depicts our working model of stress and asthma. It highlights the importance of both social and physical exposures in the exacerbation of symptoms. The basic premise of the model is that psychological stress operates by altering the magnitude of the airway inflammatory response that irritants, allergens, and infections bring about in persons with asthma. It is important to note that the model suggests that stress on its own is NOT capable of modifying immune functions in a way that leads to asthmatic symptoms. Rather, stress is viewed as a process that accentuates the airway inflammatory response to environmental triggers and, in doing so, increases the frequency, duration, and severity of patients' symptoms.
Figure 1 Model depicting the interaction of psychological stress with environmental triggers in influencing asthma exacerbations. The basic premise of the model is that stress operates by altering the magnitude of the airway inflammatory response that irritants, (more ...)
A variety of indoor and outdoor triggers have been found to contribute to exacerbations of asthma. For example, exposure to tobacco smoke can lead to wheezing and asthmatic symptoms in vulnerable individuals (Jaakkola, Nafstad, & Magnus, 2001
), and so can infections in the upper and lower respiratory tracts (Sigurs et al., 2005
). In sensitized individuals, exposure to allergens, such as cat dander and mould, can bring about bronchial hyperresponsiveness (Nelson et al., 1999
). One of the common pathways these triggers operate through is airway inflammation. Upon entry into the body, for example, inhaled allergens are taken up by dendritic cells, and subsequently presented to T helper (Th) cells (Busse & Lemanske, 2001
). Th cells have two phenotypes known as Th-1 and Th-2. Th-1 cells generally initiate and coordinate cellular immune responses by deploying cytokines such as IL-2 and IFN-g. By contrast, Th-2 cells promote B cell proliferation and differentiation, which leads to a humoral response involving antibody synthesis. They do so by releasing cytokines such as IL-4, IL-5, & IL-13. It is these humoral pathways that are generally implicated in flare-ups of asthma.
The Th-2 cytokines IL-4 and IL-13 operate by binding to B cells, and inducing them to synthesize and release IgE antibodies. IgE then binds to mast cells residing in the airways. When IgE molecules bind their cognate allergen, it causes the mast cell to degranulate, leading to the release of allergic mediators such as histamines and leukotrienes. Histamines and leukotrienes cause edema, smooth muscle constriction, and mucus, resulting in clinical symptoms of asthma including wheezing, chest tightness, and shortness of breath. This pathway constitutes the early response. A more prolonged late-phase response is generated when Th2 cells release IL-5. This cytokine recruits eosinophils into the airways, where they bring about inflammation and obstruction. Eosinophils also release mediators, such as eosinophil cationic protein and major basic protein, which can bring about damage to airway cells, and leukotrienes, which cause edema and further bronchial constriction. Hence, this late-phase response worsens clinical symptoms by promoting airway inflammation and obstruction.
Our model suggests that stress accentuates this immune response to environmental triggers. It views stress as an external demand from an individual's social environment. To have downstream influences on inflammatory processes in the airways, the external stressor must be appraised as threatening and unmanageable. This appraisal pattern brings about increases in negative emotions (e.g., anger, fear, shame) and decreases in positive emotions (e.g., vigor, joy, calmness) as well as changes in thoughts about the self and the future. These emotional and cognitive processes sensitize the Th-2 pathway, such that upon exposure to a trigger, there is a more pronounced inflammatory response, leading to increased frequency, duration, and severity of symptoms.
We note that our model differs from other depictions of stress and asthma in its explicit focus on the interaction
between social and physical exposures and in its emphasis on the pathway of inflammation. Other models have also noted that stress has direct effects on other biological systems relevant to asthma (Wright, 2005
; Wright, Rodriguez, & Cohen, 1998
) – for example, through vagally mediated bronchoconstriction or heightened interoceptive sensitivity to symptoms - and we agree that these are likely to be important contributory mechanisms as well. We also acknowledge that there are numerous other factors that may interact with stress or independently operate to affect asthma morbidity, including genetics and access to health care (Andrulis, 1998
; Ober & Hoffjan, 2006
). Nonetheless, we view the model's central precept – that stress worsens asthma symptoms by accentuating inflammatory responses to environmental triggers – as a useful heuristic framework for thinking about the big-picture of asthma.
Before reviewing evidence for this model, we first acknowledge a paradox in the stress and asthma literature. It is well-known that upon exposure to many forms of acute stress there is activation of the hypothalamic-pituitary-adrenocortical (HPA) and sympathetic-adrenal-medullary (SAM) axes, leading to increased secretion of the hormones cortisol, epinephrine and norepinephrine (Baum & Greenberg, 1995). High levels of cortisol diminish inflammation in the airways and the periphery; similarly, β-adrenergic agonists such as epinephrine are potent bronchodilators. It is also well-known that certain stressors, especially those which are severe and chronic, can suppress cellular immune functions in humans (Segerstrom et al., 2004
). Together, these observations suggest the paradoxical conclusion that stressful experiences should ameliorate rather than exacerbate symptoms of asthma. Of course, the findings from studies of asthma patients are inconsistent with this conclusion; stress has been shown repeatedly to worsen the course of illness. To resolve this paradox, we argue that after long periods of exposure to stress hormones, receptors for these molecules become down-regulated, leading to diminished regulation of inflammatory responses to asthma triggers. This is manifest in exaggerated production of Th2 cytokines and recruitment of eosinophils, both of which are known to accompany life stress in asthma patients (but not in healthy adults, see (Segerstrom et al., 2004
). These ideas are discussed in greater detail in the ‘How does stress modify inflammation?
’ section below.