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ABOUT 18 months ago Josh Cummins, then 11 years old, had one of his asthma attacks. His mother took to him straight to their GP, but the drugs that usually helped didn鈥檛 seem to be working this time. 鈥淢y chest felt very tight, and the more I became worked up, the harder I was finding it to breathe,鈥� Josh remembers. Within minutes he was being rushed to A&E. 鈥淚 felt like I needed to get to the hospital very quickly,鈥� he says. 鈥淚t was really frightening.鈥�

The hospital managed to get Josh鈥檚 symptoms under control, and the medicines he takes have been changed to reduce the risk of such a severe attack happening again. But now he needs to wear a device that pumps a drug into his body continuously through a needle in his belly. It鈥檚 strong stuff that makes Josh feels sick most of the time. And even on this regimen, he gets breathless after walking only a few metres, so he misses out on a lot of the activities other children take for granted.

Asthma is usually seen as a fairly mild condition whose symptoms can be kept in check with the right medicines, but Josh鈥檚 story shows it is one disease we are not on top of. Worryingly, it is becoming more common in western countries. Around 1 in 8 British children have the condition, for example 鈥� and no one knows why. And while most of these cases are mild, there are some people that cannot be helped by even the strongest drugs.

Our current modes of tackling asthma are clearly inadequate 鈥� but that may be about to change. A growing number of researchers have started to rethink the fundamental nature of this disease. Asthma has long been seen as an intermittent disorder, characterised by temporary bouts of inflammation of the airways, which lead to wheezing, coughing and breathlessness; after each attack, the airways return to normal. But some scientists don鈥檛 accept this view. Instead, they argue, it may be a disease of early development that causes permanent changes to the structure and working of airways. 鈥淥ur thinking is being turned around,鈥� says Stephen Holgate of the University of Southampton in the UK, one of the leading proponents of the new theory. 鈥淚f you begin to uncouple from the traditional thinking, and start to explore why we have failed to overcome the disease, you can open up a whole new range of therapeutic possibilities.鈥�

For decades, doctors have focused on the inflammatory aspects of asthma 鈥� understandably, because these are clearly central to the acute attack. When a susceptible person encounters one of their triggers 鈥� such as animal fur, pollen, cigarette smoke or house dust mite faeces 鈥� their airways quickly become inflamed. Immune cells circulating in the blood infiltrate the airways and release a cascade of inflammatory messenger chemicals. Mucus production increases and the muscles surrounding the airway tubes contract, narrowing the space through which air can flow, causing the characteristic wheezing, coughing and shortness of breath.

But what happens between attacks? The standard view used to be that the airways return to normal. But in 1992, a team led by Jean Bousquet at the University of Montpellier I in France provided clear evidence from studies of patients鈥� airways that in at least some asthmatic adults the airway walls are permanently narrowed and thickened. Over the following years, Bousquet and others went on to discover several ways in which asthmatic airways differ from healthy ones (see Graphic). The smooth muscle surrounding the tubes of the airways is three to four times as thick as in non-asthmatics, and the muscle is much 鈥渢witchier鈥�, constricting in response to normally innocuous stimuli. A layer of the tubes鈥� basement membrane is thicker and contains more collagens, key proteins that act as scaffolding for tissue. There are more and bigger mucus glands, and the whole wall is perfused with more blood vessels.

Bousquet鈥檚 team dubbed this collection of changes 鈥渞emodelling鈥� of the airways. At this stage, the prevailing idea was that remodelling was a consequence of long-term inflammation; it was seen as a kind of scarring from the repeated attacks. But in the past few years, several strands of evidence have emerged that suggest remodelling also plays a more significant role.

First came the worrying finding that steroids 鈥� which are undoubtedly the best medicine for suppressing inflammation and reducing the frequency of asthma attacks 鈥� make no long-term difference to how well people鈥檚 lungs work. At least two large-scale trials in children have shown that steroids do not benefit patients鈥� underlying lung function, as gauged by the 鈥減eak flow鈥� test, which measures the volume of air that can be forced out in a single, rapid exhalation. This despite the fact that the children who received steroids in the trials had fewer asthma attacks and fewer symptoms than those who were given placebo.

If remodelling were purely a legacy of inflammation, then calming the inflammation should stop or at least reduce it, points out Bousquet. As this does not appear to happen, the suspicion began to arise that remodelling might be fundamental to the disease, rather than simply one of its consequences.

In an effort to investigate when remodelling starts, Finn Rasmussen and colleagues at McMaster University in Hamilton, Ontario, in Canada and the University of Otago, New Zealand, tracked more than 1000 children up to their 26th birthday. They found that those who had consistently low peak flow measures at ages 18 and 26 had already had low peak flow measures by age 9 (American Journal of Respiratory and Critical Care Medicine, vol 165, p 1480). These findings suggest the process starts early, they concluded.

This idea has now found direct support from studies of tissue samples taken from the airways of children with asthma. Until recently, researchers had excluded children from biopsy studies, to avoid subjecting them to unnecessary investigations. But last year researchers at the Royal Brompton Hospital in London did a study using biopsies from children already in hospital having a bronchoscopy for medical reasons (American Journal of Respiratory and Critical Care Medicine, vol 167, p 78). They looked at biopsies from 19 children with severe asthma 鈥� one of them Josh 鈥� as well as 10 samples from non-asthmatic children and some adults.

The airways of Josh and the other children with severe asthma had significantly thicker basement membranes, a feature thought to be a key indicator of remodelling. In fact, their airways were comparable to those seen in severely asthmatic adults. Surprisingly, the extent of thickening did not correlate with the amount of inflammation in the airways at the time of the biopsy. 鈥淭his showed us that structural changes are happening to the airway much earlier than we thought,鈥� says Andrew Bush, one of the researchers.

Clinching evidence

The impact of this study, as well as others that have since replicated its results, has been profound. While the treatment trials with steroids and the long-term tracking study had provided only indirect evidence for remodelling at an early age, the bronchoscopy studies leave no doubt in Bousquet鈥檚 mind. Together, the different strands of evidence add up to a new way of looking at asthma, he says.

According to this view, remodelling is not just a consequence of asthma: it is also a cause. Bousquet believes that patients鈥� airways develop with the structural abnormalities of remodelling, and, as asthma progresses, the chronic inflammation leads to further remodelling. 鈥淚t seems that remodelling may be separate from inflammation, although it may be enhanced by inflammation,鈥� he says.

So what could be making the remodelling occur in the first place? Surprisingly for such a common disease, scientists do not know what causes asthma. Neither do they know why it is becoming more common, although theories abound (see 鈥淭he mystery of soaring asthma rates鈥�). Asthma does not follow the simple inheritance rules of single-gene disorders, but twin studies have shown that genes do play a major role. The condition probably arises when people who have inherited one or more vulnerability genes experience something in their environment, perhaps in early childhood or even in the womb.

Preliminary research suggests that, in monkeys at least, exposure at an early age to common asthma triggers causes dramatic changes to the airways, including some that in humans would be classed as remodelling. Researchers at the University of California, Davis, exposed infant macaque monkeys to air containing either extracts of house dust mite or ozone at levels seen in Los Angeles in summer, or both together.

鈥淭he results were a little disquieting,鈥� says cell biologist Charles Plopper, who led the research. The monkeys exposed to both allergen and ozone had dramatically altered lungs (Toxicology and Applied Pharmacology, vol 191, p 74). As with human asthma, their airways had more muscle and collagen, and there was also a reduced surface area for gas exchange at the alveoli. Like asthmatic humans, the monkeys also had twitchy, hyper-responsive airways.

Intriguing as these findings are, they cannot necessarily be extrapolated to people. For one thing, the growth in childhood asthma is not confined to cities with high ozone levels. Also, all the monkeys exposed to the two triggers developed damaged airways, while in humans asthma development seems to be down to a combination of environmental factors and genetic susceptibility.

The hunt for the genes involved in asthma recently hotted up. Several genes have been linked to the disease so far, but two years ago a gene that could play a role in remodelling was identified for the first time (Nature, vol 418, p 426). It was found by a collaboration of researchers at the University of Southampton, the company Genome Therapeutics in Waltham, Massachusetts, and the US-based pharmaceutical firm Schering-Plough. They studied 460 families and found that individuals with asthma were more likely to have certain variants of a gene called ADAM33, which sits on the short arm of chromosome 20.

ADAM33 encodes an enzyme that belongs to a large family known as metalloprotease-disintegrins. These enzymes sit on a cell鈥檚 surface membrane and affect cell proliferation, among other things. The ADAM33 enzyme is most commonly found in airways muscle and fibroblasts. Based on what is known about other ADAM proteins, Holgate speculates that ADAM33 controls the growth and proliferation of muscle cells and fibroblasts, so changes in its expression could lead to over-muscled airways that are more prone to overreact to allergens. 鈥淚t could generate a growth factor that could stimulate airway muscle to increase,鈥� he says.

Within the past few months, evidence has emerged that ADAM33 directly affects lung function. Angela Simpson and colleagues at Wythenshawe Hospital in Manchester, UK, was due to report at a conference this week that children with certain variants of the gene had lower than average peak flow values.

Could ADAM33 expression be affected by environmental factors too? To test this hunch, Holgate鈥檚 team has been culturing lung tissue from mouse embryos and exposing it to various chemicals, including extracts of cigarette smoke, as women who smoke during pregnancy are known to increase their babies鈥� risk of asthma. Sure enough, they say they have found that smoke components do indeed alter ADAM33 expression, and while it is a long way from mouse cells to whole humans, Holgate speculates that smoke, allergens or components of the mother鈥檚 diet could cross the placenta and affect expression of the gene. 鈥淢aybe asthma is a developmental problem in the way that the airways form,鈥� he says. 鈥淢aybe it gives the child a susceptible set of tubes that have been pre-programmed by interactions between genes and the environment. Instead of remodelling, you could call it 鈥榩re-modelling鈥�.鈥�

Remodelling is by no means universally accepted as the root cause of asthma. One leading asthma researcher, Peter Barnes at Imperial College London, goes so far as to dismiss the current excitement as a fad. 鈥淧eople make more of remodelling than they should,鈥� he says. While he does not dispute that remodelling occurs, he thinks it affects only the minority of patients with severe asthma. Only those people with the most serious asthma reach hospital, so the airway biopsies from hospitalised children that have been taken as evidence of remodelling as a root cause are hardly representative of the asthmatic population, Barnes argues.

But if Bousquet, Holgate, Bush and others are right, the remodelling theory would open the way to a new generation of asthma drugs that stopped remodelling in its tracks, and perhaps 鈥� if susceptible families could be identified early enough 鈥� before it has even begun. Asthma is such a common condition, the rewards for the drug industry could be huge.

There is already reason to believe that remodelling is no unstoppable juggernaut. Last October, a team led by Barry Kay at Imperial College London showed that some aspects of remodelling could be held back by injecting patients with a monoclonal antibody that indirectly reduces levels of a chemical mediator thought to be involved (The Journal of Clinical Investigation, vol 112, p 1029). While the antibody itself is probably not a practical asthma therapy, the researchers consider their results to be proof of principle 鈥� and that effective new drugs could follow.

Other researchers are pursuing different routes. Bush sees potential in a class of antibiotics known as macrolides, which in mice at least, seem to slow structural changes to the airways. Holgate envisions drugs that inhibit ADAM33 or other enzymes involved in remodelling. 鈥淚 am very hopeful,鈥� he says. For Josh and other children whose lives are dominated by their asthma, that has to be encouraging news.