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The identification of specific molecules that mediated cell adhesion ushered in a new era in our understanding of the inflammatory process. Through the work of many investigators (nicely reviewed in a recent series of articles in the Journal of Clinical Investigation [1]), a paradigm has emerged in which a series of specific molecular interactions between the leukocyte and the vascular endothelium leads to the migration of leukocytes out of the circulation (2). Three families of cell adhesion molecules (CAMs) play a central role in leukocyte-endothelial interactions: the selectins (6, 7), the integrins (8, 9), and the immunoglobulin superfamily (10). In addition, factors that activate leukocytes or endothelial cells, thereby resulting in CAM expression and/or chemotactic migratory responses, are also important (11). It is now accepted, at least in the systemic circulation, that these different types of CAMs and chemoattractants interact in a programmed, sequential manner to form what has been termed the "leukocyte- endothelial cell adhesion cascade" (2).
In the systemic circulation, the process of leukocyte
emigration is initiated by the slowing or "margination" of
circulating white blood cells within venules. At this stage,
the white cells are only loosely tethered to the vessel wall
and appear to "roll" along the surface of the endothelium.
This initial interaction of the adhesion cascade is largely
mediated by members of the selectin family binding to
specific carbohydrate-expressing cell surface ligands (14).
Recent in vitro data, however, suggests that for T lymphocytes, 
4
1, 47, and CD44 are also able to mediate rolling
on vascular CAM-1 (VCAM-1), mucosal addressin CAM-1
(MadCAM-1), and hyaluronate-covered surfaces (15).
The selectin-dependent adhesion of leukocytes during rolling is transient and does not lead to firm adhesion and
transmigration unless another set of adhesion molecules is
engaged. On neutrophils, this requires activation/upregulation of members of the 2 (CD11/CD18) integrin family
that bind to one of the intercellular adhesion molecules (ICAM-1 or -2) on the surface of the endothelial cells.
ICAM-1 expression can be augmented by a variety of inflammatory mediators, including tumor necrosis factor-
(TNF-), interleukin-1 (IL-1), interferon-
, and endotoxin. The increase in expression is dependent on protein
synthesis and peaks about 8 h after stimulation in both in
vitro (3) and in vivo models (18).
After firm adhesion, the leukocyte can then migrate through the junctional region of endothelial cells and move to a region between the endothelium and its basement membrane (3). After a brief pause in this location, the leukocyte finally migrates into the surrounding interstitial tissue. Leukocyte binding and transmigration are tightly linked. Because white blood cell binding to endothelium must precede transmigration, any perturbation that decreases leukocyte binding to endothelium will decrease the number of cells that transmigrate. For this reason, inhibition of selectin, CD18, or ICAM-1 function will block transmigration (3). To date, there are relatively few studies that have clearly distinguished between adhesion and transmigration.
Transendothelial cell migration does not necessarily
follow after leukocyte adhesion. One critical component is
the presence of a chemotactic gradient. Although a number of chemotactic factors, such as leukotriene B4, C5a, and
formylmethionylleucylphenylalanine, can augment leukocyte adhesion to endothelium (reviewed in Reference 19),
transmigration across a monolayer will not occur unless a chemotactic gradient has been established (20). Although
spontaneous transmigration of neutrophils through TNF--
or IL-1-stimulated endothelial monolayers has been observed (21, 22), it is likely that these cytokines also induce
potent chemotactic stimuli such as IL-8 (23).
Recent studies have implicated another adhesion molecule, platelet-endothelial CAM-1 (PECAM-1) in the
transmigration process (reviewed in References 24 and
25). PECAM-1, a member of the immunoglobulin superfamily, is expressed at relatively low levels on the surface of leukocytes and platelets but at higher levels (> 106 molecules per cell) on endothelium, primarily at the cell-cell border (26). A number of alternatively spliced forms of
human and murine PECAM-1 have been identified (27-
29). Interestingly, all of the variants isolated to date differ
in either the transmembrane or cytoplamsic domains.
PECAM-1 functions as both an adhesion molecule
through interactions with itself (homophilic adhesion) or
with other non-PECAM-1 molecules (heterophilic adhesion)and a signal transducer (24, 25).
The localization of PECAM-1 at the junctions between
endothelial cells suggested a role in transendothelial cell
migration. Using an in vitro model, Muller and colleagues
(22) demonstrated that antibodies against PECAM-1 significantly blocked leukocyte transmigration through TNF--activated endothelial cell monolayers without affecting
leukocyte-endothelial adhesion. This effect has been confirmed in animal models of neutrophil transmigration (30-
35). The mechanisms by which PECAM-1 may regulate
transendothelial migration are not yet known. However,
the possibilities include PECAM-1 as a molecular "guide"
for leukocyte passage through endothelial junctions, activation of adhesion molecules on the surface of the leukocyte (i.e., 2 integrins), and/or regulation of intracellular calcium levels in endothelial cells (36), a key factor in the ability of the endothelial cell monolayer to regulate an
opening of its junctions, which allows neutrophil transmigration (37).
It is in this setting that Piedboeuf and coworkers (38) describe experiments in which the expression of PECAM-1 was assessed in the lungs of mice after exposure of hyperoxia in this issue of American Journal of Respiratory Cell and Molecular Biology. They observed increases in PECAM-1 expression by mRNA blot hybridization, in situ hybridization, and immunohistochemistry, although no changes were seen in immunoblotting. One puzzling feature of this study was the very low level and patchy distribution of PECAM-1 on the lung microvessels at baseline when viewed by immunohistochemistry. In our experience in severe combined immunodeficiency disease and Balb/c mice, PECAM-1 is very highly expressed on all lung endothelium (30). It is possible that the C3H strain used in this study was different.
One of the most interesting properties of PECAM-1 is that the molecular structure of the cytoplasmic domain has a large impact on its ligand specificity. In L-cell aggregation assays in which PECAM-1 isoforms representing alternative spliced versions of the molecule were studied, it was found that the loss of an 18-amino-acid region corresponding to exon 14 changed PECAM-1 from a molecule that interacted in a heterophilic manner to a homophilic adhesion molecule (29, 39). It was therefore of interest to analyze the molecular isoforms of PECAM-1 expressed in the lung. Piedboeuf and colleagues (38) report the somewhat surprising finding that PECAM-1 isoforms lacking exon 14 made up almost half of the total amount of PECAM-1 RNA analyzed. It should be noted that in this study and in previous work (29), alternatively spliced isoforms have been identified at only the RNA and not the protein level. Nonetheless, these findings suggest that lung endothelial cells produce different types of PECAM-1 that might have different functions.
Perhaps the most interesting issue raised by the Piedboeuf study is the question of what function PECAM-1 plays in the lung. To date, we know of only one study that has examined this question (30). In these experiments, an anti-PECAM antibody was able to inhibit the movement of neutrophils into the alveolar space after intrapulmonary deposition of immunoglobulin complexes. It is unknown whether other types of lung inflammation, such as hyperoxic lung injury, would also be PECAM-1-dependent. To date, no experiments with PECAM-1 knockout mice have been reported.
Questions about the function of PECAM-1 in the lung raise a much larger issue. Although the paradigm of the leukocyte-endothelial adhesion cascade has been generally accepted in the peripheral circulation, its validity in the pulmonary circulation and lung remains an open question. Specifically, although there are data to indicate that the processes outlined previously may operate in the lung (40), there is also evidence that leukocyte recruitment in the pulmonary circulation may be different from that which occurs at extrapulmonary sites, depending on the stimulus (44).
In virtually all studies to date, the 2 integrins (CD11/
CD18) have been shown to be required for neutrophil emigration in various models of acute inflammation involving
the systemic vascular bed. A different pattern, however,
has been demonstrated in the lung. Although there are
several stimuli (Escherichia coli, lipopolysaccharides, and
IL-1) that mediate 2 integrin-dependent neutrophil extravasation within the lung (as they do in the systemic
circulation), there are a number of inflammatory mediators (Streptococcus pneumoniae, HCl, C5a) that have been
reported to mediate neutrophil extravasation from the
pulmonary circulation that is independent of the 2 integrins (45). These data are supported by studies of
endotoxin-induced pneumonia and cobra venom factor
(CVF)-induced lung injury in mice deficient in ICAM-1,
the principal endothelial ligand for the 2 integrins (48, 49).
Although ICAM-1 antibody and antisense oligonucleotide
inhibited neutrophil recruitment in wild-type mice, neutrophil accumulation was normal in the ICAM-1 mutant mice, suggesting that neutrophil recruitment in these models can occur independently of ICAM-1.
Studies of mutant mice with targeted deletions in both P selectin and E selectin have also been performed (50, 51). In these mice, neutrophil emigration into the peritoneal cavity was completely inhibited during S. pneumoniae-induced peritonitis. In contrast, neutrophil extravasation into the alveolar space during S. pnuemoniae-induced pneumonia was normal, and treatment with fucoidin, an inhibitor of L-selectin, did not affect neutrophil emigration. There is also evidence that neutrophil recruitment during CVF-induced lung injury can occur without the participation of P-selectin (49).
Taken together, these data suggest that under certain
circumstances, neutrophil emigration (and possibly that
of all leukocytes) from the pulmonary circulation into the
lung interstitium or alveolar space can occur through
pathways that do not require selectins, 2 integrins, or
ICAM-1. These observations, however, are not necessarily
unexpected, given that the primary site for leukocyte extravasation is in the pulmonary capillaries, not in postcapillary venules as occurs in the systemic vasculature (44).
This is significant because the average diameter of the leukocyte (particularly the neutrophil) approaches or exceeds
that of the capillaries. As a result, intracapillary leukocytes
must deform in order to travel through the pulmonary microvasculature. This ensures close apposition of the intravascular leukocyte with the pulmonary endothelium. Consequently, processes that alter the physical properties of the leukocyte or compromise its ability to deform may be
adequate to slow and arrest the leukocyte in the microcirculation of the lung (52, 53).
One of the major challenges for pulmonary scientists over the next five years will be to dissect carefully the role of specific CAMs in the context of well-characterized models of lung disease. These studies need to be carried out with an open mind and with the suspicion that major differences between the pulmonary and systemic circulation will be uncovered. With the growing availability of bioactive antimouse and antirat monoclonal antibodies and genetically engineered mice, these investigations should be possible. An understanding of the CAMs involved in specific lung disease states could lead to novel therapeutic approaches that could be both more effective and focused.
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Address correspondence to: Steven M. Albelda, M.D., 809 Maloney Bldg., University of Pennsylvania Medical Center, 3600 Spruce St., Philadelphia, PA 19104-4283.
(Received in original form April 17, 1997).
Abbreviations: cell adhesion molecule, CAM; intercellular adhesion molecule, ICAM; interleukin, IL; mucosal addressin CAM-1, MadCAM-1; platelet-endothelial CAM-1, PECAM-1; tumor necrosis factor-, TNF-;
vascular CAM-1, VCAM-1.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Crit. Care Med. |