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Increased caveolin-1 expression is a marker of the differentiation of lung alveolar epithelial type II cells into a type I phenotype. Here, we show in both a primary differentiating rat alveolar culture, and a human alveolar cell line (A549) that caveolae formation and caveolin-1 expression are dependent upon dexamethasone Dex, and is inhibited by the glucocorticoid receptor (GR) antagonist, mifepristone. Study of a panel of 20 different cell types showed the effect of (Dex) upon caveolin-1 expression to be highly cell selective for lung alveolar epithelial cells. The actions of glucocorticoid upon caveolin-1 appear indirect acting via intermediary genes as evidenced by cycloheximide (CHX) abolition of Dex-induced increases in caveolin-1 mRNA and by recombinant transfection studies using the caveolin-1 promoter cloned upstream of a reporter gene. Treatment with actinomycin D (ACD) revealed that the effects of Dex are also, at least in part, mediated by stabilisation of caveolin-1 mRNA. Collectively, these results indicate that glucocorticoids modulate the expression of caveolin-1 and caveolae biogenesis within alveolar epithelial cells via both transcriptional and translational modifications. The cell-selective effects of glucocorticoid upon caveolin may represent a previously unrecognised mechanism by which glucocorticoids affect lung development.

Caveolae are morphologically evident as omega-shaped invaginations of the plasma membrane with a diameter of 50-100 nm. They may also exist in a variety of other forms including flattened domains indistinguishable from the plasma membrane itself. At least in some cell types caveolae undertake transport functions including that of the endocytic and transcytotic movement of macromolecules, and indeed microbes and microbial toxins. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit caveolae membrane interactions with the aim to develop of novel cellular or transcellular drug delivery strategies. This overview article will provide: pertinent information on the biology of the caveolae membrane system; review the various caveolae isolation methods; highlight some of the literature evidence showing that caveolae are functional with regard to macromolecule transport; discuss the role that caveolae could fulfill in the pulmonary absorption of therapeutic proteins from alveolar airspace to capillary blood following inhalational drug delivery, and finally review some very recent work showing proof-of-principle that caveolae domains can be targeted in a tissue-specific manner with highly selective ligands., (Copyright 2002 Elsevier Science B.V.)

There has been an exponential growth in caveolae research since the early 1990s. The caveolae membrane system comprises unique lipid and protein domains, and fulfills a role in a wide range of processes. At the plasma membrane caveolae serve to compartmentalise and integrate a wide range of signal transduction processes. A key structural and functional protein for caveolae is caveolin. Caveolin proteins possess a 'scaffolding' domain which for caveolins-1 and -3 appear central to many of the reported signal regulation functions for caveolae. Caveolae or caveolin protein are increasingly implicated in the molecular pathology of a number of diseases. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit the caveolae membrane system to identify novel pharmacological targets and therapeutic strategies, including the delivery of pharmacologically active caveolin based peptides.

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.

Caveolae are omega-shaped invaginations of the plasma membrane with a diameter of 50-100 nm. Caveolae invaginations can detach from the plasma membrane to form discrete functional caveolae vesicles within the cell cytoplasm. Caveolae are most prominent in adipocytes, fibroblasts, muscle cells (skeletal, smooth and cardiac), capillary endothelium and type I pneumocytes, although other cell types also display these structures but at a lower numerical density. The key structural and functional protein for caveolae is caveolin. At the plasma membrane caveolae serve to compartmentalize and integrate a wide range of signal transduction processes. Caveolae also serve transport functions including that of the vesicular internalisation of small molecules by the process of potocytosis, and the endocytic and transcytotic movements of macromolecules. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit caveolae membrane interactions with the aim to develop novel cellular or transcellular drug delivery strategies.