Although there has been a steady advance in our understanding of the immunological aspects of allergic airway disease, there has been a paucity of knowledge regarding the mechanisms that translate the immunological response into clinical symptomatology. Symptoms of allergic rhinitis (AR) are largely, if not exclusively, due to nerve stimulation. We have previously demonstrated that the reflex responses are markedly exaggerated in AR patients compared to healthy individuals, suggesting perturbations in the neural components of the nasal mucosa. The principal objective of this proposal is to begin to discern the interrelation between the immune and nervous systems with respect to allergic airway disease. Our recent findings of elevated baseline levels of Nerve Growth Factor (NGF) in nasal fluids of AR patients compared to healthy subjects, and of immediate NGF release in nasal fluids upon allergen provocation only in AR patients, provide a distinct focal point for further investigation. Our current overall hypothesis is that neurotrophins are key messenger molecules between mast cells and sensory nerves in the human nasal mucosa. We will rigorously test this hypothesis by making use of a unique opportunity that allows a thorough study of neural physiology in viva in combination with detailed analysis of the human nasal mucosa ex viva, in patients who undergo bilateral turbinectomy. We will test whether NGF is synthesized, stored and released by human nasal mast cells by using immunohistochemistry, in situ hybridization, and functional analysis of mediator release upon stimulation with Mu late secretagogues. We will also test the hypothesis that repeated allergen provocation in atopic individuals can effect changes in the functionality and phenotype of contiguous nerve fibers. The fact that we can apply challenges unilaterally, and subsequently obtain nasal turbinates from the same patient bilaterally, allows us to rigorously test this hypothesis. We will assess whether repeated unilateral allergen provocation of the right nasal turbinate will subsequently enhance the nasonasal secretory reflex and/or the axonal reflex elicited by nerve stimulation of the right, but not of the left, nasal turbinate in viva. In parallel, we will test for concomitant upregulation of NGF and/or of neuropeptide-containing nerve fibers in the right, but not in the left, nasal turbinate ax viva. These studies may help elucidate the deleterious effects of environmental irritants on allergic airway disease.
| Wu, XinQun; Myers, Allen C; Goldstone, Andrew C et al. (2006) Localization of nerve growth factor and its receptors in the human nasal mucosa. J Allergy Clin Immunol 118:428-33 |
