You are here:
SAFETY AND EFFICIENCY OF MODULATING PARACELLULAR PERMEABILITY TO ENHANCE AIRWAY EPITHELIAL GENE TRANSFER IN VIVO
Citation:
Johnson, L. G., M. K. Vanhook, C. B. Coyne, N. H. HaykalCoates, AND S H. Gavett. SAFETY AND EFFICIENCY OF MODULATING PARACELLULAR PERMEABILITY TO ENHANCE AIRWAY EPITHELIAL GENE TRANSFER IN VIVO. HUMAN GENE THERAPY. Mary Ann Liebert, Inc., Larchmont, NY, 14(8):729-747, (2003).
Description:
ABSTRACT
We evaluated the safety of agents that enhance gene transfer by modulating paracellular permeability. Lactate dehydrogenase (LDH) and cytokine release were measured in polarized primary human airway epithelial (HAE) cells after luminal application of vehicle, ethyleneglycol-bis-(b-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), sodium caprate (C10), or sodium laurate (C12). Lung toxicity was assessed after tracheobronchial instillation to murine airways and the relative ability of these agents to enhance in vivo adenoviral (Ad) gene transfer was evaluated. Luminal C12 increased LDH release in vitro, but C10 and EGTA did not. Increased levels of IL-8 were secreted from EGTA-pretreated cystic fibrosis (CF) HAE cells after apical application of Pseudomonas (P.) aeruginosa (108 cfu/ml), whereas IL-8 secretion from C10 and C12-pretreated cells were not different from controls. In vivo toxicity studies demonstrated no effect of EGTA, C10, or C12 on weight gain, lung edema, or bronchoalveolar lavage fluid (BALF) albumin. EGTA increased BALF cell counts, neutrophils, and murine (m)MIP-2, mKC, mIL-6, and mIL1-b levels. C10 had no effect on BALF cell counts or LDH, but increased mTNFa. C12 increased BALF LDH, neutrophils, and mIL-6 levels. Histopathological analysis revealed mild focal lung inflammation more frequently in the EGTA, C10, and C12 groups than in vehicle controls with greater intensity in the C12 group relative to other groups. C10 and C12 also increased airway responsiveness to methacholine challenge compared with control and EGTA groups. Ad gene transfer to murine trachea in vivo was enhanced more efficiently by C10 than C12 or EGTA. Thus, the different toxicities may permit the selection of agents that enhance gene transfer with minimal adverse effects.