ALLERGEN, NEUROGENIC INFLAMMATION AND CHRONIC SINUSITIS

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This project will begin to investigate how allergic rhinitis may contribute to the pathophysiology of chronic sinusitis by examining the relationship between allergic rhinitis, neuronal reflexes and sinusitis. Our central hypothesis is that allergic inflammation in the nasal cavity stimulates sensory nerves that, through centrally mediated and axonal reflexes, affect epithelial function within the sinuses. The induced neurogenic inflammation, in turn, stimulates sensory nerves within the sinuses to initiate central reflexes that stimulate the nasal mucosa, creating a viscious cycle. We will study allergic and nonallergic subjects with and without chronic sinusitis to test several aspects of this hypothesis. We will monitor epithelial function by measuring cytokine production in secretions and in tissue, epithelial potential difference and evidence of changes in secretory and vascular function. In Aim 1, we will extend our observations on central nasonasal, reflex- induced glandular stimulation by testing whether neuronal reflexes alter epithelial ion and water transport and stimulate cytokine (IL-6, IL-8 and GM-CSF) generation by epithelial cells. Local anesthetics will be used to reduce neuronal transmission. Allergic subjects will be challenged with allergen, while both allergic and nonallergic subjects will be challenged with nonantigenic stimuli (bradykinin, histamine, capsaicin and methacholine). We will also compare neuronal responses in allergic subjects with and without sinusitis. In Aim 2, we will extend our studies to sinusitis patients who have undergone surgical intervention because, in these subjects, the sinus mucosa is readily accessible. This will allow us to directly measure whether neurogenic inflammation can be elicited in the ipsi- and contralateral sinuses in responses to antigenic and nonantigenic stimulation of the nasal mucosa. In Aim 3, we will determine whether intranasal glucocorticoid therapy prevents alterations of epithelial ion transport and epithelial cytokine production, induced by neuronal reflexes. In Aim 4, we will determine the answer to three related questions. First, does activation of sensory nerves within the sinuses induce reflexes with the nasal cavity? Second, since, postoperatively, the sinuses become directly accessible to environmental influences, does the inflammatory response to allergic stimulation of the sinuses mimic the responses seen in the nasal mucosa? Third, if our central hypothesis is correct, does reduction of inflammation within the sinus cavity by surgical intervention reduce nasal responsiveness? Throughout this project, we will test whether allergic subjects with asthma respond differently than allergic subjects without this condition. This project depends upon the Core for subjects and interrelates strongly with Project 2, which examines epithelial cell cytokine production in response to viral infection, and Project 3, which examines epithelial ion transport in vitro and in vivo.