Caveolae as potential macromolecule trafficking compartments within alveolar epithelium

With inhalational delivery the alveolar epithelium appears to be the appropriate lung surface to target for the systemic delivery of macromolecules, such as therapeutic proteins. The existence of a high numerical density of smooth-coated or non-coated plasma membrane vesicles or invaginations within the alveolar epithelial type I cell has long been recognised. The putative function of these vesicles in macromolecule transport remains the focus of research in both pulmonary physiology and pharmaceutical science disciplines. These vesicles, or subpopulations thereof, have been shown to biochemically possess caveolin, a marker protein for caveolae. This review considers the morphometric and biochemical studies that have progressed the characterisation of the vesicle populations within alveolar type I epithelium. Parallel research findings from the endothelial literature have been considered to contrast the state of progress of caveolae research in alveolar epithelium. Speculation is made on a model of caveolae vesicle-mediated transport that may satisfy some of the pulmonary pharmacokinetic data that has been generated for macromolecule absorption. The putative transport function of caveolae within alveolar epithelium is reviewed with respect to in-situ tracer studies conducted within the alveolar airspace. Finally, the functional characterisation of in-vitro alveolar epithelial cell cultures is considered with respect to the role of caveolae in macromolecule transport. A potentially significant role for alveolar caveolae in mediating the alveolar airspace to blood transport of macromolecules cannot be dismissed. Considerable research is required, however, to address this issue in a quantitative manner. A better understanding of the membrane dynamics of caveolae in alveolar epithelium will help resolve the function of these vesicular compartments and may lead to the development of more specific drug targeting approaches for promoting pulmonary drug delivery.