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(Chest. 1999;116:18S-24S.)
© 1999 American College of Chest Physicians

Endothelial Activation in ARDS*

Guy A. Zimmerman, MD; Kurt H. Albertine, PhD; Holly J. Carveth, MD; Edward A. Gill, MD{dagger}; Colin K. Grissom, MD; John R. Hoidal, MD; Tada-atsu Imaizumi, MD{ddagger}; Christopher G. Maloney, MD; Thomas M. McIntyre, PhD; John R. Michael, MD; James F. Orme, MD; Stephen M. Prescott, MD and Matthew S. Topham, MD

* From the University of Utah Special Center of Research in ARDS, University of Utah Health Sciences Center, Salt Lake City, UT.

Correspondence to: Guy A. Zimmerman, MD, University of Utah, CVRTI, 95 S 2000 E, Salt Lake City, UT 84112-5000; e-mail: guy_zimmerman{at}gatormail.cvrti.utah.edu


   Introduction
TOP
 Introduction
What Is Endothelial Activation?
 How Has Endothelial Cell...
 Does Endothelial Activation...
 References
 

Endothelial injury is often identified as a hallmark of ARDS.1 2 3 4 5 6 Yet endothelial cells may be altered in other ways besides frank injury in ARDS and in other pathologic syndromes. A major concept in vascular biology that has largely evolved since the time of the original description of ARDS is that endothelial cells can become activated and that this can occur independently of, or as a component or consequence of, cellular injury.7 8 Endothelial activation is now considered by some clinicians and investigators to be a principal mechanism in the complex pathologic events that result in ARDS.9 10 This broadened concept of a spectrum of endothelial alterations—including cellular activation—in response to factors such as sepsis, trauma, oxidant and chemical attack, and other insults has merit, but several questions also merit consideration.


   What Is Endothelial Activation?
TOP
 Introduction
 What Is Endothelial Activation?
How Has Endothelial Cell...
 Does Endothelial Activation...
 References
 
There is no uniform agreement on the definition of endothelial activation in the field. Earlier, endothelial activation was defined as altered synthesis of proteins that mediate functional characteristics of the cells in response to stimulation with cytokines.11 The ability of human endothelial cells, and of endothelial cells from a variety of species of experimental animals, to respond to cytokines by expressing new messenger RNAs (mRNAs) and translating them into proteins that alter the cellular phenotype has been observed consistently by many investigators using a variety of different experimental protocols.7 12 This definition corresponds to the in vivo behavior of endothelium in delayed hypersensitivity responses and was in part based on observations of these inflammatory conditions.11 The definition is too limited, however, because endothelial activation responses include functional alterations that do not require transcription of mRNA or altered synthesis of proteins (see below). A more general definition of endothelial activation is a change in phenotype or function in response to stimuli from the environment. The stimuli known to induce activation-dependent functional alterations in human endothelial cells include humoral agonists that interact with cell surface receptors including, but not limited to, cytokines and pleotropic signaling factors such as thrombin, bacterial endotoxin (lipopolysaccharide [LPS]) and other microbial products, hemodynamic perturbations, oxidants, and radiation.7 8 A corollary to this definition is that endothelial cell activation can be a regulated event in homeostatic physiologic vascular responses, or it can be a dysregulated, or unregulated, response in pathologic conditions. Dysregulated or unregulated endothelial activation13 likely distinguishes ARDS from conditions in which the functional changes in endothelial cells are reversible and limited—such as in localized bacterial pneumonia that rapidly resolves, for example—but this remains to be determined.

Are there stereotyped molecular markers that can always be found in, or on, activated endothelial cells and that are sine qua non "litmus tests" of endothelial activation? The answer is no based on current information. Endothelial activation responses vary with the stimulus, the time after application of the stimulus, its concentration or magnitude, concomittant application of different stimuli (for example, a cytokine together with a hemodynamic perturbation), sequential stimulation after previous submaximal activation ("priming"), previous injury, and other factors.

For many workers in the field, the expression of molecules that mediate adhesion and/or signaling of leukocytes is nearly synonymous with endothelial activation.7 8 11 14 In a recent essay, it was noted that a significant advance in the field was a realization that only the activated endothelium participates in the inflammatory response.15 The early recognition that ARDS triggered by sepsis or certain other inciting insults involves inflammation of lung structures16 is consistent with the concept that endothelial activation plays a critical role. While endothelial activation may be a requirement for the accumulation of inflammatory cells, even this is not stereotyped. A variety of inducible endothelial molecules are used for interactions with leukocytes, and it is known that human endothelial cells express different patterns of adhesion and signaling molecules that are recognized by different classes of leukocytes in an agonist- and time-dependent fashion.7 14 17 18 19 Furthermore, activated human endothelial cells can display different patterns of tethering (adhesion) and signaling molecules for a particular class of leukocytes, such as the polymorphonuclear leukocyte (PMN, neutrophil)—a cell of particular importance in the initiation and amplification of lung injury in ARDS.6 9

Figure 1 illustrates two patterns of tethering and signaling molecules for PMNs that are displayed when human endothelial cells are stimulated with thrombin, histamine, or certain other agonists on the one hand, or with cytokines or LPS on the other. In the first, thrombin or one of the other relevant agonists induces translocation of P-selectin from storage granules in the endothelial cells to the plasma membrane and concomittant synthesis of a phospholipid signaling molecule, platelet-activating factor (PAF). Both activation-dependent events occur within minutes. Combinatorial display of P-selectin and PAF by the activated endothelial cells results in tethering and spatially restricted signaling of PMNs. An important point to note is that P-selectin and PAF can be considered as markers of endothelial activation but, under these conditions, transcription of mRNAs and synthesis of proteins are not required.17 19 20 Thus, a "screen" for endothelial activation based on detection of new mRNA transcripts or an altered pattern of transcripts and/or new synthesis of proteins would miss these activation responses entirely, although in other circumstances the genes for P-selectin and the enzymes that synthesize PAF may be induced by cellular activation.21 22



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  		Figure 1. Activated human umbilical vein endothelial cells express different patterns of adhesion and signaling molecules for PMNs. See text and references 17 and 20 for details. Both PAF and IL-8 have been shown to signal PMNs in a juxtacrine fashion while associated with the endothelial plasma membrane.17 19 20 21

 
In the second example (Fig 1) , endothelial cells stimulated with LPS, interleukin 1 (IL-1), or tumor necrosis factor-{alpha} (TNF-{alpha}) express E-selectin and interleukin-8 (IL-8) for a prolonged period, again resulting in tethering and signaling of PMNs but with a different time course from that mediated by P-selectin and PAF when endothelial cells are stimulated with thrombin or histamine.17 In contrast to P-selectin and PAF in the first activation pattern, the expression of E-selectin and IL-8 is dependent on transcription and on de novo protein synthesis. Thus, these latter markers of endothelial activation would be expected to be, and are, identified by screens that depend on differential detection of transcripts for the factors in activated vs resting endothelial cells23 (our unpublished observations).

The two simplified paradigms of cellular activation illustrated Figure 1 demonstrate the complexity of endothelial cell responses to stimulation. In addition, newly recognized endothelial agonists that induce different patterns of tethering and signaling molecules for PMNs with different time courses continue to be reported and additional molecules that mediate interactions with PMNs and that are expressed by activated endothelial cells continue to be identified. Thus, Figure 1 is a simplified schema based on earlier observations in the field; to be comprehensive, oncostatin M and other recently identified endothelial agonists22 24 would needed to be added, ENA-78 and other signaling molecules for PMNs would have to be shown25 (and see below), and additional endothelial adhesion molecules would need to be included.7 Furthermore, PMNs themselves can induce or modulate endothelial activation responses.26 The complexity of endothelial activation responses is compounded when their interactions with other leukocytes besides PMNs are added to the equation.7 14


   How Has Endothelial Cell Activation Been Studied and Characterized Experimentally?
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 Introduction
 What Is Endothelial Activation?
 How Has Endothelial Cell...
Does Endothelial Activation...
 References
 
One of the key advances in the field of vascular biology was development of methods for the culture of human endothelial cells.7 27 In vitro systems consisting of purified human endothelial cells grown to confluence under rigorously defined conditions in which critical phenotypic features are similar to those found in in situ endothelium have yielded specific data and conceptual paradigms that have utility in consideration of endothelial activation in general, and activation of endothelial cells in ARDS and other syndromes of vascular injury in particular. A general approach has been to use this "reduced" in vitro system to characterize expression of molecules that can be considered as markers of endothelial activation, explore cell-cell interactions involving leukocytes or other cells, and examine intracellular biochemical signaling cascades that regulate activation-dependent responses. Using data or inferences generated from studies of cultured endothelial cells, additional experimental systems have then been utilized to extend and refine conceptual understanding of endothelial activation. These more complex systems include modified Stamper-Woodruff models, in situ endothelium in vessel segments, and isolated organ preparations,27 and in vivo models that include genetically altered animals.10 28 29 It is notable that many of the original observations that led to informative studies in vivo, including those using "knockout" animals with targeted deletions of adhesion molecules or other factors, were made using cultured human endothelial cells. These studies have demonstrated both remarkable similarities and important differences in certain activation responses of endothelium in the in vitro cultured cell system compared with those in in vivo models. For example, both cultured human endothelial cells30 31 32 33 and in situ endothelial cells in live mice10 28 29 34 express P-selectin on their surfaces when they are appropriately stimulated. In contrast to this concordance, however, the murine P-selectin promoter is organized differently in mice compared with that in the human P-selectin gene and TNF-{alpha} and LPS induced synthesis of P-selectin by rodent endothelium but not by human endothelial cells.35 36 Interestingly, engagement of P-selectin glycoprotein ligand 1, the ligand on PMNs that recognizes P-selectin,37 influences inside-out signaling of ß2 integrins differently in human vs mouse neutrophils.33 38 Thus, it is possible that conclusions regarding the expression and actions of P-selectin in endothelial activation and inflammatory tissue responses could be misleading if based on the murine model alone, illustrating the utility of the cultured human endothelial cell system.

The human endothelial cell type most widely utilized for culture and in vitro experiments is isolated from umbilical vessels, usually umbilical vein. In our experience, and that of other investigators, this cell has been remarkably useful if studied in primary confluent culture under rigorously defined and controlled conditions.27 However, its origin in umbilical vessels has led to questions regarding the conclusions that can be drawn from this experimental system18 : is it useful with respect to activation events that occur in systemic and/or pulmonary vessels in inflammation and vascular injury? Using expression of adhesion and signaling molecules as an index, current data in the field argue that it is a remarkably informative in vitro model in this regard. Adhesion molecules, signaling factors, and inducible enzymes now known to be expressed in vivo and to be specifically active in inflammation in experimental models and in humans were first discovered and/or identified to be expressed by endothelium using cultured human umbilical vein endothelial cells. Examples include E-selectin, P-selectin, members of the intracellular adhesion molecule family, vascular cell adhesion molecule-1, PECAM-1, IL-8, cyclooxygenase-2 (COX-2), and others. A recent addition to the list illustrates this point. As part of a search for previously unidentified signaling molecules for leukocytes that are expressed by activated endothelium, we found that cultured human umbilical vein endothelial cells express the C-X-C chemokine epithelial neutrophil activating peptide-78 (ENA-78) when stimulated with LPS, IL-1, TNF-{alpha}, or oncostatin M.24 25 Others have also reported that cultured endothelial cells, including pulmonary artery endothelial cells, express ENA-78 in response to stimulation.39 We found that both mRNA and protein ENA-78 were expressed in activated umbilical vein endothelial cells in vitro (Fig 2) , and that it mediates neutrophil adhesion under these conditions. In addition, by immunohistochemical analysis, we found that ENA-78 is present in inflamed endothelial cells in systemic vessels and in human lung25 (Fig 3) . Thus, while no isolated cell model is a perfect replica of the in situ state, cultured umbilical vein endothelial cells provide information relevant to the in vivo condition. This supports their potential utility for characterization of additional molecular species relevant to ARDS and to other vascular injury states. Our studies of degranulating factors and other inducible molecules synthesized by cultured human endothelial cells in response to stimulation indicate that critical activation-dependent responses remain to be characterized40 41 (and unpublished observations).



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  		Figure 2. Cultured human umbilical vein endothelial cells express mRNA for ENA-78 when activated by LPS, TNF-{alpha}, or IL-1. Primary monolayers of human umbilical vein endothelial cells were incubated in media alone ("unstimulated") or in media containing LPS, TNF-{alpha}, or IL-1 for 21 h, and expression of mRNA for ENA-78 was measured by the reverse transcriptase-mediated polymerase chain reaction. Expression of mRNA for IL-8 and glyceraldehyde phosphate dehydrogenase was examined in parallel. For experimental details, see reference 25 (reprinted with permission25 ).

 


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  		Figure 3. ENA-78 protein is expressed in in situ human pulmonary endothelial cells. ENA-78 was detected by immunohistochemical analysis (brown reaction product) in endothelial cells (arrows) in the lungs of a patient who died with acute bacterial pneumonia. The microvessel shown is surrounded by an infiltrate of PMNs and other inflammatory cells. Occasional macrophages are also stained by the antibody agonist ENA-78. See reference 25 for details of the staining procedures and controls.

 
A second question is whether cultured human umbilical vein endothelial cells, or cultured macrovascular endothelial cells from other sites, are representative of microvascular endothelial cells of the alveolar-capillary field or in other microvascular beds.18 There is considerable sentiment in the field that there is heterogeneity in endothelial cells and their responses at different vascular sites, and there are experimental observations to support this point.8 18 42 However, certain markers first identified as constitutive or activation-dependent endothelial cell factors in cultured macrovascular endothelial cells are also expressed in microvascular endothelium of the human lung or other organs, including von Willebrand factor, platelet-endothelial cell adhesion molecule (PECAM)-1, and ENA-78.7 25 43 Our preliminary studies indicate that P-selectin, COX-2, and other molecules identified in cultured human umbilical vein endothelial cells are also present in microvascular endothelial cells of the inflamed or injured human lung (unpublished observations; see below). Thus, cultured macrovascular endothelial cells can, in some cases, be informative about endothelium in microvessels as well and it is possible that the similarities in macrovascular and microvascular endothelial cells outweigh the differences. This question is important for a number of reasons, including the fact that many studies of microvascular endothelial cells from human lung44 45 or other tissues to date have required several passages in order to generate sufficient cells for functional analysis, a manipulation that can dramatically influence endothelial phenotype and alter intracellular biochemical pathways that mediate activation-dependent events27 46 (article in preparation).


   Does Endothelial Activation Occur in Humans With ARDS and Other Syndromes of Inflammation or Injury?
TOP
 Introduction
 What Is Endothelial Activation?
 How Has Endothelial Cell...
 Does Endothelial Activation...
References
 
As outlined above, endothelial activation has largely been defined in reduced in vitro systems. While there is evidence from animal models that endothelial activation is a component of the pathogenesis of experimental lung inflammation and inflammatory injury,10 15 ARDS remains a uniquely human disorder in that no animal model perfectly replicates the clinical syndrome, which is itself heterogeneous. Thus, the question of endothelial activation in ARDS requires examination of human samples and, ultimately, study of patients at the bedside. Morphologic observations are consistent with the possibility that activation of alveolar-capillary endothelial cells occurs as a component of ARDS.47 For example, Bachofen and Weibel48 reported in an early study that the endothelial lining of vessels in the lungs of subjects with ARDS secondary to septicemia was intact without evidence for gross damage, even at sites of leukocyte sequestration. This is consistent with the ability of LPS49 and other bacterial toxins or products50 51 to activate endothelial cells resulting in expression of adhesion and signaling molecules and local PMN accumulation (Fig 1) , although there are also other mechanisms of leukocyte sequestration in the lung.52 In addition, our studies of the adhesive behavior of PMNs from subjects with ARDS indicated that they accumulate in the lungs without necessarily being hyperadhesive in in vitro assays,53 an observation that is also consistent with endothelial activation although, again, there are other potential explanations for this experimental result. More recently concentrations of soluble adhesion molecules that may be markers of endothelial cell activation54 have been found to be increased in plasma samples from patients with ARDS, localized acute lung injury, and hypoxic acute mountain sickness or high altitude pulmonary edema,55 56 57 suggesting that endothelial beds are activated in these conditions and have responded to pathologic stimuli with increased synthesis and/or release of the circulating proteins. This conclusion is, however, tempered by the facts that the significance of circulating cell adhesion molecules remains unclear,58 59 the factors that influence the plasma concentrations of these factors in acutely or critically ill patients remain undefined (decreased clearance vs increased release, etc), and each of these markers has other cells of origin besides endothelial cells with exception of E-selectin.

Careful immunohistochemical analysis of adhesion molecules, signaling factors, and other markers that are expressed by endothelial cells or are displayed on their surfaces in an activation-dependent fashion, together with complementary studies such as in situ hybridization for selected activation markers, will likely provide invaluable information regarding endothelial activation in ARDS that can be correlated with in vitro studies and with information from other experimental models (experimental animals, etc). This approach, although traditional, will serve as a gold standard until newer strategies for in vivo cell biology60 can be applied at the bedside. In analyses of this sort, it should be remembered that systemic endothelial beds, in addition to pulmonary endothelial cells, are involved in ARDS.16 Morphologic analysis (using recently developed antibodies against markers of endothelial activation and other similar reagents) also has the potential to provide the descriptive basis for additional mechanistic and hypothesis-driven studies, as was recognized by Laennec years ago.16 Information of this sort is scanty, however, and the phenotypes of endothelial cells in the lungs of humans with ARDS and predisposing conditions with respect to adhesion molecules, signaling factors, and other activation-dependent markers are largely undefined. Furthermore, it is unknown how the expression of such markers in in situ endothelium changes with evolution or resolution of the syndrome. In ongoing studies, we are examining the characteristics of endothelial cells in the inflamed and injured human lung by establishing an archive of autopsy and biopsy tissue from subjects with ARDS or with predisposing conditions and from control subjects and patients with comparative disorders. Initial studies indicate that ENA-78 is expressed by endothelial cells in the lungs of patients with ARDS,25 as it is in bacterial pneumonia (Fig 3) , and that P-selectin is displayed on the surfaces of endothelial cells in inflamed and injured human lungs (unpublished observations). We have also found that COX-2, an enzyme expressed in an activation-dependent fashion by human endothelial cells stimulated in vitro,46 61 is also present in endothelial cells in the lungs of subjects with ARDS (unpublished observations). Of note, both ENA-78 and COX-2 are also expressed by leukocytes in inflamed and injured lungs,25 indicating that actions of the chemokine and of the eicosanoid products of COX-2 may be exerted in a topographic fashion. If so, production of these signaling molecules by activated endothelium may be particularly important because of its location at the interface between the blood and the extravascular milieu. Examination of this possibility must begin with morphologic studies. Such observations will also provide in vivo correlates for activation-dependent events originally defined in the reduced cultured endothelial cell systems discussed above. To date, these studies indicate that the concept of endothelial cell activation is relevant to our understanding of the mechanisms and natural history of ARDS.


   Acknowledgements
 
We thank fellows, technicians, and other SCOR investigators and colleagues who contributed to studies cited in this review, the staffs of the Labor and Delivery Services of LDS and Cottonwood Hospitals for collection of umbilical samples, and Leona Montoya for preparation of the manuscript.


   Footnotes
 
Currently at University of Colorado Health Science Center, Denver, CO. Back

Currently at Institute of Neurological Diseases, Hirosaki University School of Medicine, Hirosaki, Japan. Back

Supported by National Institutes of Health award P50 HL50153.


   References
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 What Is Endothelial Activation?
 How Has Endothelial Cell...
 Does Endothelial Activation...
 References
 

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