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

Abstract

Airway hyperresponsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR forty 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 hopefully better inform the development of phenotype-targeted therapy.

Inhaled corticosteroid dose response in asthma

“…Mann PD 10 Provocative dose of mannitol causing a 10% fall in FEV 1 44 Mann PD 15 Provocative dose of mannitol causing a 15% fall in FEV 1 45 …”

“…Targeting 255 ICS therapy using mannitol challenge AHR has been shown to reduce mild 256 exacerbations over and above standard guideline driven therapy 11 , in line with 257 that for sputum eosinophils 10 . However, AHR can be driven by other 258 mechanisms such as airway smooth muscle hyperplasia, and airway closure 259 itself 44 , and is therefore an area requiring further study with regards to 260 personalised asthma treatment 45 . 261 262 There is therefore a growing body of evidence suggesting that we need to include 263 inflammatory measurements routinely to best manage patients with asthma.…”

Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells

“…Exaggerated airway narrowing in diseases such as asthma and chronic bronchitis (Chapman and Irvin, ; Jha et al, ) result from airway hyperreactivity as well “remodeling” that involved increased hypertrophy and hyperplasia of airway smooth muscle (ASM) mass (Prakash, ; Elliot et al, ; Fayon et al, ; Lin et al, ). In addition to pro‐inflammatory mediators such as cytokines, structural and functional changes to the airway involve the effects of growth factors (Doherty and Broide, ; Aravamudan et al, ; Prakash, ; Thompson et al, ).…”

Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis

“…In addition, the suppression of type 2 cytokines is important for asthma control [40]. AHR has long been considered a cardinal feature of asthma and seems to be correlated with airway inflammation and remodeling [41]. AHR is postulated to be regulated by genetics, airway inflammation, smooth muscles of the airway, cytokines, among other factors.…”