Asthma

Airway smooth muscle work wins TSANZ Research Medal for Prof Alan James


Prof Alan James

Professor Alan James remembers the first time he saw a patient die from asthma. He was just starting out in medicine, working in hospitals in London and then Singapore. He recalls the small Changi Hospital with no emergency department.

“A person came in with asthma, a man – a 50-year old chap – he’d had multiple attacks before and probably didn’t realise this one was any different to the many others he’d had,” recounts Professor James of the day.

“He died in front of us. It was the first time I realised that a patient can die from asthma.”

This month the respiratory physician was the joint winner of the prestigious TSANZ Research Medal (read about co-winner Professor Shyamali Dharmage and her work on COPD trajectories here). It is awarded each year in recognition of outstanding contributions to the advancement of knowledge in respiratory medicine or science.

Reflecting on his career Professor James credits that day in Changi Hospital as being significant in his decision to pursue a career in research.

“I was captivated by asthma when I was working in the Changi Hospital in Singapore and with thoughts of my experience there I returned home to Perth and I started in the respiratory training program with colleagues Bill Musk, Gerry Ryan and Bill Finucane who were fantastic mentors.”

Together they began looking at hyper-responsiveness in asthma, setting up a trial to determine responsiveness of patients with COPD to corticosteroids.

But while none of the measures they investigated went on to predict responsiveness to the drugs, the researchers did discover in the writing of the paper of the findings, that it was the patients with sputum eosinophilia who were most likely to respond well to corticosteroid therapy. This made their team one of the first to point out the predictive value of eosinophils in that setting.

Airway smooth muscles

His next move, to Canada, came not long after he met Professor Jim Hogg, now Emeritus Professor of Pathology at the University of British Columbia, ahead of a TSANZ scientific meeting where he was charged with being the professor’s tour guide.

“I want you to drive Jim Hogg around and look after him,” he recalls of the instruction from Professor Bill Musk, now emeritus physician at Sir Charles Gairdner Hospital in Perth.

“Because I had the worst car in the department I borrowed my brother-in-law’s BMW,” he says, describing it as ‘sort of embarrassing’.

“Especially, since I was a humble trainee, I looked like I was doing much better than I was,” he jokes.

“So I got to meet Jim Hogg. Later on, when I discovered that he and Peter Pare were doing work on asthma and airway responsiveness I wrote to them and went over to British Columbia working with them between 1985 and 1987 producing about 10 papers from our research.”

One of the most lauded of those papers was the study investigating airway mechanics in asthma. It looked at how airway smooth muscle in asthma leads to mechanical changes resulting in variable airway narrowing and variable symptoms that are characteristic of asthma.

At the time, the only way airway smooth muscle could be measured was through postmortem specimens. But by looking at the internal perimeter of the airway, Professor James and colleagues were, for the first time, able to compare the airways of asthmatics and non-asthmatics qualitatively, finding more smooth muscle in asthmatics and particularly more in severe asthma.

“That set me on the path of studying airway smooth muscles and I’m still doing it today,” he says of the work that has contributed much of what’s known about the physiological pathway of asthma.

Excessive airway narrowing

The pull of family brought Professor James back to Western Australia where he picked up where he left off – looking at ways to predict airway responsiveness to drug therapy. But this time, taking what he’d’ discovered in Canada, he was looking at the reactivity of the airways of asthmatics to drugs like histamine or methacholine that make their airway smooth muscle contract.

“One of the things we were aware of when we were away was that not only do the airways of asthmatics seem to be more sensitive but there doesn’t seem to be any control over how much their airway narrows. In non-asthmatics you can’t really make their airways narrow to the point where they get wheezy and short of breath – even if you give them high doses of inhaled histamine or methacholine.”

But at the time the phenomenon of excessive airway narrowing, or loss of the limit, hadn’t been looked at in the general population apart from in a small number of people in laboratory settings. Did non-asthmatics experience airway narrowing and, if they did, what was it about their airways that protected them from the condition’s deadly effects?

It was a lead that Professor James picked up and one that took him to the Busselton Health Study – recognised now internationally as one of the longest-running population health research programs of its kind – and where he now chairs the Busselton Population Medical Research Institute.

“They were doing a survey down in Busselton that’s been running since 1966 and at the time I thought, we could see people in the community and give them high doses of methacholine to find out if people who truly don’t have symptoms or history of asthma have this limited airway narrowing and maximal response.

They found that in about one in 200 people in the cohort did.

Airway muscle thickness and asthma severity

During the late 1980s and early 1990s Professor James recalls that a wave of asthma deaths in developed countries heightened interest in asthma research around the world. Along with his PhD student at the time Neil Carroll – who Professor James now describes as life-long friend – they established a second study looking at postmortem tissues of people who had a history of asthma but who died of other causes.

“The question was, does this increased airway muscle thickness only appear in the people who die from their asthma – or is it present in people who don’t have such severe disease? Could there be some other problem, chronic inflammation perhaps, causing people with asthma to die?”

“We were able to show that the muscle thickness involved bigger and medium-sized airways and was related to the severity of asthma … from that we wanted to know whether that increased muscle was due to more or bigger muscle cells, which would give us an indication of where they might come from in the first place.”

The outcomes from those studies have contributed to much of what is known about the pathophysiology of asthma today.

“We’ve shown that while smooth muscle increase is related to asthma severity, importantly, it’s not related to how long you have asthma or how old you are.”

In other words, it looks like the increased muscle that determines how severe your asthma is, is present from early life and may be determined by factors around birth or even before birth.

“There’s been some interesting overlap between the various studies to come out of the Busselton survey,” says Professor James, referring to one in particular that received a lot of attention.

Genetic link to airways development

In 1994, more than 5,000 Busselton adults had their lung function measured and blood samples taken. DNA was extracted from the blood samples and compared against lung function information from many of the same people back to 1966 when the survey began, allowing researchers to look at changes in lung function.

“We were able to show that the genes that determine lung function are related to development of the airways in utero. So, if you’re born with small lung function you tend to remain with small lung function throughout your life.”

What’s more, they found those genes do not predict the rate of decline of lung function as an adult.

“That means there are  other processes that determine that – suggesting that what your lung function is at any time of your life is related to factors that determine lung and airway structure possibly before you’re born and other factors early in life that determine how rapidly your lungs grow before it all declines with age.”

People with certain combinations of these genes may have an increased risk of lung damage from exposure to cigarette smoke or childhood respiratory infections.

Airway smooth muscle a set determinant

Getting back to airway smooth muscle, Professor James says he’s now convinced that airway smooth muscle is one of those independent determinants of developing asthma.

“We don’t believe it’s related to proliferation because of chronic inflammation,” he says – a suggestion which has long been debated.

“We’ve done studies to demonstrate that proliferation is not increased in people with asthma and therefore that it’s a set determinant of how severe your asthma is.”

Now Professor James is trying to figure out how to treat the airway smooth muscle itself. He’s investigating a treatment called bronchial thermoplasty, a relatively new therapy that applies directed heat to the airway walls, reducing the bulk of airway smooth muscle and so the potential for airway constriction.

The device used to administer bronchial thermoplasty was registered in Australia in 2013 – but it doesn’t work for everyone and it’s unclear who the best people are to treat, explains Professor James.

At the moment he’s investigating a new technique, optical coherence tomography, to measure where the smooth muscle has increased in the space between the airway wall.

“Using this technique, we think that does open an opportunity to cure asthma – the thermoplasty does work; it’s used in moderate to severe cases of asthma where there’s already quite a lot of damage and scarring over a lifetime. There may be other ways of doing it earlier but if we learn how to measure it properly, intensively and safely then we can start looking at new treatments,” he concludes.

 Correction: An earlier version of this story incorrectly referred to Alan James’ colleague Peter Pare as Peter Pallet. We also note  the Busselton Population Medical Research Institute was incorrectly referred to as the Busselton Study Medical Research Institute. the limbic apologises for these errors.

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