STRESS & ASTHMA

1. STRESS & ASTHMA A.Berna DURSUN Atatürk Chest Diseases and Thoracic Surgery Research & Training Hospital, Allergy Division, Ankara

2. What is stress ? Stress has been defined as perceived imbalance between demands encountered in daily life and individual’s adaptive capacity or ability to cope. Emotional Signs Behavioral Signs Physicial Signs Intellectual Signs

3. Stressor: Exam, interview, job loss, death of closed one, family conflicts Chronic stressor: Ongoing-stable life diffculties, no clear endpoint insight Acute stressor: Time-limited duration, typically with a clear onset and offset Allostasis=reestablishing stability through change short-term activation of the neuroendocrine and autonomic nervous systems promotes adaptation Allostatic load: Adaptive changes lead to other consequences, including receptor desensitization, tissue damage Individual’s subjective perception of the stressor is also important. If the stressor is threatinig and unmanageable, it elicits negative emotional responses.

5. Stress and the immune system • Cellular immune system • Delayed type hypersensitivity reactions, • Mitogen-specific T cel proliferative response and • NK cell acitivty diminishes. • Expresion of adhesion molecule on lymphocyte and endothelal cells alters. • Inflammatory and immune cell trafficking • Redistribution of inflammatory cells • Reduced T regulatory cells • Th1/Th2 imbalance • Th1 type cytokine pattern (TNF-ά, IL-1, IFN- Ɣ) • Th2 type cytokine pattern (Il-4, IL-5, IL-13)

6. Short term stress Balb/c mouse model CRH-deficient mouse model 3 days 1 hour/day restraint stress OVA sensitization BAL: reduction in accumulation of inflammatory cells increased levels of IL-6, IL-9, IL-13 no change in IL-10 and IFN-Ɣ BAL: IL-4, IL-5, IL-13, RANTES, IFN-Ɣ, eotaxin specific corticosteroid inhibitor (RU486) Reversible Elevated levels of corticosteroid in stressed animals may result in reduction of inflammatory cell infiltration in the airways alter BAL cytokine levels.

7. Long term stress Balb/c mouse model 1 week Restraint stress 24 hours sound stress Increased eosinophils in BAL Increased airway reactivity BAL: Increased in all inflammatory cells No change in cytokine pattern

8. Does stress cause asthma? • Does stress aggrevate asthma symptoms? ???????????

9. Stress and developing asthma Increased maternal stress prenatally is associated with an elevated cortisol response to stress in the newborn, affecting Th1/Th2 cell differentiation. J Allergy Clin Immunol 2004; 113: 1051-1057. Gestational exposure to psychosocial stress alters immune functon in offspring. Neurosci Biobehav Review 2005; 29: 29-39. Parental reports of life stress are associated with subsequent onset of wheezing in children in early childhood. Am J Respir Crit Care Med 2002; 165: 358-365.

10. Stress and developing asthma The consequences of stress at early months of life on the toddler period: higher total IgE levels increased production of TNF-ά reduced IFN-Ɣ J Allergy Clin Immunol 2004; 113: 1051-1057. Preschoolers exposed to high level maternal stress had elevated cortisol levels They also had a history of high maternal stress exposure in infancy. They were more likely to have greater mental health difficulties in the 1st grade J Allergy Clin Immunol 2005; 116: 1301-1306.

11. Gestational stress HPA axis stimulation Glucocorticoid release Long term stress Hyporesponsiveness of the HPA axis Increased production of proinflammatory cytokines typically counterreguated by cortisol Alterations in Th1 and Th2 patterns

12. Stress and asthma exacerbation Stressful stimulation Bronchoconstriction in 35-40 % of asthmatics Psychosom Med 1992; 54: 192-216. Hypnotism and suggestion of anger, fear Recollection of asthma /exacerbation Increase in airway resistance Reduction in FEV1 Psychosom Med 1996; 58: 413-422. Psychosom Med 2000; 62: 401-412.

13. Stress and asthma exacerbation Does stressful events cause asthma exacerbation in children? 18 months follow-up Exacerbation risk at acute stress 0-2 week: none 2-4 week: OR: 1.71 4-6 week: OR: 2.17 Exacerbation risk at acute stress presence of chronic stress 0-2 week: OR: 2,98 Sandberg S et al. Lancet. 2000 Sep 16;356(9234):982-7. Variable mood states Presence of stressors Lower PEF values J Behav Med 1999; 22: 179-193.

14. Stress and asthma exacerbation Negative life events and quality of life in adult asthmatics 12 months follow-up “Asthma-specific quality of life (AQOL)” questionnaire n=189 More negative life events 1. Poorer AQOL (high numerical score) 2. Lower income status 3. More emergency room visit Thorax 2007; 62: 139-146

15. Stress and asthma exacerbation Stressful computer puzzle test Increased breathlessness Psychol Med 1999; 29: 1359-66. Allergen challenge at stressful examination periods Increased airway inflamation Am J Respir Crit Care Med 2002; 165: 1062-1067. Stress-induced changes in physiological parameters of breathing may be similiar in asthmatics and nonasthmatic but these changes may have higher clinical significance in asthmatics due to their higher baseline airway resistance. J Psychosom Res 2000; 49: 239-245.

16. Stress perception and cytokine and neurotrophins Clin Exp Allergy 2007; 38: 283-90.

17. Stress perception and cytokine and neurotrophins • In control group, there is no correlation between stress score and • T cell population • BDNF levels • In asthmatics, • A positive correlation of CD4+ T cells with stress (r=0,35; p<0,05) • A negative correlation of CD8+ T cells with stress (r=-0,38; p<0,05) • A positive correlation of TNF-ά producing T cells with stress (r=0,42; p<0,05) • A positive correlation of BDNF levels with stress (r=0,43; p<0,01) Clin Exp Allergy 2007; 38: 283-90.

18. Stress and asthma exacerbation • Stress can change an asthmatic’s perception of breathlessness. • Stress might affect self-management strategies and adherence to • treatment plans lead to deterioration of asthma control. • Psychological stress corelated with an increased risk of acute respiratory • infections, which are an important trigger of asthma exacerbation. • There is a subpopulation that is greatly affected by stressors than others. Complex mechanism Ann N.Y. Acad Sci 2006; 1088: 65-77

19. Stress and asthma paradox • Stressful events activates HPA and SAM axes. • Increased secretion of cortisol, epinephrine and norepinephrine. • Additonaly, stressors diminish cellular immune functions. • High level of cortisol diminish inflammation in the airways. • Beta -2 adrenergic agonists are potent bronchodilators. ?????

20. Stress and asthma paradox Continued exposure to elevated stress hormones Compensatory down-regulation of GC and adrenergic receptors Diminishes sensitivity to the antiinflammatory properties of GC and bronchodilatory properties of beta agonists Foster persistant inflammation and airway constriction upon exposure to asthma triggers Psychological Bulletin 2004; 130: 601-630. PNAS 2006; 103 (14): 5496-5501. Brain Behav Immun 2007; 21(8): 993-999.

21. 9,5-fold reduction 5,5-fold reduction PNAS 2006; 103(14): 5496-5501.

22. Conclusion • Stress may play have a role in the development of asthma. • Chronic stress and acute stress in the presence of chronic stress leads • exacerbations • poor quality of life • more frequent and lenghtier admissions to hospital • more functional disability • more difficulties to manage Ann N.Y. Acad Sci 2006; 1088: 65-77. Brain Behav Immun 2007; 21(8): 993-999.

23. Future directions • New animal models • Prospective, controlled human studies • Stress is an complex situation • Stress is as potent as antigenic triggers