Airway hyper-responsiveness in allergic asthma in guinea-pigs is mediated by nerve growth factor via the induction of substance P: a potential role for trkA.
BACKGROUND
The neurotrophin nerve growth factor (NGF) has been implicated as a mediator in allergic asthma. Direct evidence that inhibition of NGF-induced activation of neurotrophin receptors leads to improvement of airway symptoms is lacking. We therefore studied the effects of inhibitors of NGF signal transduction on the development of airway hyper-responsiveness (AHR) and pulmonary inflammation in a guinea-pig model for allergic asthma.


METHODS
Airway responsiveness to the contractile agonist histamine was measured in vivo in guinea-pigs that were sensitized and challenged with ovalbumin (OVA). Inflammatory cell influx and NGF levels were determined in bronchoalveolar lavage fluid (BALF). Substance P, a key mediator of inflammation, was measured in lung tissue by radioimmunoassay, while substance P immunoreactive neurons in nodose ganglia were measured by immunohistochemistry.


RESULTS
OVA challenge induced an AHR after 24 h in OVA-sensitized guinea-pigs. This coincided with an increase in the amount of NGF in BALF. Simultaneously, an increase in the percentage of substance P immunoreactive neurons in the nodose ganglia and an increase in the amount of substance P in lung tissue were found. We used tyrosine kinase inhibitors to block the signal transduction of the high-affinity NGF receptor, tyrosine kinase A (trkA). Treatment with the tyrosine kinase inhibitors (K252a or tyrphostin AG879) both inhibited the development of AHR, and prevented the increase in substance P in the nodose ganglia and lung tissue completely whereas both inhibitors had no effect on baseline airway resistance. Neither treatment with K252a or tyrphostin AG879 changed the influx of inflammatory cells in the BALF due to allergen challenge.


CONCLUSIONS
We conclude that substance P plays a role in the induction of AHR in our model for allergic asthma which is most likely mediated by NGF. As both tyrosine kinase inhibitors AG879 and K252a show a similar inhibitory effect on airway function after allergen challenge, although both tyrosine kinase inhibitors exhibit different non-specific inhibitory effects on targets other than trkA tyrosine kinases, it is likely that the induction of substance P derived from sensory nerves is mediated by NGF via its high-affinity receptor trkA.
de Vries
A
A
Immunobiology Group, Centre for Inflammation Research & Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK. Annick.deVries@ed.ac.uk
Engels
F
F
Henricks
P A J
PA
Leusink-Muis
T
T
McGregor
G P
GP
Braun
A
A
Groneberg
D A
DA
Dessing
M C
MC
Nijkamp
F P
FP
Fischer
A
A
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002227:Carbazoles / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D007150:Immunohistochemistry / Q000379:methods; D026121:Indole Alkaloids; D008168:Lung / Q000276:immunology; D008297:Male; D020932:Nerve Growth Factor / Q000276:immunology*; D009474:Neurons / Q000276:immunology; D009620:Nodose Ganglion / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D020917:Receptor, trkA / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013373:Substance P / Q000276:immunology*; D020032:Tyrphostins / Q000276:immunology
C081020:AG-879; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D020032:Tyrphostins; D013373:Substance P; D010047:Ovalbumin; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020917:Receptor, trkA