the study by Okuyama et al [6] regarding the proinflammatory effects of glucocorticoids may have been quite unexpected in the asthma field, but over the last few years, evidence is accumulating that glucocorticoids may mediate proinflammatory effects in other inflammatory models, especially models of CNS inflammation. Administration of LPS to animals that have received exogenous glucocorticoids leads to greater inflammatory injury of the liver and CNS compared to animals that have not received glucocorticoids [9] .…”

“…It was also very interesting that the increase in airway inflammation in the stressed mice challenged with ovalbumin versus the nonstressed mice challenged with ovalbumin was evident only in the females [6] . A similar observation was made in a model of experimental autoimmune encephalomyelitis [17] .…”