College of Physicians and Surgeons, Columbia University, New York, New York 10019
THE POWERFUL BARRIER PROPERTIES of the alveolar wall protect the alveolar air space from entry of external liquid. However, it has long puzzled researchers that alveolar barrier properties deteriorate rapidly in conditions associated with lung microvascular hyperpermeability. In these conditions, the alveolar wall becomes highly permissive to passive liquid flow from the perialveolar interstitium, causing alveolar edema and impairment of gas exchange. Despite their pathophysiological importance, the mechanisms that promote the alveolar entry of large quantities of liquid remain inadequately understood.
The route of liquid flow into the alveolus could involve the paracellular pathway, in which tight and adherens cell junctions restrict protein transit and thereby sieve the liquid. The route could also be transcellular, in which liquid transport occurs by vesicular transcytosis from the basolateral (interstitial) to the apical aspect of alveolar cells (5). Because alveolar liquid filling occurs at rates that are more than a million times faster than those of vesicular transport, the paracellular pathway is the likely transport route for alveolar liquid filling. However, findings have been confusing.
According to Vreim et al. (8), protein concentrations in liquid obtained from the edematous alveolus are nearly identical to those of the interstitial liquid, indicating that no sieving occurs as interstitial liquid enters the alveolar space. Because an intact alveolar membrane is expected to sieve transmembrane flows, the nonsieving of edema liquid begs the question of alveolar structure during edema formation, in particular that of alveolar integrity. Frank disruptions of the alveolar wall associated with alveolar edema in the context of excessively high vascular pressures (1), or injurious agents (3), could explain nonsieved edema formation as a process in which liquid enters the air space freely at points of injury to the alveolar wall. However, this explanation does not fit all of the data.
The enigma is that alveolar edema occurs even in the presence of intact alveolar membranes. That is, alveolar edema is induced by modest increases of pressure in which there are no obvious wall disruptions (1, 3), making it difficult to reconcile the presence of intact alveolar membranes with the nonsieved characteristics of alveolar liquid. It has been proposed that the flow of edema liquid in the interstitium bypasses the alveolar epithelial membrane altogether and that it achieves air space entry by traversing nonsieving channels in the terminal bronchiole (7). This is an attractive hypothesis, except that the existence of nonsieving channels in the airway lining remains unconfirmed.
In general, the field has lacked consideration of alveolar cellular responses that might contribute to alveolar liquid entry under proedematous conditions. In the stage of interstitial liquid loading that precedes alveolar edema, the interstitial hydrostatic pressure increases substantially (2). Such pressure increases may be responsible for mechanical distortions such as epithelial bleb formation in walls of edematous alveoli that are otherwise intact (1). Alterations in the membrane lipid profile that are described in endothelial cells of edematous lungs (6) may occur in alveolar cells. Such membrane responses could generate signaling pathways leading to barrier deterioration. Depletion of tight junction proteins by bacterial toxins, as reported in intestinal epithelial cells (4), could induce hyperpermeability of the alveolar barrier.
Such a possibility is suggested by the paper by Han et al., one of the current articles in focus (Ref 3a, see p. L259 in this issue), which explores the cellular hypothesis of alveolar liquid entry through a consideration of the tight junction proteins occludin and zonula occludens (ZO)-1, -2, and -3. Taking their cue from the finding that excess nitric oxide production, an increasingly recognized feature of lung injury, modifies tight junctions, the authors demonstrate that endotoxin-treated lungs decrease tight junction proteins while increasing alveolar barrier permeability in a nitric oxide-dependent manner. Interestingly, their bronchoalveolar lavage (BAL) data indicate that macromolecular transport into the alveolar space was size selective in that low-molecular-weight dextran was transported more than albumin. Given the caution that direct evidence for alveolar edema is not provided and that BAL may include extra-alveolar tracers, we may come to the new understanding that in the endotoxin model of lung injury, alveoli retain sieving properties even while undergoing liquid entry.
The findings of Han et al. (3a) raise several questions. First, how does the barrier repair itself? An intriguing finding by these authors is that 18 h after the endotoxin challenge, alveolar barrier properties recovered to baseline even while the ZO proteins and occludin were still depleted, suggesting that perhaps, factors other than these proteins are brought into play for alveolar repair. Future research might consider the identity of these repair mechanisms in the context of cadherins, the actin cytoskeleton, and focal adhesions. Second, what is the role of the capillary endothelial cell? The possibility that endothelial barrier proteins were depleted cannot be excluded from the immunofluorescence data of Han et al., and it keeps open the question of endothelial-epithelial interactions that may contribute to both injury and repair of the alveolar barrier. Third, to what extent does barrier protein depletion explain alveolar liquid entry in mechanically induced injury, such as in high-pressure edema? Although these and other relevant questions may be addressed in future research, the findings of Han et al. force a rethinking of the mechanism of alveolar liquid entry, providing a positive focus on the ability of the alveolo-capillary barrier to remodel its tight junctions. This opens a new chapter in the story of alveolar edema, namely how the alveolus maintains long-term integrity after a period of transient hyperpermeability.
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ACKNOWLEDGMENTS |
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