Greg King

Mechanisms of airway hyperresponsiveness in asthma.

Abstract:  Airway hyperresponsiveness (AHR) is a fundamental abnormality in asthma. There are many potential factors contributing to the excessive airway response demonstrable on airway challenge. These range from abnormalities of airway smooth muscle, airway remodelling and airway inflammation to abnormalities in the neural control of airway calibre. None of these by themselves fully explains the abnormalities seen on the dose response curves of the asthmatic. In this review, the main mechanisms are described, together with recent evidence providing a pathway by which a number of these mechanisms may interact to cause AHR through abnormality in ventilation distribution and airway closure. There is now evidence for a close relationship between ventilation heterogeneity and AHR which could be exploited clinically.

Procedures to improve the repeatability of forced oscillation measurements in school-aged children

Forced oscillation technique (FOT) parameters are less repeatable than spirometry, and the impact of technical factors, such as data acquisition and data filtering, are unknown. FOT was performed, in triplicate, on 48 children (8-11 years) and repeated two weeks later. We examined the separate effects of monitoring tidal volume (V(T)) prior to measurement and length of data acquisition on measurement repeatability. We compared the effects on repeatability of a filtering technique in which complete breaths containing respiratory artefact were rejected and statistical filters in which outlying data points were rejected. Within- and between-session repeatability of respiratory system resistance (Rrs) and reactance (Xrs) were assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC). Longer data acquisition reduced CV of Rrs and Xrs (60s vs. shorter durations, p ≤ 0.001). Monitoring V(T) reduced CV of Rrs (p = 0.05). Complete breath filtering improved CV and ICC for both Rrs and Xrs. The repeatability of FOT measurements can be improved by optimising data acquisition and filtering.

Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSKs dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

Acoustic analysis of cough

This paper describes a method for quantitatively analysing cough sound. Coughs are obtained from normal adults before and after methacholine challenge which provides an intervention altering the airway characteristics. The analysis method characterises the cough sound by a set of temporal and spectral features. The results show that although there is some variability of these features within a subject, they are able to characterise significant differences in the cough sound after methacholine challenge. This suggests that acoustic analysis of the cough is able to provide information on the airway flow mechanics during cough that could be useful in diagnosis.

Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma

It is unclear whether the failure to reverse bronchoconstriction with deep inspiration (DI) in asthma is due to reduced maximal dilatation of the DI. We compared the effect of different DI volumes on maximal dilatation and reversal of bronchoconstriction in nine asthmatics and ten non-asthmatics. During bronchoconstriction, subjects took DI to 40%, 70% and 100% inspiratory capacity, on separate days. Maximal dilatation was measured as respiratory system resistance (Rrs) at end-inspiration and residual dilatation as Rrs at end-expiration, both expressed as percent of Rrs at end-tidal expiration prior to DI. DI volume was positively associated with maximal dilatation in non-asthmatics (ANOVA p=0.055) and asthmatics (p=0.023). DI volume was positively associated with residual dilatation in non-asthmatics (p=0.004) but not in asthmatics (p=0.53). The degree of maximal dilatation independently predicted residual dilatation in non-asthmatics but not asthmatics. These findings suggest that the failure to reverse bronchoconstriction with DI in asthma is not due to reduced maximal dilatation, but rather due to increased airway narrowing during expiration.

Airway Hyperresponsiveness in Asthma: A Better Understanding Yet to Yield Clinical Benefit

Airway inflammation and hyperresponsiveness (AHR) are important features of asthma. Both inflammation and AHR are complex traits that can each originate from a plethora of factors, where every factor can be independent, interconnected and dispensable. This review examines the complexity of the indices that we use to assess airway responsiveness. These indices entail intricate information regarding the individual and the combined dynamic behavior of all the airways that constitute the tracheobronchial tree during the activation of airway smooth muscle (ASM). Because many factors other than ASM contractility can influence airway narrowing, the defects responsible for the manifestation of AHR are difficult to infer. New tests and technologies are being developed to decipher the meaning of the indices of airway responsiveness and have already leaped forward our understanding of AHR. This review also gives prominence to the concept of ASM plasticity.ASM mass and contractile capacity is not fixed over time. Several facets of inflammation can increase ASM force indirectly over a prolong period of time by causing tissue damage and repair, which ultimately leads of airway wall remodeling that embodies an enlargement of ASM mass. This could contribute to the fixed component of AHR. The gain of force due to inflammation can also be transient and conditional to the presence of inflammatory mediators that are capable of increasing the contractile capacity of ASM. This could contribute to the variable, and more readily modifiable, component of AHR. We are now aware that a multitude of muscle and non-muscle factors can contribute to AHR within an asthmatic individual, and that these factors are often times distinct between individuals. Consequently, the relative contribution of a single factor within a group of patients is usually very small. This is the reason why our ever-growing understanding of AHR in asthma does not quite yet avail patients.