Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come

Abstract

Airway hyper-responsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR 40 years ago initiated many important contributions to our understanding of asthma and other airway diseases. However, our understanding of AHR in asthma remains complicated by the multitude of potential underlying mechanisms which in reality are likely to have different contributions amongst individual patients. Therefore, the present review will discuss the current state of understanding of the major mechanisms proposed to contribute to AHR and highlight the way in which AHR testing is beginning to highlight distinct abnormalities associated with clinically relevant patient populations. In doing so we aim to provide a foundation by which future research can begin to ascribe certain mechanisms to specific patterns of bronchoconstriction and subsequently match phenotypes of bronchoconstriction with clinical phenotypes. We believe that this approach is not only within our grasp but will lead to improved mechanistic understanding of asthma phenotypes and we hoped to better inform the development of phenotype-targeted therapy.

Figure 1. Representative dose response curves (DRC) to methacholine in a healthy and a severely asthmatic subject

Airway hyperresponsiveness is characterised by both an increased sensitivity, seen as the leftward shift in the DRC of the asthmatic patient (A), and excessive bronchoconstriction, resulting in the loss/increase in the maximal response plateau (B).

Figure 2. The contribution of airway narrowing and airway closure to the fall in FEV₁ during bronchial challenge

FEV₁ is reduced by airway narrowing because a narrowed airway loses some capacity to transmit flow. However, FEV₁ is also determined by the number of parallel airways contributing to flow and is thus reduced by functional airway closure (both true airway closure and severe airway narrowing). By contrast, FVC is determined by the volume of air in communication with the mouth and is reduced by functional airway closure but not by airway narrowing. Air narrowing, per se, is thus reflected in the ratio FEV₁/FVC. There is substantial variation in the contribution of airway narrowing and airway closure to the fall in FEV₁ amongst patients with asthma. Shown are dose response curves for an asthmatic subject with predominantly airway narrowing (A: 24 years old, baseline FEV₁ 122%pred, PC₂₀FEV₁ 0.23µmol) and one with predominantly airway closure (B: 24 years old, baseline FEV₁ 78%pred, PC₂₀FEV₁ 0.28µmol). These examples represent extremes of a continuum of responses, with the majority of subjects falling in between. The extent of airway narrowing is expected to contribute to airway closure so to determine excessive airway closure we have analysed the relationship between %fall FVC and FEV₁/FVC (C). A steeper slope represents greater airway closure for a given level of airway narrowing. Absolute FEV₁/FVC, rather than % fall FEV₁/FVC, maintains the contribution of baseline airway calibre. Representative regression lines were calculated from the mean baseline FEV₁/FVC, mean fall in FEV₁/FVC and mean % fall FVC for lean non-asthmatics (blue), lean asthmatics (red), obese non-asthmatics (green), non-allergic obese asthmatics prior to bariatric surgery (purple) and the same subjects 12 months following bariatric surgery (dashed purple). Data were adapted from two of our previous studies (53, 130). Important to note is the increased slope in asthmatics compared to non-asthmatics, and in all obese groups compared to the two lean groups. Following weight loss, the slope of the obese non-allergic asthmatics decreased suggesting reduced predisposition to airway closure. Interestingly, the position and slope of obese non-allergic asthmatics post-surgery is almost identical to obese non-asthmatics suggesting that the effect of obesity on airway closure is dependent upon the level of adiposity in non-allergic subjects.