Psychologic stress and asthma: neuropeptide involvement.

In a recent Grand Rounds in Environmental Medicine article, Wright and Steinbach (1) highlighted the influence of psychosocial stress on asthmatic attacks. The reported case histories support basic neuroimmunologic studies, which document modulation of immune reactivities by psychologic stress, and the need to consider psychologic stress along with environmental chemical and physical stresses, which alone or in combination can alter physiologic homeostasis resulting in ill health (2,3). With the four case histories described by Wright and Steinbach (1), the influence of emotional factors is brought into context with physiologic disturbances, and the reference to violence as “an unrecognized environmental exposure” emphasizes the need to make more researchers aware of the impact that psychologic status can have on neuroimmune interactions and health (4). Wright and Steinbach (1) stated that their report was “... to alert clinicians and researchers to a potential risk factor [psychologic stress] for increased asthma morbidity that has not previously been recognized.” However, it has been known for more than a century that cognitive neural circuits can alter immune responsiveness. In 1886, a New England physician demonstrated that individuals with an allergy to roses could have an allergic response triggered by the perceived presence of the allergen, an artificial rose (5). Thus, allergic responses can be elicited in the absence of allergen, and asthma has been reported to occur with emotional changes (6). Although it may be argued that not all asthmatic episodes are allergic or even immunologically driven, there is substantial evidence connecting immune responses and asthma, and it is well documented that the nervous system can regulate immune functions. More specifically, it has been suggested that neural control of airways is involved in the pathogenesis of asthma (7), but the mechanistic connections have not been confirmed (8,9). As referenced by Wright and Steinbach (1), central nervous system involvement in asthma is related to environmental stresses that can occur from psychologic disturbances. Although, to date, the involvement of specific neurotransmitters or neuropeptides has not been fully delineated in asthmatic processes, neuropeptides from C-fibers of the sensory (sympathetic) nervous system, which innervate the lungs as well as other organs (10), are known to have multiple effects on immune reactivities. Vasoactive intestinal peptide increases mast cell trafficking (11); nerve growth factor (NGF) and substance P influence mast cell development and degranulation (12–14); and histamine from mast cells is known to induce asthmatic responses. Another cell associated with asthma is the eosinophil; calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide enhance eosinophil chemotaxis (15,16). Neuropeptides also can modulate IgE synthesis, which is implicated in allergic asthma (17). Interestingly, in a report by Larsen et al. (18), a mouse strain that produced an IgE response to aerosolized ovalbumin (BALB/c mice) had an enhanced airway response to electrical field stimulation, but a strain that produced mainly IgG did not show an enhanced response. The enhanced BALB/c response could be transferred to a nonimmunized syngeneic mouse by peribronchial lymph node cells; the authors suggested that the lymph node cells from sensitized BALB/c mice altered neural control of airways (18). Further complexities of neuroendocrine immune circuit involvement in airway physiology/pathology, as well as other immune-associated pathologies, have been documented with production of regulatory neuropeptides by lymphocytes and macrophages (19–23) and immune cytokine alteration of neuropeptide production (24,25). A posited link between allergies and depression also has been suggested (26). In addition, psychologic influences on lymphocyte proliferation (27) and multiple other immune parameters (4), including lung infection (28), have been reported. More to the point of the psychologic impact on asthma, neuropeptides, which can be immunomodulatory, are released by emotional stress. The influence of psychologic stress on asthma was the topic of a workshop sponsored by the National Institutes of Health (NIH) (29). Research regarding neural control of airways has been recommended by the NIH and the World Health Organization to be an area that requires further research (30). Exercise (31) and hyperventilation from physical or emotional stresses (32) can initiate an asthmatic attack. Analyses of childhood asthma have shown substantial interfacing between the biology of asthma, behavior, stress, and immune reactivities (33). Psychologic stress increases NGF production as well as receptors for NGF on lymphocytes (34,35). NGF release is especially problematic for asthmatic patients because, in addition to its effects on mast cells, NGF is known to cause negative regulation of glucocorticoid receptors (36), and inhaled glucocorticoid is a major therapy for asthma. The various cell types, neuropeptides, and immune factors involved in asthma are pieces to the puzzle, but these interconnecting pieces need to be mechanistically associated before the mysterious rise in asthma incidence can be further understood. The types of interorgan regulatory controls (e.g., between the endocrine, immune, and nervous systems exemplified by the reported violence and asthma associations) indicate the need for multidisciplinary approaches to disease analyses. It is often necessary to take a reductionistic approach in order to focus on the mechanisms of a single cell type. The complextities of any one system demand substantial attention. However, no one organ system functions independently of other organ systems. Just as psychologic, chemical, and physical stresses can team to alter health, teams of researchers with different experiences will be needed to unravel the multidirectional pathways controlling responses to environmental factors. Psychoneuroimmunology research has been ongoing for almost a quarter of a century, and most mechanisms remain elusive. Toxicant effects on the neuroendocrine immune circuitry (neuroimmunotoxicology research) is even less far along (37), but researchers need to consider the psychologic stress on their animals when evaluating the mechanisms associated with their favorite toxicant. Lack of appreciation for psychologic effects may increase the variances within results, which could especially be important for therapeutic drug trials. The potential involvement of psychologic stress (one form being violence) on asthma has not actually been unrecognized; it is a research area that has been neglected.