ALPHA 1 ANTITRYPSIN GENE IN NASAL EPITHELIUM--CYSTIC FIB

Vanderbilt University, Nashville TN

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Abstract

HYPOTHESIS: We are developing the nasal lavage model as a means of studying the inflammatory response of respiratory epithelium in vivo. In preliminary studies, we have found that concentrations of the pro-inflammatory cytokine interleukin-8 (IL-8) are higher in nasal lavage fluid from CF patients than from normals. In this proposal, we plan to define the inflammatory state of the nasal mucosa more thoroughly in CF patients, then test our hypothesis that the AAT gene can be delivered to the nasal mucosa in CF subjects using plasmid/cationic liposome complexes and that expression of the AAT gene locally in respiratory epithelium will suppress inflammation. SPECIFIC AIMS: 1) To characterize the inflammatory and protease/antiprotease state of the nasal mucosa in patients w/CF by: a)measuring in nasal lavage fluid the concentrations of inflammation-related cytokines, AAT protein and free elastase; and b) determining in nasal mucosal scrapings the numbers of inflammatory cells present and which inflammation-related cytokine genes are expressed. 2) To determine whether the AAT gene canbe delivered to the nasal mucosa of patients w/CF using cationic liposomes; to define the magnitude and time course of transgene expression; and to determine whether AAT gene expression in nasal mucosa decreases inflammation. We are currently conducting the experiments outlined in Specific Aim #1. Specific Aim #2 will require the facilities in the GCRC.