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Neuronal remodeling in asthma and COPD

Investigators involved: Loes Kistemaker, Reinoud Gosens

Airway nerves regulate many aspects of airway function, including breathing, airway smooth muscle tone, mucous secretion and cough. In obstructive lung diseases such as asthma and COPD, there is an increase in neural tone, which contributes to bronchoconstriction and airflow limitation in these diseases. Drugs inhibiting the effects of the neurotransmitter acetylcholine, so called anticholinergic drugs, are effective bronchodilators in asthma and COPD, and represents a first line of treatment in the latter. However, the mechanisms underlying an increase in neural tone have only partly been resolved and it is unknown how chronic lung disease affects airway nerve structure. In this research project, we investigate the hypothesis that airway nerves undergo changes in asthma and COPD, including changes in phenotype and isotype, termed as remodeling of airway nerves, or neuronal remodeling. We investigate the nature of neuronal remodeling in the lung in detail and hypothesize that this is driven by neurotrophins; mediators which exhibit neuronal growth activity.
Neuronal remodeling

A particularly interesting neurotrophin in asthma pathogenesis is brain-derived neurotrophin factor (BDNF). BNDF expression is upregulated in asthma and there are genetic associations of the BDNF gene with asthma. It is already shown that BDNF plays a role in neurogenesis in the airway (see picture). A clear link exists between neurotrophins and an increased cholinergic tone, however, it is unknown whether BDNF drives neuronal remodeling in asthma. We hypothesized that neuronal remodeling is a characteristic feature of asthma, which is driven by BDNF, and contributes to airway hyperresponsiveness, airway inflammation, and airway remodeling; all core features of asthma. We have the unique opportunity to study this both in models of allergic asthma and in human tissues. Neuronal remodeling in these tissues will be characterized in detail, using several imaging techniques. In addition, a gene expression signature of neuronal remodeling in asthma will be defined using existing databases. Moreover, we are investigating the functional consequences of neuronal remodeling on airway hyperresponsiveness, airway inflammation, and airway remodeling. Understanding the mechanisms that drive an increased cholinergic tone may lead to improved treatment for asthma and COPD patients.

Relevant literature:

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling. Kistemaker LE, Gosens R. Trends Pharmacol Sci. 2015 36(3):164-171.

Last modified:03 October 2017 1.11 p.m.