Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma - 20/08/11
, David Dawbarn, PhD b, , Kenneth Pollock, PhD c, Shelley Jane Allen, PhD b, Veit Johannes Erpenbeck, MD, PhD a, Emma Spies a, Norbert Krug, MD a, Armin Braun, PhD a, ⁎ 
Reprint requests: Armin Braun, PhD, Immunology and Allergology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.Hannover, Germany, and Bristol and Surrey, United Kingdom
Abstract |
Background |
Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to promote hyperreactivity of sensory neurons and to induce airway inflammation. Hyperreactivity of sensory nerves is one key mechanism of airway hyperreactivity that is defined as an abnormal reactivity of the airways to unspecific stimuli, such as cold air and cigarette smoke. Neurotrophins use a dual-receptor system consisting of Trk receptor tyrosine kinases and the structurally unrelated p75 neurotrophin receptor.
Objective |
The aim of this study was to characterize the distribution, allergen-dependent regulation, and functional relevance of the Trk receptors in allergic asthma.
Methods |
BALB/c mice were sensitized to ovalbumin. After provocation with ovalbumin or vehicle aerosol, respectively, Trk receptor expression was analyzed in lung tissue by means of fluorescence microscopy and quantitative RT-PCR. To assess the functional relevance of Trk receptors in asthma, we tested the effects of the intranasally administered pan-Trk receptor decoy REN1826. Allergic airway inflammation was quantified and lung function was measured by using head-out body plethysmography.
Results |
Trk receptors were expressed in neurons, airway smooth muscle cells, and cells of the inflammatory infiltrate surrounding the bronchi and upregulated after allergen challenge. Local application of REN1826 reduced IL-4 and IL-5 cytokine levels but had no effect on IL-13 levels or the cellular composition of bronchoalveolar lavage fluid cells. Furthermore, REN1826 decreased broncho-obstruction in response to sensory stimuli, indicating a diminished hyperreactivity of sensory nerves, but did not influence airway smooth muscle hyperreactivity in response to methacholine.
Conclusion |
These results emphasize the important role of Trk receptor signaling in the development of asthma.
Clinical implications |
Our data indicate that blocking of Trk receptor signaling might reduce asthma symptoms.
Le texte complet de cet article est disponible en PDF.Key words : Sensory nerves, airway hyperreactivity, airway inflammation, reflex bronchospasm, capsaicin
Abbreviations used : BALF, BDNF, EF50, HBP, MCh, NGF, NT, OVA, P75NTR, PC, PD, REN1826, Tb, TBS, TRPV1
Plan
| Supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 587, B4) and by direct financial support from ReNeuron Ltd and the Fraunhofer Society. Disclosure of potential conflict of interest: C. Nassenstein has received grant support from the German Research Foundation. D. Dawbarn has received grant support from Wellcome Trust and ReNeuron PLC. S. J. Allen has received grant support from Wellcome Trust and ReNeuron PLC. K. Pollock is employed by ReNeuron Ltd. The rest of the authors have declared that they have no conflict of interest. |
Vol 118 - N° 3
P. 597-605 - septembre 2006 Retour au numéro
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