A major factor regulating the pharmacological or biological actions of substances delivered to the lumen of the airways is epithelial permeability. Passage of drug through the epithelium is prerequisite for an action or subepithelial target cells, such as airway smooth muscle.
Studies on changes on epithelial permeability have centered on investigations of mechanisms associated with induction of airway hyperreactivity. In support of an important role for epithelium in regulating the biological activity of inhaled substances, airway reactivity to aerosolized bronchoconstrictors has been correlated inversely with the epithelial thickness . A variety of irritant stimuli, such as antigen and cigarette smoke, increase airway epithelial permeability to small solutes in animal models [128,129]. On the basis of such studies, this process has been suggested to enhance the penetration of irritants or bronchoactive substances to their bronchoconstrictor sites of action (such as sensory nerves, inflammatory cells, or smooth muscle cells) and thereby to contribute to airway hyperreponsiveness [130,131]. The mechanism by which the permeability of the epithelium changes is not well understood, although disruption of intercellular epithelial tight junctions  and penetration through disrupted cells  have been suggested. In addition to known chemically induced influences on epithelial permeability, disease states, such as asthma, may also be associated with changes in epithelial permeability [132,133]. In addition, regions of epithelium may be absent from the airways of asthmatics .
In the same way that epithelial penetration of aerosolized tracer molecules may be enhanced by certain pathological conditions, so too might aerosolized drugs be more efficiently delivered to the airways. Accordingly, it may be hypothesized that, under conditions of augmented epithelial permeability, therapeutic agents delivered into the airway lumen may become more potent because they have readier access to their subepithelial targets.
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