Stress and Asthma: The Plot Thickens

John Bienenstock, M.D.

Brain-Body Institute, McMaster University, Hamilton, Ontario

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Study of the role of emotions as a determinant of asthma has a long and chequered history. A careful reading of this literature suggests that there is evidence for and against the proposition (1). Nevertheless, on clinical experience alone, many physicians continue to question the importance of emotion on the course and treatment of this disease.

A paper by Liu and colleagues (2) in this issue of AJRCCM (pp. 1062-1067) shows that the stress of school examinations on otherwise apparently healthy young college students with mild asthma had several effects: it promoted the number of eosinophils in blood and sputum, increased IL-5 generation by sputum cells, decreased the ratio of interferon (IFN)- to interleukin (IL)-5, caused a shift in cytokine generation to that of a Th2 character, increased the amount of eosinophil-derived neurotoxin in sputum supernatants, and caused an inverse correlation between sputum eosinophils and FEV₁.

The authors concluded that stress was a co-factor, even in the four individuals who dropped out of the study during examination week. The gender of these individuals was not disclosed so that the known differential effect of stress on females versus males, which may have confounded the study, is not available. The data, however, very strongly support the contention that stress promoted at least some hallmarks of inflammation associated with asthma.

Chronic stress is somewhat ill-defined but is regarded as a negative emotional state induced by a whole range of stressors. These may be acute or chronic, and be as varied as pain, infection, depression, anxiety or rage, crises in life, or responses to a variety of chemical, therapeutic, and environmental factors (3).

Stress effects may be opposite depending on the circumstances in which they are experienced and the length of exposure. The immunological effects had been thought to be universally immunosuppressive, partly because of the elevation of cortisone through stimulation of the hypothalamic-pituitary-adrenal axis by corticotropin releasing factor (4). However, Dhabhar and McEwen (5) showed that acute stress could enhance, and chronic stress depress, delayed hypersensitivity reactions, thus bringing a new perspective to the issue. Many studies of stress have implicated immune suppression as a key cause of greater susceptibility to infections. As with any attempts to simplify complex events, there are several opposing additional actions on immunity of the neurohormonal response to stress. For example, corticotropin releasing factor has a variety of proinflammatory effects. Both intracerebral and systemic corticotropin releasing factor lead to mast cell degranulation in the skin, lung, and intestine (6). Acute or chronic stress causes increased intestinal smooth muscle reactivity, vascular and intestinal permeability, increased goblet cell discharge of mucin, and increased intestinal motility, amongst other significant physiological alterations, in the rodent. Corticotropin releasing factor also enhances the effect of substance P on guinea pig bronchial smooth muscle (7), again indicating a potential new direction for investigation in asthma. Activation of mast cells appears to be central because most intestinal stress effects do not occur in mast cell deficient rats (8). Much wider interaction between stress and the nervous system seems to be the case because cholinergic, adrenergic, and even ganglionic blockade may all separately interfere with the physiological end results in the gut. Inhibitors of corticotrophin releasing factor abrogate intestinal stress effects (6) and behavioral responses in primates (9). The activity of these substances in asthma remains to be investigated.

Stimulation of the hypothalamic-pituitary-adrenal axis also leads to increased adrenal secretion of epinephrine and norepinephrine, whose role is often overlooked. They have significant effects on immune responses, particularly natural killer cells and downregulate IFN-, which can be interpreted as immune deviation toward Th2. Marshall and colleagues examined the effect of examinations on a group of individuals and showed IFN was depressed and IL-10 increased (10). In addition to being a potent Th2 cytokine, IL-10 has significant immunosuppressive effects but is necessary also for the expression of bronchial hyperreactivity.

As Liu and coworkers carefully discussed (2), the upregulation of eosinophils in the lung may well reflect the effects of stress on bone marrow, and distribution or redistribution to tissue sites (5) and reemphasizes a major recent focus of investigation in asthma, namely the bone marrow.

Another less well known effect of stress is on the increased synthesis and secretion of nerve growth factor which is a pleiotropic molecule with very heterogeneous effects on immunity, inflammation, and nerve growth (11). As its name implies, nerve growth factor is elevated in stress (12), causes new nerve growth, lowers the threshold for subsequent neuronal responses, and is implicated in the promotion of asthma in a murine model (13). It can also shift the phenotype of nerves so as to promote synthesis and expression of substance P not previously found in that nerve.

Although the literature on the effects of poor psychosocial conditions and stress in asthma is somewhat controversial, there is more certainty as to their negative effects in the gastroenterological literature. Irritable bowel syndrome is characterized by smooth muscle hypersensitivity, visceral hyperalgesia, or lowered neuronal afferent hypersensitivity. A major determinant of postinfectious irritable bowel syndrome is poor psychosocial circumstances (14).

The paper by Liu and coworkers (2) draws our attention to our difficulties with quantitation of stress, and our inadequacy to determine whether and how stress may have more or less effects in different individuals. It helps us focus on a very important but complex subject. In a review on asthma and stress, Rietveld and colleagues (1) concluded that in many parts of science today, it is time to put together the pieces that we tend to examine individually, to obtain better understanding of complex systems whose properties are not fully explained by an understanding of their component parts.

Through carefully designed experiments, we may slowly become more insightful as to how factors in our environment such as our complex psychosocial circumstances and emotions can interact with our genetic and biological makeup to promote, cause, or even ameliorate physical distress and disease.

	References

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