Vol. 305, Issue 2, 440-450, May 2003

Acute Mechanism of Medium Chain Fatty Acid-Induced Enhancement of Airway Epithelial Permeability

Carolyn B. Coyne, Carla M. P. Ribeiro, Richard C. Boucher and Larry G. Johnson

Cystic Fibrosis/Pulmonary Research and Treatment Center and the Departments of Pharmacology and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

The localization of viral receptors to the basolateral surface of airway epithelia is an obstacle to the effectiveness of luminal viral-mediated gene transfer to the lung. The tight junction (TJ) serves as a rate-limiting barrier to the penetration of viral vectors. We have previously identified the sodium salt of the medium chain fatty acid (MCFA) capric acid (C10) as an agent that can enhance the ability of adenoviral vectors to transduce well differentiated (WD) primary human airway epithelial (HAE) cells. Previous studies have suggested that intracellular calcium (Ca_i²⁺) levels may play a central role in the long-term C10-mediated increases in junctional permeability. In this study, we investigated the effects of C10 and lauric acid (C12) on Ca_i²⁺ in WD primary HAE cells and determined whether these effects were necessary for the acute MCFA-induced reduction in transepithelial resistance (R_T) and increased permeability. In addition, we characterized the effects of C10 and C12 on components localized to the TJ, including ZO-1, junctional adhesion molecule (JAM), and the claudin family of transmembrane proteins. In addition to rapidly decreasing R_T, C10 and C12 increased cellular and paracellular permeability. C10 induced a rapid, sustained increase in Ca_i²⁺. However, buffering Ca_i²⁺ did not block the effects of C10 on R_T. Both C10 and C12 caused reorganization of claudins-1, -4, JAM, and -catenin, but not ZO-1. These data suggest that C10 and C12 exert their acute effects on airway TJs via a Ca²⁺-independent mechanism of action and may alter junctional permeability via direct effects on the claudin family of TJ proteins.