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Social stress and asthma: The role of corticosteroid insensitivity

2010; Elsevier BV; Volume: 125; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2009.11.005

1097-6825

Angela Haczku, Reynold A. Panettieri,

Climate Change and Health Impacts

Psychosocial stress alters susceptibility to infectious and systemic illnesses and may enhance airway inflammation in asthma by modulating immune cell function through neural and hormonal pathways. Stress activates the hypothalamic-pituitary-adrenal axis. Release of endogenous glucocorticoids, as a consequence, may play a prominent role in altering the airway immune homeostasis. Despite substantial corticosteroid and catecholamine plasma levels, chronic psychosocial stress evokes asthma exacerbations.Animal studies suggest that social stress induces corticosteroid insensitivity that in part may be a result of impaired glucocorticoid receptor expression and/or function. Such mechanisms likely promote and amplify airway inflammation in response to infections, allergen, or irritant exposure. This review discusses evidence of an altered corticosteroid responsive state as a consequence of chronic psychosocial stress. Elucidation of the mechanisms of stress-induced impairment of glucocorticoid responsiveness and immune homeostasis may identify novel therapeutic targets that could improve asthma management. Psychosocial stress alters susceptibility to infectious and systemic illnesses and may enhance airway inflammation in asthma by modulating immune cell function through neural and hormonal pathways. Stress activates the hypothalamic-pituitary-adrenal axis. Release of endogenous glucocorticoids, as a consequence, may play a prominent role in altering the airway immune homeostasis. Despite substantial corticosteroid and catecholamine plasma levels, chronic psychosocial stress evokes asthma exacerbations. Animal studies suggest that social stress induces corticosteroid insensitivity that in part may be a result of impaired glucocorticoid receptor expression and/or function. Such mechanisms likely promote and amplify airway inflammation in response to infections, allergen, or irritant exposure. This review discusses evidence of an altered corticosteroid responsive state as a consequence of chronic psychosocial stress. Elucidation of the mechanisms of stress-induced impairment of glucocorticoid responsiveness and immune homeostasis may identify novel therapeutic targets that could improve asthma management. Discuss this article on the JACI Journal Club blog:www.jaci-online.blogspot.com. [T]he regulation of gene expression by social factors makes all bodily functions … susceptible to social influences.—Eric Kandel, Nobel Laureate1Kandel E.R. A new intellectual framework for psychiatry.Am J Psychiatry. 1998; 155: 457-469Crossref PubMed Google Scholar Ethnic disparity in asthma prevalence, morbidity, and mortality is highly correlated with low socioeconomic status and urban living, both of which are predisposing factors to psychosocial stress. Perception of stress in epidemiologic studies associates with socioeconomic status and health.2Adler N.E. Boyce T. Chesney M.A. Cohen S. Folkman S. Kahn R.L. et al.Socioeconomic status and health: the challenge of the gradient.Am Psychol. 1994; 49: 15-24Crossref PubMed Google Scholar Social stress was identified next to air pollution and urban living as one of the most significant contributors to asthma exacerbations.3Wright R.J. Subramanian S.V. Advancing a multilevel framework for epidemiologic research on asthma disparities.Chest. 2007; 132: 757S-769SCrossref PubMed Scopus (87) Google Scholar, 4Wright R.J. Health effects of socially toxic neighborhoods: the violence and urban asthma paradigm.Clin Chest Med. 2006; 27 (v): 413-421Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Predisposing factors to psychosocial stress such as low socioeconomic status also correlate with health care disparity in asthma prevalence, morbidity, and mortality.5Subramanian S.V. Ackerson L.K. Subramanyam M.A. Wright R.J. Domestic violence is associated with adult and childhood asthma prevalence in India.Int J Epidemiol. 2007; 36: 569-579Crossref PubMed Scopus (37) Google Scholar Both physical and social factors induce stress.3Wright R.J. Subramanian S.V. Advancing a multilevel framework for epidemiologic research on asthma disparities.Chest. 2007; 132: 757S-769SCrossref PubMed Scopus (87) Google Scholar, 4Wright R.J. Health effects of socially toxic neighborhoods: the violence and urban asthma paradigm.Clin Chest Med. 2006; 27 (v): 413-421Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Evidence suggests that stressful experiences evoke asthma exacerbations.6Marshall G.D. Neuroendocrine mechanisms of immune dysregulation: applications to allergy and asthma.Ann Allergy Asthma Immunol. 2004; 93: S11-S17Abstract Full Text PDF PubMed Google Scholar, 7Miller B.D. Wood B.L. 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Depression and asthma: a potentially lethal mixture.J Allergy Clin Immunol. 1987; 80: 481-486Abstract Full Text PDF PubMed Google Scholar Patients with asthma respond with increased bronchial tone to distressful experiences,13Beggs P.J. Curson P.H. An integrated environmental asthma model.Arch Environ Health. 1995; 50: 87-94Crossref PubMed Google Scholar listening to stressful interactions,14Kolbe J. Garrett J. Vamos M. Rea H.H. Influences on trends in asthma morbidity and mortality: the New Zealand experience.Chest. 1994; 106: 211S-215SCrossref PubMed Google Scholar or exposure to asthma-related visual brain stimulation.15Rosenkranz M.A. Busse W.W. Johnstone T. Swenson C.A. Crisafi G.M. Jackson M.M. et al.From the cover: neural circuitry underlying the interaction between emotion and asthma symptom exacerbation.Proc Natl Acad Sci U S A. 2005; 102: 13319-13324Crossref PubMed Scopus (83) Google Scholar Further, school examinations induce asthma exacerbations in children.16Liu L.Y. Coe C.L. Swenson C.A. Kelly E.A. Kita H. Busse W.W. School examinations enhance airway inflammation to antigen challenge.Am J Respir Crit Care Med. 2002; 165: 1062-1067Crossref PubMed Google Scholar The mechanisms of bronchoconstriction in response to such acute stress may include alterations in adrenergic (sympathetic) and cholinergic (parasympathetic) neural control. Asthma exacerbations were also noted in patients suffering from chronic depression and anxiety as well as in adults17Miller B.D. Wood B.L. Psychophysiologic reactivity in asthmatic children: a cholinergically mediated confluence of pathways.J Am Acad Child Adolesc Psychiatry. 1994; 33: 1236-1245Abstract Full Text PDF PubMed Google Scholar and children18Miller G.E. Gaudin A. Zysk E. Chen E. Parental support and cytokine activity in childhood asthma: the role of glucocorticoid sensitivity.J Allergy Clin Immunol. 2009; 123: 824-830Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar who had inadequate social support. For instance, greater caregiver-perceived stress was independently associated with subsequent risk of recurrent wheeze in early childhood, and high levels of caregiver stress predicted increased wheezing in the index children.19Wright R.J. Cohen S. Carey V. Weiss S.T. Gold D.R. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study.Am J Respir Crit Care Med. 2002; 165: 358-365Crossref PubMed Google Scholar Severely negative life events in another study increased the risk of asthma attacks in children, and this risk was magnified if the child's life situation was characterized by multiple chronic stressors.20Sandberg S. Paton J.Y. Ahola S. McCann D.C. McGuinness D. Hillary C.R. et al.The role of acute and chronic stress in asthma attacks in children.Lancet. 2000; 356: 982-987Abstract Full Text Full Text PDF PubMed Google Scholar Chronic caregiver stress in early childhood was also associated with the development of atopy, whereas increased stress in the home predicted higher levels of IgE expression, enhanced allergen-specific lymphocyte proliferation, and differential cytokine expression in children.21Wright R.J. Finn P. Contreras J.P. Cohen S. Wright R.O. Staudenmayer J. et al.Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy.J Allergy Clin Immunol. 2004; 113: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The increase in asthma symptoms during chronic stress may be a result of the combined effects of hormones, neurotransmitters, and neuropeptides involved in the autonomic control and inflammation of the airways. Although stress may alter the magnitude of the airway inflammatory response elicited by allergens, irritants, and/or infections in persons with asthma,22Chen E. Miller G.E. Stress and inflammation in exacerbations of asthma.Brain Behav Immun. 2007; 21: 993-999Crossref PubMed Scopus (90) Google Scholar the precise mechanisms are unknown. This review discusses evidence that highlights the role of altered corticosteroid function in modulating airway inflammation caused by social stress. Hans (János) Selye defined stress as a state of altered homeostasis resulting from either an internal or external stimulus. Stressors can be physical or psychological in nature. All organisms experience stress, which by itself, is necessary for biological and social adaptation to the environment and for health.23Vig R.S. Forsythe P. Vliagoftis H. The role of stress in asthma: insight from studies on the effect of acute and chronic stressors in models of airway inflammation.Ann N Y Acad Sci. 2006; 1088: 65-77Crossref PubMed Scopus (41) Google Scholar The physiological response to stress involves the development of adaptive neuroendocrine mechanisms.24Selye H. A syndrome produced by diverse nocuous agents.Nature. 1936; 138: 32Crossref Google Scholar, 25Selye H. A syndrome produced by diverse nocuous agents. 1936.J Neuropsychiatry Clin Neurosci. 1998; 10: 230-231PubMed Google Scholar, 26McEwen B.S. Stress, adaptation, and disease: allostasis and allostatic load.Ann N Y Acad Sci. 1998; 840: 33-44Crossref PubMed Google Scholar These mechanisms are designed to counteract stress and to restore homeostasis. Stress, however, also evokes physiological changes that may potentially promote disease. Selye called this kind of stress "distress": The reaction to noxious physical or psychological stimuli involves a short-term activation of the neuroendocrine and autonomic nervous systems that promotes adaptation and survival during the period of challenge. Such mechanisms, termed allostasis, literally mean "re-establishing stability through change."26McEwen B.S. Stress, adaptation, and disease: allostasis and allostatic load.Ann N Y Acad Sci. 1998; 840: 33-44Crossref PubMed Google Scholar During allostasis, adaptive mechanisms operate at a higher or lower level than during "normal" homeostasis. For example, emotional distress elevates heart rate and blood pressure as well as elevating glucocorticoid levels and suppressing expression of inflammatory cytokines. Assuming allostatic responses cease when no longer needed, the organism adapts to and survives the immediate challenge without suffering long-term consequences. If, however, the same responses are repeatedly activated or persist over a longer period, receptor alterations and tissue damage occur that precipitate or exacerbate disease processes. This has been termed allostatic load.26McEwen B.S. Stress, adaptation, and disease: allostasis and allostatic load.Ann N Y Acad Sci. 1998; 840: 33-44Crossref PubMed Google Scholar Acute stress, the "flight-or-fight response" (positive stress), is a response to a perceived threat or challenge that requires a short period in which to adapt successfully. Such stress evokes an immediate activation of the hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic corticotrophin-releasing hormone (CRH) stimulates adrenocorticotropic hormone secretion from the pituitary that in turn promotes the release of corticosteroids from the adrenal cortex. The HPA axis is one of the central mechanisms by which stress, detected by the brain, promotes adaptive physiological responses. Acute stressors, through the stimulation of the sympathetic nervous system, prepare the body for an immediate response and are beneficial. The HPA axis modulates immune/inflammatory responses to prevent such responses from becoming unchecked. The aforementioned adaptive responses to acute stress stand in distinction from those of chronic stress, in which the presence of prolonged stress induces maladaptive responses that promote disease. Traditionally, stress in clinical studies suggests chronic psychological (maladaptive) stimuli. Reduced social status, loss of a job, death of a loved one, long-term anxiety, repeated exposure to violence, and depression4Wright R.J. Health effects of socially toxic neighborhoods: the violence and urban asthma paradigm.Clin Chest Med. 2006; 27 (v): 413-421Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 23Vig R.S. Forsythe P. Vliagoftis H. The role of stress in asthma: insight from studies on the effect of acute and chronic stressors in models of airway inflammation.Ann N Y Acad Sci. 2006; 1088: 65-77Crossref PubMed Scopus (41) Google Scholar, 27Miller G. Chen E. Cole S.W. Health psychology: developing biologically plausible models linking the social world and physical health.Annu Rev Psychol. 2009; 60: 501-524Crossref PubMed Scopus (135) Google Scholar are examples of such stressors. The clinical studies linking psychosocial factors with asthma severity are observational and cannot determine causality. Animal models may offer novel insight into the mechanisms relating psychosocial risk factors to physical health.27Miller G. Chen E. Cole S.W. Health psychology: developing biologically plausible models linking the social world and physical health.Annu Rev Psychol. 2009; 60: 501-524Crossref PubMed Scopus (135) Google Scholar To date, few studies have investigated the effects of stress on allergen-induced airway inflammation. For example, in a rat model of unpredictable changes in daily living conditions, increased edema and cellular influx were observed in inflamed paws and airways.28Datti F. Datti M. Antunes E. Teixeira N.A. Influence of chronic unpredictable stress on the allergic responses in rats.Physiol Behav. 2002; 77: 79-83Crossref PubMed Scopus (18) Google Scholar Repeated ultrasound-induced stress in ovalbumin-sensitized mice increased inflammatory cell number, IL-4, IL-5,29Joachim R.A. Quarcoo D. Arck P.C. Herz U. Renz H. Klapp B.F. Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma.Psychosom Med. 2003; 65: 811-815Crossref PubMed Scopus (75) Google Scholar TNF-α,30Joachim R.A. Sagach V. Quarcoo D. Dinh T. Arck P.C. Klapp B.F. Upregulation of tumor necrosis factor-alpha by stress and substance p in a murine model of allergic airway inflammation.Neuroimmunomodulation. 2006; 13: 43-50Crossref PubMed Scopus (15) Google Scholar and eotaxin31Joachim R.A. Sagach V. Quarcoo D. Dinh Q.T. Arck P.C. Klapp B.F. Effect of stress on eotaxin and expression of adhesion molecules in a murine model of allergic airway inflammation.J Neuroimmunol. 2007; 182: 55-62Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar in the airways. In pregnant BALB/c mice, maternal stress increased susceptibility of the offspring to allergic sensitization to ovalbumin.32Pincus-Knackstedt M.K. Joachim R.A. Blois S.M. Douglas A.J. Orsal A.S. Klapp B.F. et al.Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation.J Immunol. 2006; 177: 8484-8492Crossref PubMed Google Scholar A model of social disruption stressor (SDR) has been used to study the effects on allergic airway inflammation in our laboratory. Because this platform mimics human psychological stress, such an approach may be more relevant than exposure to sound, ultrasound, or physical stressors. In SDR, the social hierarchy of a cohort of young male mice is disrupted by an older, aggressive intruder, and a stress response is elicited by repeated experience of defeat and loss of social status.33Avitsur R. Padgett D.A. Dhabhar F.S. Stark J.L. Kramer K.A. Engler H. et al.Expression of glucocorticoid resistance following social stress requires a second signal.J Leukoc Biol. 2003; 74: 507-513Crossref PubMed Scopus (38) Google Scholar, 34Avitsur R. Stark J.L. Dhabhar F.S. Padgett D.A. Sheridan J.F. Social disruption-induced glucocorticoid resistance: kinetics and site specificity.J Neuroimmunol. 2002; 124: 54-61Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 35Avitsur R. Stark J.L. Dhabhar F.S. Sheridan J.F. Social stress alters splenocyte phenotype and function.J Neuroimmunol. 2002; 132: 66-71Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 36Eells J.B. Misler J.A. Nikodem V.M. Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice.Neuroscience. 2006; 140: 1117-1126Crossref PubMed Scopus (34) Google Scholar, 37Sonoda J. Chida Y. Sudo N. Kubo C. Social disruption stress exacerbates alpha-galactosylceramide-induced hepatitis in mice.Neuroimmunomodulation. 2005; 12: 375-379Crossref PubMed Google Scholar, 38Kinsey S.G. Bailey M.T. Sheridan J.F. Padgett D.A. Avitsur R. Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice.Brain Behav Immun. 2007; 21: 458-466Crossref PubMed Scopus (49) Google Scholar Exposure to psychological defeat as a consequence of confrontation is a relatively common experience in industrialized societies. Accordingly, epidemiologic and psychosocial studies show that younger age, lower educational level, and subordinate socioeconomic status or rank all lead to repeated experience of defeat and contribute to stress.39DeVries A.C. Glasper E.R. Detillion C.E. Social modulation of stress responses.Physiol Behav. 2003; 79: 399-407Crossref PubMed Scopus (161) Google Scholar, 40Avitsur R. Stark J.L. Sheridan J.F. Social stress induces glucocorticoid resistance in subordinate animals.Horm Behav. 2001; 39: 247-257Crossref PubMed Scopus (147) Google Scholar, 41Yeh W.Y. Cheng Y. Chen C.J. Social patterns of pay systems and their associations with psychosocial job characteristics and burnout among paid employees in Taiwan.Soc Sci Med. 2009; 68: 1407-1415Crossref PubMed Scopus (16) Google Scholar Social stressors may also modulate immune responses and predispose to asthma morbidity in human beings.4Wright R.J. Health effects of socially toxic neighborhoods: the violence and urban asthma paradigm.Clin Chest Med. 2006; 27 (v): 413-421Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 5Subramanian S.V. Ackerson L.K. Subramanyam M.A. Wright R.J. Domestic violence is associated with adult and childhood asthma prevalence in India.Int J Epidemiol. 2007; 36: 569-579Crossref PubMed Scopus (37) Google Scholar, 27Miller G. Chen E. Cole S.W. Health psychology: developing biologically plausible models linking the social world and physical health.Annu Rev Psychol. 2009; 60: 501-524Crossref PubMed Scopus (135) Google Scholar By using the SDR model, we showed that combined exposure to allergen and repeated stress prolonged and enhanced the allergic airway response and reduced the glucocorticoid sensitivity of TH2 cytokine release by immune cells in vitro.42Bailey M.T. Kierstein S. Sharma S. Spaits M. Kinsey S.G. Tliba O. et al.Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production.J Immunol. 2009; 182: 7888-7896Crossref PubMed Scopus (23) Google Scholar, 43Bailey M.T. Kierstein S. Spaits M. Sheridan J.F. Panettieri R.A.J. Haczku A. Social stress enhances allergen-induced airway inflammation in mice.Am J Respir Crit Care Med. 2006; 175: A237Google Scholar Recently, stress-related glucocorticoid resistance of TH2 cytokine production by T cells was also described in children with asthma who reported inadequate social support.18Miller G.E. Gaudin A. Zysk E. Chen E. Parental support and cytokine activity in childhood asthma: the role of glucocorticoid sensitivity.J Allergy Clin Immunol. 2009; 123: 824-830Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The molecular mechanisms by which SDR enhances allergic airway inflammation remain unclear. Earlier findings in rodent models of stress revealed acute atrophy of the immune organs that increased susceptibility to viral or bacterial infections.24Selye H. A syndrome produced by diverse nocuous agents.Nature. 1936; 138: 32Crossref Google Scholar, 25Selye H. A syndrome produced by diverse nocuous agents. 1936.J Neuropsychiatry Clin Neurosci. 1998; 10: 230-231PubMed Google Scholar Stress in the SDR model, however, was not immunosuppressive. We found increased spleen mass and enhanced p65 expression in the nuclear extract of the SDR mice, suggesting activation (not suppression) of the innate immune cells and TH2-type immune mediators. There are indications that both the duration (acute vs chronic or repeated) and type of stressors can alter the effects of corticosteroids.44Okuyama K. Ohwada K. Sakurada S. Sato N. Sora I. Tamura G. et al.The distinctive effects of acute and chronic psychological stress on airway inflammation in a murine model of allergic asthma.Allergol Int. 2007; 56: 29-35Crossref PubMed Scopus (24) Google Scholar Opposing effects of short-term and long-term stress on the immune system were suggested in models of restraint44Okuyama K. Ohwada K. Sakurada S. Sato N. Sora I. 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Significance of endogenous glucocorticoid sensitivity for airway eosinophilia in a murine model of allergy.Acta Otolaryngol. 2005; 125: 378-385Crossref PubMed Scopus (10) Google Scholar suggesting that endogenous corticosteroids effectively suppress allergic inflammation. Accordingly, corticotropin-releasing hormone–deficient mice experienced significantly enhanced cellular inflammation to allergic sensitization as compared with that of wild-type mice.48Silverman E.S. Breault D.T. Vallone J. Subramanian S. Yilmaz A.D. Mathew S. et al.Corticotropin-releasing hormone deficiency increases allergen-induced airway inflammation in a mouse model of asthma.J Allergy Clin Immunol. 2004; 114: 747-754Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Direct comparison of the SDR stressor with a repeated restraint stress paradigm also suggests differential effects on the immune function.49Hermann G. Tovar C.A. Beck F.M. Sheridan J.F. 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Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen.J Neuroimmunol. 2004; 148: 106-115Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Further, development of glucocorticoid insensitivity of cytokine production by splenocytes53Quan N. Avitsur R. Stark J.L. He L. Lai W. Dhabhar F. et al.Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice.J Neuroimmunol. 2003; 137: 51-58Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar was observed in SDR but not the restraint stress model.54Avitsur R. Kavelaars A. Heijnen C. Sheridan J.F. Social stress and the regulation of tumor necrosis factor-alpha secretion.Brain Behav Immun. 2005; 19: 311-317Crossref PubMed Scopus (61) Google Scholar Taken together, exposure to sound29Joachim R.A. Quarcoo D. Arck P.C. Herz U. Renz H. Klapp B.F. Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma.Psychosom Med. 2003; 65: 811-815Crossref PubMed Scopus (75) Google Scholar, 30Joachim R.A. Sagach V. Quarcoo D. Dinh T. Arck P.C. Klapp B.F. Upregulation of tumor necrosis factor-alpha by stress and substance p in a murine model of allergic airway inflammation.Neuroimmunomodulation. 2006; 13: 43-50Crossref PubMed Scopus (15) Google Scholar, 31Joachim R.A. Sagach V. Quarcoo D. Dinh Q.T. Arck P.C. Klapp B.F. Effect of stress on eotaxin and expression of adhesion molecules in a murine model of allergic airway inflammation.J Neuroimmunol. 2007; 182: 55-62Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 32Pincus-Knackstedt M.K. Joachim R.A. Blois S.M. Douglas A.J. Orsal A.S. Klapp B.F. et al.Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation.J Immunol. 2006; 177: 8484-8492Crossref PubMed Google Scholar or psychological stressors55Chida Y. Sudo N. Sonoda J. Hiramoto T. Kubo C. Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus-pituitary-adrenal axis.Am J Respir Crit Care Med. 2007; 175: 316-322Crossref PubMed Scopus (32) Google Scholar enhances an allergic immune response whereas restraint stress suppresses it. Further, whereas acute stress evokes immunosuppression, after prolonged or repeated stress, glucocorticoid insensitivity may develop. Although paradoxical, increases in circulating corticosterone caused by repeated psychological stress may promote a loss of the anti-inflammatory properties of corticosteroids and in fact perpetuate airway inflammation.55Chida Y. Sudo N. Sonoda J. Hiramoto T. Kubo C. Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus-pituitary-adrenal axis.Am J Respir Crit Care Med. 2007; 175: 316-322Crossref PubMed Scopus (32) Google Scholar Endogenous glucocorticoid levels can regulate the development, distribution, and function of immune and structural cells,56Ashwell J.D. King L.B. Vacchio M.S. Cross-talk between the T cell antigen receptor and the glucocorticoid receptor regulates thymocyte