Asthma: A Loss of Post-natal Homeostatic Control of Airways Smooth Muscle With Regression Toward a Pre-natal State

Abstract

The defining feature of asthma is loss of normal post-natal homeostatic control of airways smooth muscle (ASM). This is the key feature that distinguishes asthma from all other forms of respiratory disease. Failure to focus on impaired ASM homeostasis largely explains our failure to find a cure and contributes to the widespread excessive morbidity associated with the condition despite the presence of effective therapies. The mechanisms responsible for destabilizing the normal tight control of ASM and hence airways caliber in post-natal life are unknown but it is clear that atopic inflammation is neither necessary nor sufficient. Loss of homeostasis results in excessive ASM contraction which, in those with poor control, is manifest by variations in airflow resistance over short periods of time. During viral exacerbations, the ability to respond to bronchodilators is partially or almost completely lost, resulting in ASM being "locked down" in a contracted state. Corticosteroids appear to restore normal or near normal homeostasis in those with poor control and restore bronchodilator responsiveness during exacerbations. The mechanism of action of corticosteroids is unknown and the assumption that their action is solely due to "anti-inflammatory" effects needs to be challenged. ASM, in evolutionary terms, dates to the earliest land dwelling creatures that required muscle to empty primitive lungs. ASM appears very early in embryonic development and active peristalsis is essential for the formation of the lungs. However, in post-natal life its only role appears to be to maintain airways in a configuration that minimizes resistance to airflow and dead space. In health, significant constriction is actively prevented, presumably through classic negative feedback loops. Disruption of this robust homeostatic control can develop at any age and results in asthma. In order to develop a cure, we need to move from our current focus on immunology and inflammatory pathways to work that will lead to an understanding of the mechanisms that contribute to ASM stability in health and how this is disrupted to cause asthma. This requires a radical change in the focus of most of "asthma research."

Keywords: Asthma; airways smooth muscle; evolution; exacerbations; homeostasis; poor control; research direction.

Figure 1

Advert for Medihaler (1956) http://museum.aarc.org/gallery/asthma-management/.

Figure 2

Bronchial hyper-responsiveness consists of two components; how sensitive the airways are to agonists driving shortening of ASM and how much the ASM shorten when the normal homeostatic mechanisms fail. The impact of shortening can be amplified in presence of significant airways secretions and plugging. The sensitivity and reactivity of vary between asthmatics and probably accounts for different patterns of symptoms from mild frequent to infrequent severe. Steroids have significant effects on sensitivity but may have little or no effect on reactivity once destabilization is triggered.

Figure 3

Impact of inhaled corticosteroids on lung function and bronchial responsiveness (sensitivity). Impact on sensitivity is relatively slow when commencing ICS but rapidly fades on discontinuing treatment. This largely explains the need for high levels of compliance (>80% of twice daily doses). Study by Reddell et al. (middle panels) indicates that even when asthma appears well controlled, ASM homeostasis can be severely disrupted during viral infections. The ability to induce/facilitate bronchoconstriction and the associated impaired bronchodilator responsiveness after the airways constrict might explain why the Finnish/Scandinavian approach of aggressive bronchodilator and ICS therapy early at first sign of increasing symptoms is successful at minimizing severe exacerbations and why combination products used intermittently appear to be helpful in mild to moderate asthmatics (65).