Neural mechanisms and axon reflexes in asthma: Where are we?

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For many years, asthma has been classified as a “neural” disease, with an imbalance between constrictor and dilator nerves being responsible for the symptomatology. Although, nowadays, asthma is recognized as an inflammatory disorder of the airways, neural mechanisms remain very important; axon reflexes, in particular, have received a lot of attention in recent years. In this commentary, an overview is given on the innervation of the airways and its relevance in asthma, and potential new insights in airway innervation are discussed. In a second part, the role of axon reflexes is highlighted. Although neuropeptides such as substance P and neurokinin A are present in human airways, where they produce many of the features characteristic of asthma, and although there is an elevation of their content in induced sputum from asthmatics, there is still no clear direct evidence for the existence of operational axon reflexes in human airways. Most of the research focused on this subject is performed in guinea pigs, where such an axon reflex clearly operates in the airways. In these animals, different receptors have been identified on C-fiber endings, which, upon stimulation, cause inhibition of neuropeptide release. Some of these receptors have also been identified on human airway nerves. Therefore, it has been suggested that modulation of axon reflexes could be of potential benefit in asthma treatment. Indeed, some drugs (e.g. sodium cromoglycate, nedocromil sodium, and ketotifen), which have been demonstrated to partially inhibit neuropeptide release in guinea pig airways, have anti-inflammatory effects in asthma. Other drugs, however, such as β 2-mimetics, which have a much more pronounced inhibitory effect on neuropeptide release in guinea pig airways, do not seem to have any anti-inflammatory effects in human asthma. In conclusion, although there is a lot of indirect evidence for the existence of axon reflex mechanisms in human airways, most of the data now available are derived from animal studies. The key question of whether axon reflexes are operational in human airways remains unanswered. Hopefully, the near future will bring a solution to this enigma with the introduction of very potent tachykinin antagonists for the treatment of human asthma.