The basic defect responsible for the pathology of cystic fibrosis (CF) remains unknown and efforts to rigorously investigate the cause of this disease are handicapped by the unavailability of suitable laboratory animals with a similar disease state. Recently, Heinz-Erian et al. (1) proposed that CF is caused by, or associated with, a profound deficiency in the amount of vasoactive intestinal peptide (VIP) associated with the acini and ducts of human sweat glands. Their conclusions are based on the results of immunohistochemical studies employing anti-VIP antibodies and a fluorescently-labelled second antibody. They described VIP-immunoreactive nerve fibers surrounding normal, but not CF, sweat gland ducts and acini. This observation is pertinent to CF because VIP is a peptide hormone that is known to stimulate Cl- reabsorption in other tissues and a defect in VIP action at the sweat gland duct could conceivably lead to excessive sweat Cl- secretion, which is known to be the principal sign of CF. The present application is designed to test this hypothesis, that the exocrine defect in CF is related to VIP, in a more quantitative and systematic way. VIP receptors will be measured in skin fibroblasts from normals and CF patients. It is anticipated that the number of VIP receptors will be elevated in CF tissue if the effective VIP concentration in this tissue is lower than normal. VIP receptor number and affinity will be measured in binding experiments and further experiments designed to isolate and characterize the VIP receptor will be performed if the initial binding data suggests an abnormality in the VIP receptor. Additionally, CF serum will be tested for the presence of a VIP antagonist or blocking factor by conducting VIP binding experiments in the presence of normal and CF serum. These studies should allow us to demonstrate whether or not CF tissue contains an abnormal number of VIP binding sites, an abnormal VIP receptor or a humoral VIP blocker or antagonist. Long-term goals for this research effort include improved understanding of the basic defect in CF, development of an animal model for CF based on VIP antagonism and improved therapy for CF patients utilizing a VIP agonist.
| Elgavish, A; Pillion, D J; Meezan, E (1989) Evidence for vasoactive intestinal peptide receptors in apical membranes from tracheal epithelium. Life Sci 44:1037-42 |
