Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma.
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.


CONCLUSIONS
These results emphasize the important role of Trk receptor signaling in the development of asthma.


CONCLUSIONS
Our data indicate that blocking of Trk receptor signaling might reduce asthma symptoms.
Nassenstein
Christina
C
Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
Dawbarn
David
D
Pollock
Kenneth
K
Allen
Shelley Jane
SJ
Erpenbeck
Veit Johannes
VJ
Spies
Emma
E
Krug
Norbert
N
Braun
Armin
A
D000485:Allergens / Q000502:physiology; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008168:Lung / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D000485:Allergens; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC