Mechanisms of bronchoconstriction from nonimmunologic environmental stimuli.

Athma is characterized by repeated episodes of bronchoconstriction, often triggered by environmental stimuli. Since much of the therapy of asthma is aimed at preventing these episodes of bronchoconstriction, understanding the mechanisms by which environmental stimuli cause bronchoconstriction has obvious clinical importance. This review will discuss the general mechanisms by which inhaled agents can cause bronchoconstriction and what little is known about the specffic mechanisms of action of non-immunologic stimuli. Some of the well-recognized nonimmunologic stimuli to bronchoconstriction are listed in Table 1. These stimuli are all capable of causing marked bronchoconstriction in subjects with asthma, but have little effect on normal human subjects. Although at high concentrations some of these stimuli do produce measurable bronchoconstriction in animals, the relevance of these effects to realistic environmental exposures is uncertain. Thus, the major source of useful information on the mechanisms of action of these agents is experiments conducted on human subjects with asthma. The ethical and technical constraints of such experiments largely explain the limited nature of present understanding of these mechanisms. Three of the stimuli listed in Table 1 are virtually certain to cause clinically significant effects in patients with asthma. These three stimuli: exercise, fbg (distilled water aerosol), and the air pollutant sulfur dioxide, have been the most extensively studied and form the basis of subsequent discussion in this review. Exercise has been well recognized as a cause of clinically important bronchoconstriction in patients with asthma since at least the 17th century.’ Over the past ten years, studies from several laboratories have confirmed that the bronchoconstrictor effects of exercise can be mimicked by voluntary hyperpnea at an equivalent minute ventilation, suggesting that exercise-induced asthma is at least in part due to the local effects of exercise-induced hyperpnea on the airways.2 Studies reporting that hyperpnea-induced bronchoconstriction could be ameliorated by inhalation of warm humid air and potentiated by inhalation of cold dry air led to the suggestion that airway cooling might be the actual stimulus to exercise-induced bronchoconstriction.58 Recently, largely due to the pioneering studies of Anderson and co-workers,9 this notion has been questioned. In particular, the observation from three separate laboratories that the water content of inspired air was an important determinant of the magnitude of exercise or hyperpnea-induced bronchoconstriction, whereas the temperature was not, supported the hypothesis that exercise-induced bronchoconstriction might be due to airway drying rather than airway cooling.’#{176} Recent evidence based on direct calculations of airway heat loss and airway water loss during hyperpuea with dry air at two widely different temperatures (21#{176}C and 39#{176}C) suggests that neither heat loss nor water loss alone is likely to explain hyperpnea-induced bronchoconstriction and that it is therefore likely that both stimuli contribute to this effect. The recognition that fog may be an important stimulus to bronchoconstriction is considerably more recent. Nonetheless, over the past ten years reports from several laboratories have shown that inhalation of an aerosol of water (the major constituent of natural fog) rapidly causes bronchoconstriction in most subjects with asthma.’3’4 Distilled water aerosol causes bronchoconstriction on the basis of its low osmolarity since increasing the osmolarity of the inhaled aerosol by addition of dextrose or a variety of chemically unrelated solutes prevents fog-induced bronchoconstriction.’3 Interestingly, inhalation of hyperosmolar aerosols is also a potent stimulus to bronchoconstriction.14’5 Although hyperosmolar aerosols are not generally encountered in the environment, this effect provides support for the notion that airway water loss can