The lungs provide a unique absorptive surface for drug delivery and the inhalation route allows for the deposition of high drug concentrations while minimizing systemic effects. However, some pharmacologically active compounds cannot be administered through the inhalation because of inadequate bioavailability for sub epithelia targeting, and this may limit the usefulness of these compounds. This lack of uptake across the epithelia can be caused by many reasons including; poor aqueous solubility, degradation of active compound with the local enzymes and poor membrane permeability . Poor membrane permeation can occur due to the large-molecular weight of a compound, as is the case with proteins and other macromolecules, or an insufficient partition coefficient that allows uptake or transport into biological membranes, as with many hydrophilic, low-molecular weight compounds. Airway epithelial cells are a major obstacle for drug delivery to the lung parenchyma. Several transport routes exist in airway epithelial cells, which potentially can be exploited for enhancing drug permeability. Compared to the transcellular pathways via passive diffusion, transporters, adsorptive and receptor-mediated transports, the paracellular flux is very limited. The Epithelial barrier forms tight junctions that restrict or completely block the free passage of hydrophilic molecules . Therefore, a promising strategy for drug delivery is the modulation of the tight junctions to allow molecules to pass through this cellular barrier where sub epithelium targeting is required. The paracellular route has more advantages compared to the transcellular route including; 1) drug modification is not needed and 2) various drugs could benefit by the same tight junction modulator. Selected compounds that are capable of modulating tight junctions and thereby increase paracellular drug transport have been investigated for intestinal drug absorption  but limited studies have been performed to modulate airway tight junctions . These modifiers include hypertonic saline , sodium caprate (sodium salt of medium chain fatty acid), and oleic acid (fatty acid). It has been shown that hypertonic solution of NaCl increases the permeability of the tight junctions of the airway epithelium through an unknown mechanism . It has been claimed that the opening of the tight junctions is simply due to mechanical stress caused by shrinking of the cells, but in a study by Hogman et al. using lanthanum ions transported after modulating the tight junctions with hypertonic saline, they demonstrated that this mechanism is unlikely to be the major effect . They have suggested that hypertonic NaCl can effect on tight junctions by affecting the intracellular concentration of calcium ions and/or cAMP, or that it affects the structure of the cytoskeleton. They have also shown that this effect is reversible in a mouse model. Sodium caprate has been also shown to dilate tight junctions reversibly, increase the permeability of fluorescein Na and decrease transepithelial electrical resistance (TEER) via phospholipase C activation and upregulation of intracellular Ca2+, which can lead to contraction of actin–myosin filaments attached to the intracellular domain of tight junctions . Oleic acid has an effect on membrane fluidity and paracellular permeability of dermal, gastrointestinal, alveolar and blood–brain barriers . The exact target for oleic acid is not known yet, but membrane microdomains or lipid rafts could be involved. It has been demonstrated that it has a reversible effect on tight junction dilation in an experiment in vivo. To the authors’ knowledge, only Na caprate is currently used as an absorption enhancer in pharmaceutical applications .
In this study, the effect of already stablished tight junction modulators for the oral route including; hypertonic NaCl, Na caprate, and oleic acid on an antifibrotic hydrophilic drug PXS25 has been investigated on airway epithelial cells.