Central Airways

The lumenal surface of the epithelium of the central airways (trachea to terminal bronchioles) is covered by a blanket of mucus that is a heterogeneous mixture of water, inorganic salts, glycoproteins, proteoglycans, lipids and other proteins, and peptides [5,6]. Inhaled drug would initially deposit on the mucus layer, in which it may become dissolved or complexed [7]. The mucus of the airways, together with concerted, coordinated beating of cilia on ciliated columnar epithelial cells, constitutes what is known as the mucociliary escalator. This system serves to move the mucus toward the pharynx for expulsion from the airways, and, accordingly, a portion of drug present in the mucus will be removed by it (Fig. 1). In addition, it is possible that some of the drug may be effectively lost through complexing with constituent substances in the mucus or degradation by enzymes contained in the mucus. A drug that passes through the mucus layer must then traverse the epithelium to gain access to subepithelial target cells.

The epithelium of the central airways consists primarily of ciliated epithelial cells. Adjacent cells of the epithelium are coupled tightly by junctional processes that normally prevent the passage of macromolecules between cells, i.e., paracellular transport [8-10]. As a result, transport of substances across the epithelium requires passage through, rather than between, epithelial cells, a process called transcytosis [10]. Under these conditions, absorption of a drug will be influenced by processes governing passive diffusion through cells, i.e., not saturable, and the rate of diffusion will be directly related to the drug components, and (4) be removed by diffusion into submucosal blood vessels before reaching its target cell, e.g., airway smooth muscle cell. In the peripheral airways, a drug designed for delivery to the blood stream may (1) be diluted and diffuse in the surfactant, (2) be taken up by alveolar macrophages, (3) diffuse through the interstitium and be removed by lymphatic capillaries, and (4) be biotransformed by enzymes associated with pulmonary endothelial cells.

concentration gradient across cell membranes, lipid solubility, and inversely related to molecular size and ionization. It is unclear whether this transport is like the alveolar epithelium in using caveolae or vesicles (vide infra), although the presence of caveolins (structural proteins associated with caveolae) in isolated bronchial epithelial cells [11] would support such a possibility. Carrier-mediated transport systems that are saturable, energy dependent, and selective may also contribute to the passage of drugs, such as cromolyn sodium, across the pulmonary epithelium [12]. Paracellular passage of macromolecules may be enhanced under pathophysiological conditions that influence epithelial permeability, such as those attending application of an irritant or inflammatory stimulus to the airways [9,13]. Fecal pellets of house dust mite, a common allergen, contains a proteinase that disrupts airway epithelial tight junctions and thereby enhances its paracellular penetration of the epithelium [14]. Mechanisms governing tight junction permeability represents an area of active research. (for a review, see Ref. 15.) In passage through the epithelium, the drug or inhaled compounds may be biotransformed or inactivated by enzymes associated with the epithelium and/or may react or bind with cellular or extracellular components of the epithelium [16].

Once a compound has traversed the epithelium and the basement membrane (to which the epithelium is attached), it can diffuse through the loose connective tissue of the submucosa to gain access to target tissues, such as proinflammatory cells (e.g., mast cells), glands, sensory nerves, blood vessels, smooth muscle cells, or autonomic nerves. Submucosal blood flow in an airway segment may also represent a site of loss of drug by "washing out" administered drug from the tissue [17].

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