Acute mechanism of medium chain fatty acid-induced enhancement of airway epithelial permeability.
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(i)2+) 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(i)2+ 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(i)2+. However, buffering Ca(i)2+ did not block the effects of C10 on R(T). Both C10 and C12 caused reorganization of claudins-1, -4, JAM, and beta-catenin, but not ZO-1. These data suggest that C10 and C12 exert their acute effects on airway TJs via a Ca(2+)-independent mechanism of action and may alter junctional permeability via direct effects on the claudin family of TJ proteins.
Coyne
Carolyn B
CB
Cystic Fibrosis/Pulmonary Research and Treatment Center, 7123A Thurston Bowles Bldg., CB no. 7248, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA.
Ribeiro
Carla M P
CM
Boucher
Richard C
RC
Johnson
Larry G
LG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000258:Adenovirus Infections, Human / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D022761:Gene Transfer, Horizontal / Q000187:drug effects; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects; D018613:Microscopy, Confocal; D012137:Respiratory System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014966:Xanthenes
D005227:Fatty Acids; D005456:Fluorescent Dyes; D014966:Xanthenes; C034657:Texas red; D000255:Adenosine Triphosphate; D002118:Calcium