New clue on delayed asthma attack

BBC News has reported that scientists have “stumbled on a potential new treatment for delayed asthma attacks”. Delayed attacks, also known as late asthmatic response (LAR), can occur several hours after exposure to asthma triggers such as pollen.

In experiments on rats and mice, researchers found that blocking sensory nerve signals can significantly reduce the symptoms of a LAR, which can affect up to 50% of asthma sufferers. The researchers were also able to identify specific biological molecules called ‘TRPA1 channels’ that seem to be important in this process in rats and mice, and which could provide further targets for future research.

However, as this is early-stage research in rodents it is not clear whether the new findings of this animal study will be directly applicable to humans. Further experiments on human asthma suffers will be needed to better understand the processes of LAR in people. The researchers mention that they may have found a potential new asthma treatment in nerve-blocking ‘anticholinergic’ drugs, which are already used in the management of chronic obstructive airways diseases such as bronchitis. However, before they could be used to treat asthma they would need an extension to their licence. Studies of anticholinergic drugs in asthma have already been undertaken, and this new research may add further information on how use of these medications might be optimised.

Where did the story come from?

The study was carried out by researchers from Imperial College London and was funded by the Medical Research Council. The authors declare having no competing interests. The study was published in the peer-reviewed medical journal Thorax.

The BBC has generally covered the story accurately, highlighting that the experiments were in mice and rats. However, the assertion that a “potential new treatment” may have been discovered would depend on the results of trials in humans, and must be considered alongside existing research on asthma treatment that has been performed and summarised by the Cochrane Collaboration.

What kind of research was this?

This research was a laboratory-based study of asthma-like responses in rats and mice that were induced to have a reaction when exposed to a specific allergen.

Asthma attacks occur as a result of exposure to allergens such as pollen or house dust mites. In people, exposure to relevant allergens leads to an early asthmatic response (EAR) within minutes. The researchers say that approximately 50% of people who experience EAR will also develop a late asthmatic response (LAR) three to eight hours after the initial allergen exposure. LAR has a large impact on the lives of people with asthma, and it is also used in a clinical setting to assess treatments for asthma. Despite this, the biological mechanisms leading to LAR are unclear, and so this study sought to better understand the process.

Animal experiments are an appropriate first stage in understanding the underlying biology of a disease such as LAR, as discoveries in mice and rats can potentially tell us important things about the disease in humans. Research on humans is typically the next step towards better understanding the processes of a disease.

What did the research involve?

Rats and mice were made sensitive to a specific substance called ovalbumin, which would act as an allergen. The rats and mice were then exposed to ovalbumin or a saline aerosol spray that caused them to display asthma-like symptoms and biological responses. Once exposed to the antigen trigger the animals were tested for their LAR responses.

LAR was assessed using subjective measures. Researchers listened for an audible wheeze, looked for visual signs of respiratory distress and measured lung function. These tests were performed on animals that were awake, as anaesthetising them could have interfered with their nerve signals (which are thought to be important in the process leading to LAR).

To investigate the effect of anaesthetic on LAR the researchers anaesthetised the conscious rats after LAR was induced using ovalbumin. Anaesthetics work by blocking the sensory nerves in the body.

In a separate experiment, the rats were given a variety of different drugs that block specific biological processes within the body. The researchers aimed to see whether any of the drugs would disrupt the LAR, which would indicate which processes are important in LAR. Among the drugs they tested was tiotropium, which is prescribed for the long-term management of chronic obstructive airways disease. The drug is a type of ‘anticholinergic’, meaning that it reduces neurological signals by acting on a specific substance called acetylcholine. Tiotropium is marketed under the name ‘Spiriva’ in the UK.

What were the basic results?

• Exposure to the allergen caused EAR and LAR in the rats and mice
• Clinically-effective asthma drugs (for humans) relieved EAR symptoms but did not impact on the LAR in the animals.
• General anaesthesia did not affect EAR but reduced LAR completely – this implied that sensory nerve activation was particularly important in causing LAR.
• Use of an anticholinergic drug (tiotropium) significantly reduced the effect of LAR. This reinforced the hypothesis that neurological signalling, particularly via acetylcholine, is important in LAR.
• Blocking a specific ion channel (TRPA1) was found to inhibit LAR in both the rats and mice. TRPA1 is known to be important in initiating airway reflexes in response to certain stimuli.

How did the researchers interpret the results?

The researchers concluded that their results suggest that LAR is caused by a two-phase process: initially an allergen triggers airway sensory nerves via the activation of TRPA1 ion channels, which then triggers a series of further neurological signalling involving acetylcholine. This signalling then leads to airway constriction, which causes the breathing difficulty associated with asthma.

The researchers suggest that their results may explain the mechanisms that cause anticholinergic substances to improve the symptoms and lung functioning of asthma patients – an observation reported in other recent studies.

Conclusion

This animal research contributes important new information to the biological understanding of LAR in mice and rats, some of which may be applicable to humans in the future. Through their work the authors of this study have demonstrated the importance of the role of sensory neurones in LAR, and they have identified specific biological molecules (TRPA1 channels) that seem to be important in this process in rats and mice.

However, it is not clear whether the findings of this animal study will be directly applicable to humans yet as further experiments on human asthma patients may be needed to better understand the processes in people.

This knowledge can potentially guide further research aiming to use anticholinergic drugs to reduce the symptoms of human asthma. As systematic reviews are already available on related areas it is important that any new research is seen in the context of what is already known about these drugs.