The Expression of Adhesion Molecule and ARDS. Asrar B. Malik and Masashi Bando
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1 The Expression of Adhesion Molecule and ARDS Asrar B. Malik and Masashi Bando Introduction The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity and mortality (10 to 90%)1). The reported annual incidence in the United States is 150,000 cases2). Since there are many accepted causes of ARDS, ARDS is a heterogenous disorder. In some cases, the damage is initiated on the endothelial cell side of the alveolar wall such as fat embolism and in some cases, the damage is initiated on the epithelial side of the alveolar wall such as aspiration. According to the American-European Consensus Conference on ARDS1), ARDS induces injury to both the lung endothelium and the epithelium. In general, it is useful to think of the pathogenesis as consisting of two pathways; the direct effects of an insult on lung cells and the indirect result of an acute systemic inflammatory response. These inflammatory responses include both cellular and humoral components. The cellular response involves neutrophils, macrophages/monocytes, and lymphocytes. Cellular events that may have a role in the process include adhesion, chemotaxis/chemokinesis, and activation. In these processes, adhesion molecules expressed on vascular endothelial cells mediate cell-cell and cell-matrix adhesive interactions that are essential for the regulation of trafficking of leulocytes across the vascular endothelial barrier3). The expression of adhesion molecules on vascular endothelial cells, such as E-selectins, ICAM-1 and VCAM-1, have been shown to be critically involved in the pathogenesis of ARDS and acute lung injury. In this review, we will focus on the structure and biology of ICAMs, E-/P-selectins and VCAM-1 and their respective ligands and discuss their involvement in the pathophysiology of ARDS. Endothelial Adhesion Molecules in ARDS There have been many studies indicating that the polymorphonuclear leukocyte (PMN) is central to lung injury in ARDS4'5. Examination of lung biopsies obtained from patients with ARDS confirms a marked influx of PMNs into the lung. These observations support the hypothesis that products of PMNs participate in the initiation and propagation of the lung pathology. However, some reports have described ARDS in patients with neutropenia and no pulmonary neutrophil sequestration6)7). These reports suggest that products of PNINs may not in fact be necessary for the syndrome to develop. One mechanism of PMNs recruitment from systemic circulation to the lung is directed chemotaxis. In the initial stage of ARDS, cells of the lung may be produce substances chemotatic for PMNs. Products of alveolar macrophages with such chemotactic activity include interleukin 1(IL-1), interleukin 8 (IL-8), tumor necrosis A second mechanism of PMN recruitment is the result of activation in the lung microvasculature endothelial cells. Recent reviews of pulmonary adhesion molecules, highlight the importance of neutrophilendothelium reactions8)9). Several endothelial adhesion molecules with highly specialized functions have been characterized (Table 1). A family of endothelial selectins consisting of (a) E-selectin (ELAM-1; the endothelial leukocyte adhesion molecule-1) is expressed exclusively on endothelial cells and (b) P-selectin is expressed on endothelial and platelet plasmalemmal mambranes. The common lectin domain on E- and P-selectins is Department of Pharmacology, The University of Illinois at Chicago College of Medicine, Chicago, Illinois
2 Table 1 Cell adhesion molecules expressed on endothelial cells involved in the binding to specific carbohydrate residues (e.g., sialyl-lewis X) present on leukocytes. Another set of adhesion receptors, the intercellular adhesion molecules (ICAMs), ICAM-1, ICAM-2 and ICAM-3, are member of the immunoglobulin superfamily. The CD11/CD18 family of integrin are the counter-receptors for ICAM-1 and ICAM-2. The vascular cell adhesion molecule (VCAM-1), another member of immunoglobulin superfamily, binds to the integrin very late activation antigens-4 (VLA-4 group) found on leukocytes. CD11/CD18 Integrins on Leukocytes in ARDS While neutrophil rolling appears to be a prerequisite for eventual firm adherence to blood vessels, selectin-dependent adhesion of leukocytes does not lead to firm adhesion and transmigration unless a second set of adhesion molecules is engaged. For neutrophil, the second stage of adhesion requires engagement and CD11b/CD18. Although the integrins are constitutively expressed by neutrophils, they do not bind to their counter-receptor (ICAM-1, ICAM-2) unless the neutrophil is activated. Activation causes the integrins to undergo a conformational change. The development of the ARDS in trauma patients coincides with the expression of leukocyte CD11b/ CD18. Neutrophil oxidative metabolism increases after the onset of CD11b/CD18 expression in neutrophils of these patients10). There is a relationship between CD11b/CD18 expression and development of ARDS in trauma patients. This has also been observed in experimental septic injury model where there was increased exnression of neiitronhil CD11 /CD1 R after septicemia associated with acute lunc iniury11). Intercellular Adhesion Molecule-1 (ICAM-1; CD54) ICAM-1 is a 90-kD inducible transmembrane glycoprotein that promotes leukocyte adhesion in inflammatory reaction. The cellular distribution of ICAM-1 is different from other endothelial cell adhesion molecules such as E-selectin and VCAM-1 in that it is expressed in hematopoietic and non-hematopoietic cells such as endothelial cells, fibroblasts, and keratinocytes and other epithelial cells. ICAM-1 is the known ligand for CD11a/CD18 as well as CD11b/CD18. The constitutive expression of ICAM-1 on the endothelial cell surface remain elevated for 72 hrs12). Although the evidence is circumstantial, it is believed that ICANI-1 expression is regulated by activation of second-messenger Pathways. Staurosporine or the isoquinosulphonamide derivative, H7, both of which prevent protein kinase C (PKC) activation, inhibited the cytokine-mediated ICAM-1 expression and neutrophil adhesion to endothelial cells13). Other studies showed that TNFa-induced activation of ICAM-1 occurred independently of PKC activation14~. Therefore, the involvement of PKC in the response
3 The Expression of Adhesion Molecule and ARDS 31 1 mrna expression (Bando and Malik, unpublished data). The interaction of CD11/CD18 and ICAM-1 is an important event in both neutrophil adhesion and migration events. Monoclonal antibodies (mabs) against CD11/CD18 integrins were used to study the relative contribution of CD11a/CD18 and CD11b/CD18 in mediating neutrophil adhesion15). Each mab inhibited approximately 50% of the adhesion induced by phorbol dibutyrate, whereas both mabs together fully inhibited the response. Anti-ICAM-1 mabs also produced a 50% inhibition of the adhesion. In neutrophils activated with chemotactic agents, combination of anti-cd11a and anti-cd11b mabs fully inhibited neutrophil adhesion and diapesis16). These results support the hypothesis that a cooperative interaction of CD11a/CD18 and CD11b/CD18 with ICAM-1 is required for the neutrophil adhesion and transendothelial migration events. A role for ICAM-1 in acute lung injury induced by phorbol myristate acetate has been shown by antibody blocking with an anti-icam-1 mab17). ICAM-1 plays an important role in neutrophil migration into inflammatory sites in lungs. Therefore reagents that block ICAM-1 function may be useful therapeutic agents in acute lung injury. E-Selectin (CD 62E) Endothelial lenkocyte adhesion molecule-1 (ELANI-1 or E-selectin), a member of the Selectin family of cell surface glycoproteins, is an endothelial cell adhesion protein involved in the initial binding of PMNs and other leukocytes to the venular endothelium at sites of inflammation. E-Selectin ligands on PMN are fucose-rich glycoproteins containing sialylated Lewis X and other related oligosaccharides. The expression of E-Selectin was transient, reaching a maximum at 4 hr and decaying by 24 hr; the kinetics of E-Selectin expression paralleled the adhesion of leukocyte to endothelial cells18). The factors regulating E-selectin gene expression are likely to be important in the initial phases of the inflammatory response because selectins are expressed early after cytokine challenge of endothelial cells. Studies quantifying neutrophil recruitment in primates within 2hr after LPS challenge19). This was associated with neutrophil adhesion as well as neutrophil extravasation. E-selectin decreased with time and was not evident by 9hr. In contrast, ICAMJ activity did not change in response to endotoxin challenge during this period, pointing to E-selectin expression as the P-selectin (CD 62P) P-selectin (also known as platelet activation dependent granule external membrane protein (PAD-GEM) or granule membrane protein-140 [GMP-140]) is an integral membrane glycoprotein. P-selectin is located in P-selectin is rapidly redistributed from secretory granule membranes to the surface of platelets and endothelial cells as a result of exocytosis, where it mediates adhesion of PMNs, monocytes, and subsets of lymphocytes. The expression of P-selectin is restricted to megakaryocytes and endothelial cells. Steady-state induced increase in mrna was maximal at 4hrs and was substantially decreased by 6hrs21). The intracellular mechanisms leading to P-selectin exocytosis are not yet clear, but it is likely that they involve activation of second-messenger pathways. P-selectin is responsible for rapid adhesion of leukocytes to endothelial cells. The rapid kinetics of P-selectin expression in vivo paralleled the in vitro response, and an anti-p-selectin mab reduced the neutrophil sequestration, permeability increase, and hemorrhage22). P-selectin also mediated plateletneutrophil adhesion, and thus contributes to accumulation of platelets and neutrophils at the same sites. Vascular Cell Adhesion Molecule-1 (CD106) The vascular cell adhesion molecule-1 (VCAM-1) is a 110-kD member of the immunoglobulin gene superfamily first identified as an adhesion molecule expressed on activated endothelial cells. VCAM-1
4 mediates leukocyte-binding to endothelial cells through its interaction with the intergrin counter-receptor, the very late activation antigen-4 (VLA-4). Because of the selective expression of VLA-4 on monocytes and lymphocytes (but not on PMNs), VCAM-1 plays an important role in mediating mononuclear leukocyteselective adhesion. In contrast to the endothelial cells where its expression is dependent on inflammatory cytokines, VCAM-1 is expressed constitutively in other cell types. VCAM-1 mrna is barely detectable in of monocyte binding, which is detectable 2 hrs after cytokine treatment and is sustained for at least 48 hrs. Sequential Neutrophil Adhesion Response Endothelial cells treated with inflammatory cytokines expressed E-selectin and ICAM-1. Both adhesion molecules were involved in neutrophil adhesion with the initial response being more E-selectin-dependent, with the later response being more ICAM-1 dependent. Neutrophils did not migrate across endothelial cells when endothelial cells had been treated with cytokines for 24 hrs, whereas significant ICANI-1 and adhesivity activities were expressed as this time, suggesting that the adhesion and transendothelial migration events are separate events regurated by different mechanisms. Neutrophil migration across the endothelium may depend on the sequential series of interations between the activated endothelial cells and neutrophils24). Circulating neutrophils express minimal CD11/CD18 integrin activity and have low binding toward the unstimulated endothelium. However, the expression of E-selectin after endothelial activation by cytokines or LPS and the engagement of E-selectin to sialy Lewis X on neutrophils may induce the activation of CD11/CD18 integrins24). The enhanced CD11/CD18 activity promotes ICAM-1-dependent adhesiveness between neutrophils and endothelial cells (Fig. 1). This sequence of adhesion Fig. 1 Proposed model of sequential activation of E-selectin and CD11/CD18 integrins on neutrophils. Engagement of carbohydrate structures related to sialyl-lewis X on neutrophils with the E-selectin on endothelial cells signals neutrophils to increase their CD11/CD18 functional activity. This sequential activation ensures tightness of adhesion and enables neutrophil recruitment at inflammatory sites. (Modified from Lo et at., 1991, used with permission of the authors).
5 The Expression of Adhesion Molecule and ARDS 33 events is capable of delivering cellular signals to the neutrophil to induce high avidity neutrophil adhesion that can withstand the shear stress forces encountered in microvessels25). Once the neutrophils are stably adherent, they are then capable of migrating across the endothelial barrier. Hence, according to this model, the selectin family, which mediates leukocyte rolling, and the CD11/CD18 integrins, which strengthen leukocyte attachment to the endothelium, act in concert to promote transendothelial migration of leukocytes. Conclusions Adhesion molecules on endothelial cells orchestrate a complex series of responses between endothelial cells and leukocytes. The primary role of these adhesive interactions is to facilitate leukocyte migration across the endothelial barrier to defend the host during infeciton. The adhesion response serves as an important initial step in the host-defense response. However, inappropriate attachment of leukocytes to the hyperadhesive or activated endothelial cell surface can occur by the expression of one or more endothelial adhesion molecules. This may contribute to the pathogenesis of ARDS and acute lung injury. The finding that the adhesion molecules are essential for leukocyte adhesion and migration and that adhesion and migration can be separately inhibited by mabs directed against these molecules suggests that it is possible to control as well as reverse the progression of the inflammatory response. Important questions that remain to be addressed relate to the (a) mechanisms of induction of the endothelial adhesion molecules at the level of the gene and the involvement of second-messenger pathways, (b) cooperation and interactions between the leukocyte and endothelial adhesion molecules, (c) precise role of the adhesion molecules in the host-defense response and in the mediation of inflammatory disorders such as ARDS, and (d) operation of these molecules in the intact microcirculation under varying shear stress and flow conditions. References 1) Bernard GR, Artigas A, Brigham KL, et al: The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med 1994; 149: ) Villar J, Slutsky AS: The incidence of the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 140: ) Malik AB, Lo SK: Vascular endothelial adhesion molecules and tissue inflammation. Pharmacological Rev 1996; 48: ) Corrin B: Lung pathology in septic shock. J. Clin Pathol 1980; 33: ) Repine JE, Beehler CJ: Neutrophils and adult respiratory distress syndrome: Two interlocking perspectives in Am Rev Respir Dis 1991; 144: ) Glauser FL, Fairman RP: The uncertain role of the neutrophil in increased permeability pulmonary edema. Chest 1985; 88: ) Ognibene FP, Martin SE, Parker MM: Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med 1986; 315: ) Malik AB: Cellular mechanisms of leukocyte adhesion. In: Pathophysiology of shock, sepsis and organ failure. Springer-Verlag, Berlin. Edited by G. Schlag,, 1993; ) Shanley TP, Warner RL, Ward PA: The role of cytokines and adhesion molecules in the development of inflammatory injury. Molecular Med 1994; ) Simms HH, D'Amico R: Increased PMN CD11b/CD18 expression following post-traumatic ARDS. J Surg Res 1991; 50: ) Walsh CJ, Leeper-Woodford SK, Carey PD, et al: CD18 adhesion receptors, tumor necrosis factor, and neutropenia during septic lung injury. J Surg Res 1991; 50: ) Pober JS, Bevilacqua MP, Mendrick DL. et al: Two distinct monokines interleukin-1 and tumor necrosis factor, each independently induce biosythesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 1986; 136: ) Lane TA, Lamkin GE, Wancewicz EV: Protein kinase C inhibitors block the enhanced expression of interecellular adhesion molecule-1 on endothelial cell activated by interleukin-1, lipopolysaccharide and tumor necrosis factor. Biochem Biophys Res Commun 1990; 172:
6 14) Ritchie AJ, Johnson DR, Ewenstein BM, et al: Tumor necrosis factor induction of endothelial cell surface antigens is independent of protein kinase C activation or inactivation. Studies with phorbol myristate and staurosporine. J Immunol 1991; 146: ) Lo SK, Van-Seventr GA, Levin SM, et al: Two leukocyte receptors (CD11a/CD18) and (CD11b/CD18) mediate transient adhesion to endothelium by binding to different ligands. J Immunol 1989; 143: ) Smith CW, Martin SD, Rothlein R, et al: Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest 1989; 83: ) Barton RW, Rothlein R, Ksiazek J, et al: The effect of anti-intercellular adhesion molecule-1 on phorbol-esterinduced rabbit lung inflammation. J Immunol 1989; 143: ) Bevilacqua MP, Stengelin S, Gimbrone Jr. MA, et al: Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 1989; 243: ) Munro JM, Pober JS, Cotran RS: Recruitment of neutrophils in the local endotoxin response: association with de novo endothelial expression of endothelial leukocyte adhesion molecule-1. Lab Invest 1991; 64: ) Rahman A, Roebuck KA, Malik AB: Transcriptional regulation of endothelial adhesion molecule gene expression by oxidants and cytokines. In: Role of free radicals in pulmonary vasculature. Proceedings of the VII Grover Conference. Weir EK, Archer SL, Reeves JT, editors. Futura Publishing Co., NY, 1996; ) Sanders WE, Wilson RW, Ballantyne CM: Molecular cloning and analysis of in vivo expression of murine P-selectin. Blood 1992; 80: ) Mulligan MS, Varani J, Dame MK, et al: Role of endothelial-leukocyte adhesion molecule (ELAM-1) in neutrophilmediated lung injury in rats. J Clin Invest 1991; 88: ) Osborn L, Hession C, Tizzard R: Direct expression cloning of vascular cell adhesion molecule-1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 1989; 59: ) Lo SK, Lee S, Ramos RA, et al: Endothelial-leukocyte adhesion molecule 1 stimulates the adhesive activity of leukocyte integrin CR3 (CD11b/CD18, Mac-1) on human neutrophils. J Exp Med 1991; 173: ) Perry MA, Granger DN: Role of CD11/CD18 in shear rate-dependent leukocyte-endothelial cells interactions in cat mesenteric venules. J Clin Invest 1991: 87:
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