Airway Physiology

Role

The Airway Physiology Group studies people with and without airways disease, to describe and measure the physiological features that characterise the disease or reflect its severity, in order to understand the physiological mechanisms that cause the disease and its manifestations.

Research

Small airways disease in asthma
Abnormalities of the small peripheral airways are very difficult to measure, but they can have a profound effect on clinical outcomes of asthma. In this project, funded by the CRC for Asthma and Airways, Sue Downie investigated whether inhaled corticosteroid aerosols with different particle sizes have different effects either on clinical outcomes, or on specific markers of small airway function. Two commercial preparations of beclomethasone dipropionate (BecotideTM) that used either CFC (large particle size) or HFA (small particle size) propellents were used to treat 24 asthmatic subjects for three months. Small airway function was measured using the MBNW, which was established in our laboratory as part of a collaboration with Dr Sylvia Verbanck, in Belgium, and Dr Bruce Thompson, in Melbourne. Inflammation of the small airways was measured using a new technique for measuring exhaled nitric oxide, which allows a separate assessment of inflammation in the alveolar spaces and the larger conducting airways. The study found that there were no significant differences between patients treated with large or small particle aerosols in terms of symptoms, airway hyperresponsiveness, small airway function or inflammation of the small airways. These findings imply that targeting treatment at the small airways does not lead to increased clinical benefits.

Ventilation heterogeneity in older asthmatics
We have recently discovered that ventilation heterogeneity, or uneven distribution of air throughout the lungs, is a strong predictor of airway hyperresponsiveness (AHR) in people with asthma. A follow-up study, funded by the Asthma Foundation of NSW is beginning to investigate the mechanisms that underpin the association between uneven ventilation and AHR. Because we believe that the uneven ventilation is caused by structural changes in the airways, known as airway remodelling, we are studying older asthmatic subjects who are likely to have greater airway remodelling as a result of the longer duration of their disease. Remarkably, the preliminary data suggest that uneven ventilation is poorly related to AHR in older asthmatics. The findings suggest that there is a different pattern of ventilation distribution in older people, which is not associated with AHR.

Deep inspirations and airway closure
In normal subjects without asthma, simply avoiding taking deep breaths for twenty minutes increases the amount of airway narrowing that can be induced during a bronchial challenge test, i.e. the airways become more responsive. The mechanism that causes this increased responsiveness is not known, but understanding how it occurs may help us understand what makes the airways of asthmatics hyperresponsive. In this study undertaken for his Graduate Diploma in Science, David Chapman investigated the effect of deep breaths (and their avoidance) on airway closure in non-asthmatic subjects. Airway closure is an important component of bronchoconstriction in asthma and is related to small airway abnormalities and ventilation heterogeneity. David found that avoiding deep inspirations increased the amount of airway closure induced by bronchial challenge, and speculates that this is brought about by an increase in ventilation heterogeneity.

Development of simple physiological markers of airway remodelling in asthma
Airway remodelling describes a range of structural changes in the airways that are presumed to be the result of damage inflicted by chronic inflammation in the airways. The clinical significance of airway remodelling has not been established, but it seems highly likely that it contributes to uneven ventilation. The difficulty in investigating airway remodelling lies in the fact that current methods for measuring remodelling are invasive, resource-intensive and time-consuming, which means that their application is limited to small groups of highly selected subjects. The aim of this project, which is funded by the CRC for Asthma and Airways and being undertaken by Nathan Brown, is to develop a simple physiological marker of airway remodelling, by using the FOT to measure the distensibility of the airways. To date, the study has shown that there are substantial and significant differences in distensibility between asthmatic and non-asthmatic subjects. These differences are not explained by other abnormalities, such as airway smooth muscle tension or lung elasticity that are also abnormal in asthma. The most recent discovery in this series of studies is that there is a very strong relationship between airway distensibility measured using our new physiological marker and distensibility measured by high resolution CT imaging. This finding provides an important confirmation that this physiological measurement is a true reflection of events occurring within the airways.

Bronchodilator response in COPD
Support from the Boehringer Ingelheim Research Fellowship has allowed the continuation of an investigation of the response to bronchodilator treatment in chronic obstructive pulmonary disease (COPD). COPD is classically regarded as a disease in which airway obstruction is poorly reversible by bronchodilators, but nevertheless many patients benefit from these drugs. In COPD bronchodilators can help to reduce hyperinflation – a condition where the lungs are overfilled with air, making breathing very uncomfortable. However, reducing hyperinflation reduces the volume of the lungs and can mean that airways are actually narrower and more prone to closure. Chantale Diba undertook a preliminary study this year to examine the effect of bronchodilators on airway closure and ventilation heterogeneity in six patients with moderately severe COPD. Interestingly, she found that the bronchodilator treatment not only improved airway calibre and reduced hyperinflation, but, in some subjects, it also opened up airways that were previously closed. However, the opening of these closed airways appeared to cause a worsening of ventilation heterogeneity, so that the distribution of air in the lungs became more uneven. Because uneven distribution of air in the lungs can reduce the efficiency of the transfer of oxygen, it is very important that we investigate this effect in more detail. Boehringer Ingelheim have recently agreed to provide funding to allow a more detailed study of the effects of bronchodilator on ventilation distribution, using the new SPECT/CT imaging facilities at Royal North Shore Hospital.

Methods for measuring exhaled nitric oxide
Airway inflammation is a well-established determinant of AHR, and it is becoming increasingly evident that simple measures of airway inflammation are useful both in the diagnosis and management of asthma. The level of nitric oxide in the exhaled breath (eNO) is a simple measure of airway inflammation, and the development of simple, inexpensive methods for measuring eNO form part of our current research program for the new CRC for Asthma and Airways. We first established that our new measurement technique is accurate and highly reproducible in adults. Melissa McClean then undertook a preliminary study in children from the CAPS cohort to determine the feasibility of these new methods in children. We found that the smaller lung volumes in children required a modification of the device, and our biomedical engineer, Aaron Skelsey, was able to solve the problem. A follow-up study using the modified device has shown a vast improvement in the repeatability and accuracy of the device in children. The new device will be further tested in children with a wider age range as part of a new collaboration that has been established with paediatric respiratory specialists Dr Paul Robinson and Dr Hiran Selvadurai at The Children’s Hospital at Westmead.

Use of the FOT to measure airway calibre
Standard spirometric techniques used to measure airway calibre are technically very difficult to perform correctly and require a lot of effort from the patient. The FOT is used to measure airway calibre without the need for deep breaths or maximal efforts from the patient. As part of our research program for the CRC for Asthma and Airways we are currently undertaking studies to compare our new FOT measurements with standard spirometry for measuring changes in airway calibre induced either by bronchodilator (increased airway calibre) or bronchial challenge (reduced airway calibre).

Bronchodilator response is being measured in 600 people over the age of 40 as part of the BOLD study which is being carried out by the WIMR Epidemiology Group. Preliminary analysis of data from 77 healthy normal subjects tested in the BOLD study has been compared with data from 18 patients with COPD studied in the laboratory. Bronchodilator caused significant improvements in airway calibre in both normal subjects and patients with COPD. The magnitude of improvement in one of the FOT variables, namely the reactance, was greater in the COPD patients than in the normals, suggesting that it might be used as a diagnostic tool. However, further studies are needed to know if these changes in reactance are clinically meaningful.

Bronchial challenges are used to measure the sensitivity of the airways to stimuli that cause airway narrowing. A study commissioned by our CRC partner, Pharmaxis Ltd, has just commenced to determine if the response to Aridol challenge can be measured reliably using FOT variables.