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The mechanism of exercise-induced asthma is …,☆☆

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Abstract

Exercise-induced asthma (EIA) refers to the transient narrowing of the airways that follows vigorous exercise. The mechanism whereby EIA occurs is thought to relate to the consequences of heating and humidifying large volumes of air during exercise. In 1978 airway cooling was identified as an important stimulus for EIA; however, severe EIA also occurred when hot dry air was inspired, and there was no abnormal cooling of the airways. In 1986 the thermal hypothesis proposed that cooling of the airways needed to be followed by rapid rewarming and that these two events caused a vasoconstriction and a reactive hyperemia of the bronchial microcirculation, together with edema of the airway wall, causing the airways to narrow after exercise. The osmotic, or airway-drying, hypothesis developed from 1982-1992 because neither airway cooling nor rewarming appeared to be necessary for EIA to occur. As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell volume loss. It is proposed that the regulatory volume increase, after cell shrinkage, is the key event resulting in release of inflammatory mediators that cause airway smooth muscle to contract and the airways of asthmatic subjects to narrow. This event may or may not be associated with airway edema. The osmotic and thermal theories come together by considering that inspiration of cold air not only cools the airways but also increases the numbers of airway generations becoming dehydrated in the humidifying process. (J Allergy Clin Immunol 2000;106:453-9.)

Section snippets

Observations not explained by the airway cooling and thermal hypotheses

The most important observation that does not appear to be explained by the airway cooling theory is the documentation of quite severe EIA under conditions of inspiring hot dry air.6, 7, 8, 9 Further, the percent fall in FEV1 increased from 32% to 48% by increasing the duration of exercise from 4 to 8 minutes during inspiration of hot dry air.3 This is approximately the same as the increase in severity of EIA from 35% to 48% fall in FEV1 obtained by cooling the inspired air from +24°C to –10°C.6

The case against airway cooling and the thermal hypothesis of EIA

In 1986 the airway cooling theory was questioned by the original proponents15 and revised to the thermal hypothesis that was developed in two major studies.4, 16 The revision considers that “airway cooling, of itself, was insufficient to produce bronchial narrowing and that rapid rewarming was essential for the obstruction to develop.” “If rewarming is prevented or limited, either by having asthmatics inhale frigid gas in the immediate post-hyperpnea period… the obstructive response is

Alternative interpretation for involvement of the bronchial circulation

There is no doubt that the bronchial circulation has the potential to contribute to the pathophysiologic mechanisms of EIA. The bronchial circulation is an important source of water for the airways, and bronchial blood flow increases in response to an increase in osmolarity.25 An increase in bronchial blood flow would not only increase delivery of water to the airways to reduce dehydration and hence the osmotic stimulus but also enhance the clearance of mediators. These two events would be in

The case for water loss and the osmotic hypothesis

As referred to above, the osmotic hypothesis of EIA1 arose out of the failure of the airway cooling hypothesis to account for well-established findings on EIA. It was developed after finding that subjects with EIA were also sensitive to aerosols of hypertonic saline solution.28 It was further developed as the marked similarities in the airway response to dry air hyperpnea and hypertonic aerosols became evident.29, 30

The osmotic effect of respiratory water loss really came into focus at the time

The mechanism for water loss to cause mediator release

The osmotic gradient created in response to the loss of water by evaporation from the airway surface liquid acts as a stimulus for water to move from the surrounding cells to the lumen. As cells lose volume they are subjected to the biochemical events associated with regulatory volume increase. These events include the increase in concentration of intracellular calcium and inositol triphosphate.46 These same events are required for the release of mediators47 and the evidence that an increase in

What facts about eia does the osmolarity hypothesis account for?

If changes in osmolarity caused by water loss lead to the release of mediators, an increase in bronchial blood flow, and bronchoconstriction, it would serve to explain many of the facts about EIA. For example, it would explain why both intensity and duration of exercise are important determinants of severity of EIA. The longer and more intense the exercise, the higher the ventilation rate and the greater the number of generations of airways that will be recruited into the humidifying process.

Bringing the hypotheses together

We conclude that neither abnormal airway cooling nor rapid rewarming of the airways is a prerequisite for EIA and that the thermal hypothesis does not explain many of the facts about EIA, particularly EIA that occurs under hot dry conditions. We agree that airway cooling and rapid rewarming of the airways do occur when cold air is inhaled during exercise, but these events are not necessary for EIA to occur. We suggest that hyperpnea with cold dry air be considered not only for its capacity to

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    Supported by the National Health and Medical Research Council of Australia.

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    Reprint requests: Sandra D. Anderson, PhD, DSc, Department of Respiratory Medicine, Level 9, Page Chest Pavilion, Royal Prince Alfred Hospital, Missenden Road, Camperdown 2050, Australia.

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