The rise and rise of asthma
Box 2 | Australian research
Whilst Australia has one of the highest rates of asthma in the world, Australian researchers are uncovering more about its causes and finding potential new mechanisms with which to treat it. Finding out more about the reasons why allergic (extrinsic) asthmatics react so strongly to their allergic triggers is being studied by several Australian research teams.
One of the great mysteries of the allergic type of asthma – or indeed of any allergic condition – is why the body makes such a fuss over totally harmless airborne particles. We know that what we call allergens are simply materials mistaken for invading microbes or their products. It’s a costly mistake: the entire immune system is put on red alert to counter a non-existent threat, and the result is the gamut of symptoms that sufferers must endure. But why? Grass pollen or mite faeces should not be genuine problems for the human body; after all, the majority of people don’t react to them at all.
Asthma begins in early life
Research stemming from Perth has established that a large proportion of asthma that occurs during the school years and often continues into adulthood is a result from damage to the growing lung and airways when a person is only 2 to 3 years of age. The main culprits are allergies to airborne agents such as dust mites and respiratory viruses. Teams from the Telethon Institute for Child Health Research led by Professors Patrick Holt and Peter Sly (now at the University of Queensland) and from the University of Western Australia School of Paediatrics and Child Health led by Professor Peter Lesouef have produced some new findings involving the inflammatory pathways that are triggered by such airborne irritants. The team have discovered that “storms” of cytokines – small cell-signaling protein molecules – are created in the airways, cause more pro-inflammatory cells to be released from the bone marrow. This in turn leads to the rapid worsening of symptoms in the airways. Understanding more about this mechanism is going a long way to explaining the annual epidemics of severe asthma that fill paediatric hospital beds around the world during autumn and winter, and is providing exciting new clues for the development of more effective asthma treatments.
Eosinophils respond to allergens in asthmatics
Researchers know that the chief culprit in causing much of the damage in an asthma attack is a fairly rare type of white blood cell called the eosinophil. Eosinophils are designed to be the ‘heavy force’ of the immune system, being equipped to deal with occasional 'big' invaders such as worms. It seems quite bizarre, but in asthmatics these cells are unleashing their strong destructive power onto the patient’s uninfected tissue without any provocation.
So why and how are the eosinophils brought into the airways and lungs by allergens? In 1985, a team in London headed by Professor Colin Sanderson discovered that interleukin (an immune system molecule) was controlling eosinophil production. His team moved to Perth in 1993 and their research has since shown that there are actually two chemical messengers involved in eosinophil control, known now as interleukin-4 (IL-4) and interleukin-5 (IL-5). These signaling molecules are secreted into the bloodstream by other cells of the immune system (T-cells), and can attract eosinophils. Researchers are now continuing to investigate how the release of these interleukins can be blocked, in order to stop the accumulation of eosinophils that may subsequently lead to an asthma attack.
MicroRNA as a new target in asthma
The genomics revolution is increasingly providing many new opportunities for asthma research. For example at the University of Newcastle Professor Paul Foster’s group are attempting to tease apart some of the complex mechanisms that underlie the body’s excessive white blood cell response to inhaled asthma triggers. It has now been revealed that specific receptors on cells of the immune system are important for detecting the molecular patterns of airborne antigens that become trapped in mucous lining the airways, causing T cell responses. Professor Fosters group have shown that purposely setting off these receptors with house dust mite allergen (a major trigger of asthma attacks) causes allergic disease, and that importantly, this process is associated with the expression of a unique subset of small molecules known as microRNAs. They have found that selectively blocking these microRNAs decreases many of the major characteristics of asthma, such as airway inflammation, sensitivity to inhaled irritants, recruitment of eosinophils, and secretion of mucus which can plug the airways during an asthma attack. Their findings point towards targeting microRNA in the airways as an exciting new approach towards developing new anti-inflammatory treatments for allergic asthma.
Smooth muscle cells as active participants as opposed to innocent bystanders in inflammatory processes in the asthmatic airways
At the University of Sydney and the Woolcock Institute of Medical Research Professor Judith Black and colleagues are changing perceptions of the role of the airway smooth muscle –which lines the airway walls and which contracts to bring about the narrowing of the airways, wheeze and shortness of breath which occurs in asthma. Traditionally believed to be one of the main targets of airway inflammation causing the symptoms of asthma, it has been found that the smooth muscle is actively involved in both the generation and regulation of local inflammatory processes in conjunction with its neighbours – the epithelial and inflammatory cells. Evidence is rapidly accumulating that the smooth muscle itself may be innately abnormal. Certainly the amount of smooth muscle in the airways of people with asthma is increased and Professor Black’s team have shown that muscle cells taken from people with asthma multiply in the lab at nearly twice the normal rate. Researchers are hoping that this recently acquired knowledge will help in the development of new asthma treatments.
 Prof Judith Black’s team at the University of Sydney are studying the cellular and molecular basis of lung diseases such as asthma. Here PhD student Jade applies stain to sections of human lung tissue. (Image:Woolcock Institute of Medical Research, Sydney. Photography (c) Chris L Jones. |
Lipid pathways in allergic airways inflammation
Professor Charles Mackay’s research group at the Garvan Institute of Medical Research in Sydney is also providing new insights into asthma, including the role of lipids – a naturally occurring class of molecules in the body that include fats. They have found that a fatty acid binding protein called aP2 – a molecule already known to be involved in type 2 diabetes and obesity – is present in the lung where it plays a crucial role in controlling inflammation. The aP2 binding protein helps to recruit certain white blood cells into the lungs, and even more aP2 was produced when it was exposed to cytokines often associated with allergies and asthma. Using a mouse model, researchers removed the gene controlling aP2 production, and found that mice without aP2 were subsequently protected from asthma attacks. Blocking aP2 function is now being investigated as a novel approach to treat asthma and other inflammatory lung diseases.
In a further novel twist in the lipid saga, the Mackay group have also used mice to show that the short chain fatty acids produced by the fermentation of dietary fibre by microbes in the intestine may also play a central role in reducing inflammation outside of the gastrointestinal tract, including in asthma. This finding provides a potential mechanism for earlier findings in humans which suggest that control of the microflora via regular feeding of prebiotics or probiotics can in some circumstances protect against airway inflammation, and that maintaining a “normal” gut flora seems to be important in resistance to many inflammatory diseases. Lipid metabolites of this nature may therefore play an unexpectedly important mediator role, and it is hoped that finding out more about the pathways involved may lead to novel therapies in the future for asthma and other diseases.
Related sites
Asthma CRC Research
Developments in asthma research (the Asthma Foundation)
Telethon Institute for Child Health Research (Subiaco, Western Australia)
Centre for asthma and respiratory diseases (University of Newcastle, NSW)
Woolcock Institute of Medical Research (Glebe, NSW)
The Garvan Institute (Darlinghurst, NSW)
Cytokine Molecular Biology and Signalling Group (John Curtin School of Medical Research, The Australian National University, Canberra)
Asthma and Allergy Group (John Curtin School of Medical Research, The Australian National University, Canberra)
The modulation of allergic airways disease by Interleukin-4 and -5: Studies using cytokine deficient mice (McMaster University, Canada)
Information about asthma (National Asthma Council of Australia)
The asthma puzzle (Australia Advances, CSIRO) (requires QuickTime)
Page updated February 2011.