- Aanvrager: Mevrouw L.E.M. Kistemaker
Congresbezoek ERS 2018 periode 15 september 2018 t/m 19 september 2018 Betrokken project 4.2.15.039JO Posterpresentatie "Allergen-induced BDNF expression and neuronal remodeling contributes to airway hyperresponsiveness".
Long-acting anticholinergic drugs have recently been established as effective bronchodilators in asthma (1, 2). This underscores the importance of the cholinergic tone in asthma, which is the predominant driver of neurally mediated bronchoconstriction. It is generally accepted that cholinergic tone is increased in asthma. However, the mechanisms underlying an increased cholinergic tone have only partly been resolved and it is unknown how chronic asthma affects airway nerve structure. It is known that the expression of neurotrophins, which are growth factors for neurons, is increased in asthmatic patients. In particular the neurotrophin brain-derived neurotrophic factor (BDNF) is relevant, as the expression is increased in asthmatic airways (3) and in animal models of asthma (4), and there are genetic associations of the BDNF gene with asthma, further highlighting the relevance of BDNF in asthma (5). We hypothesize that the expression of BDNF is increased, which promotes remodeling of the airway nervous system and contributes to airway hyperresponsiveness (AHR).
This was investigated using animal models of asthma. Wild type and TrkB knock-in mice (the receptor for BDNF) were sensitized to ovalbumin (OA) and challenged acutely or chronically with OA. AHR to methacholine (MCh) was assessed in vivo in control and vagotomized animals and ex vivo in lung slices using MCh and vagal electrical field stimulation (EFS). Expression of the neuronal markers PGP9.5 and neurofilament, eosinophil number and smooth muscle mass were assessed by histology and Western Blot, and BDNF expression by ELISA.
Interestingly, chronic, and not acute OA exposure, increased PGP9.5 expression around the airways by 3.3-fold, suggesting that there is increased nerve density in asthma. Similar findings were observed for neurofilament expression assessed by Western Blot. This increased nerve density was associated with AHR, in particular in the chronic model. Thus, OA-induced AHR after acute exposure was not affected by vagotomy, whereas AHR in response to chronic exposure was attenuated. In lung slices, airway narrowing in response to MCh was not altered, whereas the response to EFS was significantly enhanced by OA, suggesting that it is vagally mediated. This was associated with a 1.6-fold increase in BDNF expression in lung tissue. Furthermore, using TrkB mice in which BDNF cannot signal anymore, no
increase in airway nerve density was observed, indicating that BDNF drives the increase in nerves density. In line with this, no AHR was observed in response to EFS in lung slices in TrkB KI mice, in contrast to control animals in which AHR was observed. Remarkably, airway inflammation and smooth muscle remodeling were not affected in TrkB KI mice, suggesting that the neuronal remodeling process occurs independent of that (6).
These results suggest that increased neuronal activity is involved in allergen-induced AHR, in particular in the chronic model, and supports the existence of a remodeling process of the airway nervous system that might be mediated via BDNF (6).
Neuronal remodeling is a novel concept in the field of asthma research. Interestingly, the concept is supported other data presented at the conference and published this month. It was shown by Drake et al. that airway innervation, in particular sensory innervation, and substance P expression were increased in moderate persistent asthmatic patients compared to mild intermittent asthmatic patients and healthy subjects (7). Furthermore, using a mouse model of asthma, the increase in sensory innervation was confirmed and associated with the level of eosinophils (7). In addition, increased sensory nerve density is observed in patient with chronic cough, which is a neuronal reflex mechanism and often associated with asthma (8). Finally, data was presented at ERS demonstrating that maternal exposure to the allergen house dust mite in mice affects sensory airway innervation in the offspring. Thus, acute house dust mite challenge increased sensory innervation in mice of exposed mothers, whereas it did not affect the innervation in mice that were not exposed before. Interestingly, this was associated with airway hyperresponsiveness.
Together, these data suggest that airway nerves undergo remodeling in airway diseases including asthma, which contributes to airway hyperresponsiveness and might be driven by neurotrophins including BDNF. Targeting neuronal remodeling or increased neurotrophin levels holds the potential as a novel treatment option for asthma in the future.