Enhancing Paracellular Permeability of Airway Epithelium by Opening Tight Junctions via Osmo-Mechanical Stimulation

Pulmonary drug delivery offers significant advantages for local and systemic therapy by directly targeting the lungs, minimizing off-target effects and avoiding first-pass metabolism. However, the airway epithelium, which serves as a protective barrier, presents significant challenges for effective drug delivery. Tight junctions (TJs) between epithelial cells and mucociliary clearance hinder drug absorption, especially for high-molecular-weight drugs. To address this, various TJ modulators, such as chelators and surfactants, have been explored but their safety concerns limit clinical application. In clinical settings, hyperosmotic sodium chloride (NaCl) and mechanical vibration are used for mucus clearance, but their effects on the TJ permeability remain underexplored. In this study, we investigate the synergistic effects of hypertonic saline (HTS) solution (1.8% NaCl) and mechanical vibration (frequency: 70 Hz; duration: 30 min) on the opening of TJs in the rat tracheal epithelium. Our results show that this combination effectively increases the epithelial permeability, offering a novel and safe strategy for enhancing pulmonary drug delivery. This work provides insights into utilizing established clinical techniques to overcome barriers in pulmonary drug administration, paving the way for more effective treatments.