Caveolae as potential macromolecule trafficking compartments within alveolar epithelium
Introduction
The permeability characteristics of the lung and recent advances in inhalational aerosol device technology have led to an increasing interest in exploiting the pulmonary route for the systemic delivery of macromolecule therapeutics, particularly recombinant proteins and polypeptides [1]. The lung deposition and absorption studies of Colthorpe et al. [2], [3] elegantly demonstrated that the extents of systemic absorption of insulin or growth hormone following lung administration positively correlate with the depth of deposition of these administered proteins within the lung. Anatomical determinants [4] would also support the view that the lung periphery, and the alveolar epithelium in particular, is the appropriate lung surface to target when aiming to systemically deliver macromolecules. Some of these anatomical determinants would include: location of the alveolar surface beyond the clearance mechanisms of the mucociliary escalator; the large alveolar surface area potentially available for absorption; the high blood flow to the alveolar region, and the thin cellular barrier from airspace to capillary blood presented by the alveolar epithelial and pulmonary capillary cells. Further, in the transport of macromolecules across the pulmonary alveolar epithelial–capillary endothelial barrier, evidence indicates that it is the alveolar epithelium that possesses a more restrictive paracellular pathway than that provided by the capillary endothelium [5]. As a corollary the mechanisms of transport of macromolecules within alveolar epithelium are the subject of genuine interest [6], and in particular the nature and extent of any vesicular trafficking mechanism(s) such as that potentially provided by caveolae.
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Caveolae and the structural role of caveolins
At the electron-microscopic level caveolae are most frequently observed as “smooth coated” or “non-coated” omega-shaped invaginations (diameter of 50–100 nm at the widest point) connected to the plasmalemma or plasma membrane by a neck-like structure which affords spatial continuity with the extracellular environment (Fig. 1a). At least in endothelial cells caveolae-like vesicles may also be observed as fused lines or clusters of vesicles at the plasmalemma [7]. The term “smooth coated” or
Alveolar epithelial–pulmonary capillary barrier
The lower respiratory tract consists of the respiratory bronchioles, the alveolar ducts, and the alveoli themselves which represent the main location for gaseous exchange. Alveolar epithelium is predominantly comprised of two cell types, the terminally differentiated squamous alveolar epithelial type I (ATI) cell which constitutes approximately 93% of the alveolar epithelial surface area (33% of alveolar epithelial cells by number) and the surfactant producing cuboidal alveolar epithelial type
Transport role for caveolae in alveolar epithelium
While the morphometric data for the ATI cell vesicle populations is intriguing in terms of their putative function as endocytic or transcytotic compartments, direct evidence for their role in transport within alveolar epithelium is at present extremely limited. Certainly, the functional characterisation of ATI vesicle populations lags considerably behind the progress made in determining a transport role for caveolae in endothelium. However, until comparatively recently the role of endothelial
Caveolae and caveolin in cultured alveolar epithelium
Due to the complex nature of the lung architecture, the alveolar epithelium is not a readily accessible absorption surface to study. Therefore the use of cultures of alveolar epithelium cells as an in-vitro experimental model for the prediction of the extent, rate and mechanism of alveolar absorption of pharmaceuticals has gained acceptance amongst investigators [83].
Consistent with the in-vivo hypothesis of the ATII cell transdifferentiating into the in-vivo ATI cell [18], isolated ATII cells
Conclusion
There is a genuine clinical and commercial interest in exploiting the pulmonary route for the systemic delivery of macromolecules, particularly recombinant proteins and polypeptides. The alveolar epithelium appears to be the appropriate lung surface to target when aiming to systemically deliver macromolecules. 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.
References (90)
Mechanisms of macromolecule absorption by the lungs
Adv. Drug Deliv. Rev.
(1996)- et al.
Caveolin, a protein component of caveolae membrane coats
Cell
(1992) - et al.
Mutational analysis of caveolin-induced vesicle formation
FEBS Lett.
(1998) - et al.
Baculovirus-based expression of mammalian caveolin in Sf21 insect cells
J. Biol. Chem.
(1996) - et al.
Mutational analysis of the properties of caveolin-1
J. Biol. Chem.
(1997) - et al.
Caveolin-1 expresion and caveolae biogenesis during cell transdifferentiation in lung alveolar epithelial primary cultures
Biochem. Biophys. Res. Commun.
(1999) - et al.
Pinocytotic vesicles in the endothelium of rapidly frozen rabbit lung
Microvasc. Res.
(1981) - et al.
Albondin-mediated capillary permeability to albumin: differentiation role for receptors in endothelial transcytosis and endocytosis of native and modified albumins
J. Cell Biol.
(1994) - et al.
Endothelial caveolae have the molecular transport machinery for vesicle budding, docking, and fusion including VAMP, NSF, SNAP, annexins, and GTPases
J. Biol. Chem.
(1995) - et al.
Vesicular transport across endothelium: simulation of a diffusion model
J. Theor. Biol.
(1969)
Calculations on the passage of small vesicles across endothelial cells by brownian motion
J. Theor. Biol.
Differential distribution of the cell surface charge on the alveolar capillary unit. Characteristic paucity of anionic sites on the air–blood barrier
Microvasc. Res.
Effect of absorption enhancers on pulmonary absorption of fluorescein isothiocyanate dextrans with various molecular weights
Int. J. Pharm.
Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae
J. Biol. Chem.
Receptor-mediated endocytosis of insulin by cultured endothelial cells
Tissue Cell
Caveolar internalisation of growth hormone
Exp. Cell Res.
Transcytosis and surface presentation of IL-8 by venular endothelial cells
Cell
Detection of duffy antigen in the plasma membranes and caveolae of vascular endothelial and epithelial cells of nonerythroid organs
Blood
Respiratory epithelial cell culture models for evaluation of ion and drug transport
Adv. Drug Deliv. Rev.
Monoclonal antibodies specific to apical surfaces of rat alveolar type I cells bind to surfaces of cultured, but not freshly isolated, type II cells
Biochim. Biophys. Acta
Type 1 cell-like morphology in tight alveolar epithelial monolayers
Exp. Cell Res.
Breathing life into protein drugs
Nat. Biotechnol.
The pharmacokinetics of pulmonary delivered insulin: a comparison of intra-tracheal and aerosol administration to the rabbit
Pharm. Res.
The influence of regional deposition on the pharmacokinetics of pulmonary-delivered human growth hormone in rabbits
Pharm. Res.
Morphological basis of alveolar–capillary gas exchange
Physiol. Rev.
The integrity of the air–blood barrier
The role of vesicles in the transport of ferritin through frog endothelium
J. Physiol.
De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin
Cell Biol.
Expression of caveolin-1 and polarised formation of invaginated caveolae in Caco-2 and MDCK II cells
J. Cell Sci.
VIP21-caveolin, a membrane protein constituent of caveolae coat, oligomerizes in-vivo and in-vitro
Mol. Biol. Cell
Oligomeric structure of caveolin: implications for caveolae membrane organisation
Proc. Natl. Acad. Sci. U.S.A.
Cell number and cell characteristics of normal human lung
Am. Rev. Respir. Dis.
Cell cycle kinetics in the alveolar epithelium
Am. J. Physiol.
Distribution of vesicles in cells of the air–blood barrier in the rabbit
J. Appl. Physiol.
Number and distribution of plasmalemma vesicles in the lung
Fed. Proc.
Numerical denisties of cellular vesicles and cellular attentuation in the pulmonary alveolar septa of edematous dog lungs
Microvasc. Res.
Morphometric study of rat lung cells: numerical and dimensional characteristics of parenchymal cell populations
Am. Rev. Respir. Dis.
Morphometry of pinocytic vesicles in the capillary endothelium of rabbit lungs using automated equipment
Circ. Res.
Morphological data on the endothelium of blood capillaries
J. Cell Biol.
An uptake of cationized ferritin by alveolar type I cells in airway-instilled goat lung: distribution of anionic sites on the epithelial surface
J. Submicrosc. Cytol. Pathol.
Endocytic vesicles of type I pneumocytes. Immunocytochemical colocalisation of calmodulin with clathrin molecules
J. Histotechnol.
Characterisation of caveolin-rich domains isolated from an endothelial rich source: implications for human disease
J. Cell Biol.
Loss of caveolin-1 expression in type I pneumocytes as an indicator of subcellular alterations during lung fibrogenesis
Histochem. Cell Biol.
Caveolin and its cellular and subcellular immunolocalisation in lung alveolar epithelium: implications for alveolar type I cell function
Cell Tissue Res.
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