The assessment of airway stiffness as a measurement of airway remodelling in human asthma

Asthma is a common illness characterised by inflammation of the airways which leads to airway obstruction and ultimately shortness of breath. Asthma is a cause of significant long term morbidity and reduced quality of life due to acute respiratory symptoms (2008). Currently, treatment for asthma largely focuses on suppressing airway inflammation thereby reducing airway obstruction and symptoms. Unfortunately, several inflammatory processes can continue, altering the airway wall cellular architecture (Bai et al. 2005), a process termed airway remodelling. Airway remodelling leads to; airway wall thickening (Ward 2002), airway stiffening (Ward et al. 2001), a more rapid decline in lung function with age (James et al. 2007), and the development of irreversible airflow obstruction (Bumbacea et al. 2004). The treatment of airway remodelling in asthma has been recently highlighted as a significant research goal (Holgate et al. 2008a) as there are currently no drug therapies which specifically reverse the process of airway remodelling or halt its progression. One of the primary limitations in developing treatments for airway remodelling is that there are very few options that allow the non-invasive assessment of airway remodelling. One proposed method to assess airway remodelling is to measure the reduction in airway stiffness that occurs in association with airway remodelling (Ward et al. 2001). As such, the primary aim of this thesis was to develop techniques to measure airway stiffness and as such to assess airway remodelling in subjects with asthma. There are two potential methods to assess airway stiffness; direct measurements or indirect measurements which are likely to be more clinically applicable. This thesis addresses both. Firstly, this thesis addresses the need for a technique that can directly assess airway stiffness in humans by the measurement of airway compliance. Currently, no methods are available to measure airway compliance in humans, but measurements have been made in animals (Gunst et al. 1988a; Brown et al. 1996; Brown et al. 1997a; Bacharier et al. 2004). In these studies, airway compliance was measured directly by the determination of the change in airway diameter per unit change in transmural pressure. Chapter 2 of this thesis outlines the development of a method that allows the determination of in vivo airway compliance in humans. The basis of the technique is a mathematical algorithm which combines measurements of airway diameter obtained at multiple lung volumes by high resolution computed tomography with the pressurevolume characteristics of the lung measured via oesophageal balloon. The result is a comprehensive description of airway compliance, where airway compliance can be determined for any airway size and at any transpulmonary pressure and was represented as a three dimensional surface. This study further outlined a useful way to quantify the nonlinear airway diameter-pressure relationship, where the gradient is the compliance, namely ‘airway plateau pressure’. Specifically airway plateau pressure defines the pressure at which 95% of the dilation at TLC has occurred and represents the ‘ease’ by which airways expand with increasing pressure. A low plateau pressure represents a highly compliant airway that is easily dilated and a high plateau pressure represents a stiff airway that is difficult to dilate. The main result of this study was that small airways are more compliant, more easily dilated, than the large airways in normal healthy subjects. The development of this new method to determine and quantify in vivo airway compliance in Chapter 2 allowed the bronchodilator response of in vivo airway compliance in subjects with asthma to be assessed in Chapter 3. At present, animal studies have shown strong relationships between airway compliance and airway smooth muscle tone (Brown et al. 1996; Brown et al. 1997a). However, no such relationships have been determined in adults with asthma. This study demonstrated that airway compliance in subjects with asthma increased at low transpulmonary pressures following the administration of a short acting bronchodilator; that is, plateau pressure decreased. The largest decrease in plateau pressure occurred in the smaller airways (<3 mm); a finding that highlights the relatively greater responsiveness of the small airways to alterations in airway smooth muscle tone. Ultimately this study demonstrated that the in vivo airway compliance measurement has the potential to assess the mechanical properties (stiffness) of the airways in subjects with asthma. The determination of airway stiffness is ideally assessed through the direct measurement of airway compliance; where compliance is the change in airway diameter per unit change in transmural pressure. Despite the likely value of direct measurements of airway stiffness, the measurement remains too invasive to be useful as a common clinical test. It follows, that a non-invasive measurement of airway stiffness is also required, which would have a greater clinical utility. The measurement of airway distensibility by the Forced Oscillation Technique (FOT) has recently been proposed as just such a measure (Brown et al. 2004; Brown et al. 2007). The FOT measurement of airway distensibility uses respiratory conductance as a surrogate measure of airway calibre and lung volume as an equivalent measure of transpulmonary pressure. Recently, the FOT measurement of airway distensibility in subjects with asthma has shown that distensibility is reduced at high lung volumes (>75%TLC) and is not influenced by smooth muscle tone (Brown et al. 2007). From this study it is not clear why airway distensibility was reduced only at high lung volumes, but it may be that airway closure, which increases at low lung volumes, influences the measurement at those lung volumes. Furthermore, from this previous study it is not clear why airway smooth muscle tone did not alter airway distensibility when in vivo studies in animals have shown clear relationships between airway smooth muscle tone and airway compliance (Brown et al. 1996; Brown et al. 1997a). A potential explanation is that as changes in airway compliance have been shown to mostly occur at low pressures, the measurement of airway distensibility above FRC only limits the ability to detect alterations due to airway smooth muscle tone at low lung volumes. To better characterise the FOT determination of airway distensibility these issues must be overcome. Accordingly, Chapter 4 addressed the need for further characterisation of the FOT measure of airway distensibility. This study aimed to (1) the investigate airway distensibility across all lung volumes in subjects with asthma and healthy controls, (2) assess the effect of airway smooth muscle tone on airway distensibility at all lung volumes, and (3) examine the influence of airway closure on the measurement of airway distensibility. This study demonstrated that airway distensibility in subjects with asthma was reduced both at high and low lung volumes, that airway distensibility increases at low lung volumes (FRC and RV) following the administration of a short acting bronchodilator and lastly that airway distensibility at low lung volumes is independent of airway closure. These findings support the utility of airway distensibility measured by the FOT as a non-invasive measurement of airway mechanics in asthma. In conclusion, this thesis has developed a new method for assessing in vivo airway compliance in humans and used this technique to measure increases in airway compliance following a bronchodilator induced reduction in smooth muscle tone. In addition, the FOT measurement of airway distensibility was comprehensively characterised showing that; airway distensibility has the ability to measure changes in airway compliance following bronchodilator administration and that the assessment of these changes were not influenced by changes in airway closure. In the future, the assessment of in vivo airway compliance in humans will be a useful tool to investigate airway structure-function relationships; however, due to the invasive nature of oesophageal manometry this technique will have limited clinical utility. In contrast, the FOT distensibility is easy to perform, non-invasive and appears to be capable of measuring the changes in airway compliance that has been demonstrated in vivo. Therefore this thesis promotes the utility of airway distensibility determined by the FOT as a useful and practical measure of airway remodelling in asthma.