key: cord-0006638-yzc36x26 authors: Hamacher, J.; Schaberg, T. title: Adhesion molecules in lung diseases date: 1994 journal: Lung DOI: 10.1007/bf00164437 sha: 6c34887faa847fc215bf1d17c26effbb03f06616 doc_id: 6638 cord_uid: yzc36x26 The human body possesses highly specialized cellular defense mechanisms that, when activated pathologically, can induce a number of immunologic disorders. For a normal cellular immune response, the following conditions must be fulfilled: (1) accumulation of white blood cells, (2) their diapedesis through the vessel walls of the inflammatory area affected by an injurious agent, and (3) normal cellular effector functions in the tissue. This cascade of inflammatory processes has recently been shown to be regulated by a group of molecules that are termed adhesion molecules and consist of three subfamilies: selectins, the immunoglobulin supergene family, and integrins. The cellular functions influenced by adhesion molecules include, among others, cytotoxic T-cell responses, CD4-dependent activation of B lymphocytes by T lymphocytes, activation of granulocytes and macrophages, phagocytosis of opsonized particles by monocytes, macrophages, and granulocytes, antigen-presenting function of macrophages, their antibody-dependent cytotoxicity, initiation of a respiratory burst by white blood cells, and activation of fibroblasts. Studies performed in recent years have shown that pathogenetically relevant changes in the expression and function of adhesion molecules are involved in a variety of pulmonary diseases. These changes include the accumulation and activation of alveolar macrophages in smokers, experimentally induced bronchial hyperreactivity in bronchial asthma, accumulation of eosinophils in allergic rhinitis, bleomycin-induced pulmonary fibrosis, binding of viruses and bacteria to respiratory mucosa, and various mechanisms of acute damage to pulmonary parenchyma. Though their role in tumor development is still unclear, adhesion molecules are obviously involved in determining the route and organotropism of metastases. Further studies of the function of adhesion molecules in pulmonary diseases will contribute to our understanding of the pathomechanisms of these diseases and, through the development of specific antibodies, may provide attractive new therapeutic approaches to problems for which treatment is not yet available Our understanding of the physiology of inflammatory processes has increased markedly over the last 10 years. This is due especially to the discovery and description of a group of molecules closely associated with the mechanisms of accumulation and activation of inflammatory cells at the site of inflammation. These cell-surface molecules were designated as adhesion molecules because of one of their first-described properties. In a multicellular organism, adhesion processes are involved in embryonal development, the organization of organ differentiation, the preservation of tissue architecture, and the ability of the organism to react to injuries, infections, and tumors [4, 124, 141] The adhesion molecules, which are expressed by all body cells, primarily regulate cell-cell and cell-matrix interactions and ensure anchorage of the cells in the tissue [2] . In addition, these molecules also mediate signals for the growth, differentiation, and activation of cells [110] . It is the aim of this survey article to present the family of adhesion molecules in a systematic way, to describe their structural and functional properties, and to discuss their possible role in pulmonary diseases. In a simplified classification, the adhesion molecules can be subdivided into three families which share a number of structural, functional, and genetic properties. The epithelial, endothelial, and leukocytic adhesion molecules characterized so far belong to either the immunoglobulin supergene family, the selectin gene family, or the integrin gene family [16] ( Table 1) . The immunoglobulin (Ig) supergene family is characterized by one or more repetitive immunoglobulin-like domains consisting of about 100 amino acids and a central disulfide bond. This family includes the adhesion molecules ICAM-1, ICAM-2, and ICAM-3 (intercellular adhesion molecules 1, 2, and 3), VCAM-1 (vascular cell adhesion molecule 1), NCAM (neural cell adhesion molecule), and PECAM-1 (platelet endothelial cell adhesion molecule 1) [40, 49, 138] . Lymphocyte surface molecules, which play a crucial role in activation, antigen recognition, and adhesion processes, also belong to the Ig supergene family; among them are the receptors CD2 and its ligand LFA-3, parts of the CD3 complex, CD4, CD8, MHC class-I and class-II receptors, immunoglobulins, platelet-derived growth factor (PDGF) receptor [144] , and carcinoembryonic antigen (CEA) [81] . The shared structural properties, high structural constancy, and wide biological spread are regarded as evidence for evolutionary significance and the proven stability of these structures [124] . Adhesion molecules of the immunoglobulin supergene family are expressed by epithelial and endothelial cells, lymphocytes, monocytes, platelets, and granulocytes [101] . While ICAM-2, ICAM-3, and PECAM-1 are constitutional cell-surface components, ICAM-1 and VCAM-1 show stronger expression after stimulation mediated primarily by cytokines (e.g., tumor necrosis factor-alpha, interleukin-beta, interferon-gamma, interleukin-8, granulocyte-macrophage CSF) but also by endotoxins or lipopolysaccharides [93, 124, 135] . The family of selectins has an important role in margination along the vessel wall and the initially loose adhesion of leukocytes to endothelial cells in the vascular bed. Members of this family are the molecules P-selectin, E-selectin, and L-selectin, which are also called GMP-140 (granule membrane protein 140), ELAM-1 (endothelial leukocyte adhesion molecule 1), and LECCAM-1 (leukocyte endothelial cell adhesion molecule 1) [22, 61, 101, 120, 123, 124, 140] . Their ligands are carbohydrate molecules. Integrins mediate adhesion to other cells and to components of the extracellular matrix. They consist of two noncovalently bound, structurally different peptide chains (alpha-, beta-heterodimers) [16, 70, 111, 110, 124] . Table 2 lists the most important integrins according to their function [3] . Six different betachains have been identified so far and these can combine with a large number of alpha-chains to form the corresponding receptors [16] . The extent of integrin expression differs widely from one cell type to another. Cultured cells express 2 to 10 different types of integrins. Some of these are cell-type-specific, e.g., gpIIb/IIIa (megakaryocytes and platelets) and the CD11/CD18 group, which is expressed only by leukocytes [110] . The ill-Subfamily includes the VLA (very late activation antigen) receptors, while the subfamily that shares the fl2-shain determined on chromosome 21 comprises the LeuCAM receptors (CD11/CD18) [4] . The/33-subfamily consists of the two cytoadhesins, vitronectin receptor and thrombocyte-glycoprotein IIbIIIa (gpIIbIIIa) [58, 59, 76, 110] . The extracellular domain of the integrins contains cysteine-rich repeats within the/3-chain, i.e., repetitive regions with disulfide bonds that ensure a rigid tertiary structure [74] as well as a disulfide bond that stabilizes the large loop of the N-terminal region of the extracellular domain [4] . The extracellular domain of the alpha-chain also contains disulfide bonds, which stabilize the secondary structure, and its large loop, which leans toward the/3-chain, includes regions binding to calcium and other divalent cations [4, 63] (Fig. 1) . Little is known about the transmembranous region, but it is the intracellular domain of these receptors that is of interest. The latter contains regions that can bind to actin filaments of the cytoskeleton by means of the cytoskeleton proteins talin, vinculin, or alpha-actinine [77, 82] , and are involved in motor phenomena that are important for transmigration and processing of signals between receptor molecules and intracellular second messenger substances. Vitronectin A special feature of/32-integrins is that the affinity of the receptor can be enhanced transiently by intracytosolic signals [139] through an Mg 2+dependent change in the conformation of the receptor structure on the cell exterior [7] after phosphorylation of intracellular parts [136] . Only after this change in their conformation are integrins able to bind to their ligands ICAM-1, ICAM-2, or ICAM-3 with high affinity [23, 43] . This phenomenon plays an important role in the adhesion cascade of leukocytes because their interaction must be transient and they must be able to detach again from their temporary binding site. /32-integrins are constitutional molecules expressed by all leukocytes. The flz-integrins CD1 lb/CD18 and CDI lc/CD18 are stored in the granules of neutrophils and monocytes and can be released to the cell surface within minutes. Upon stimulation, the expression of CD 11 a/CD 18 remains unchanged on neutrophils and shows only a slight increase on monocytes [74] . Resting memory T cells express significantly more adhesion molecules than native T cells; the number of CD 11 a/CD 18 receptors on the surface of native cells is 50,000-60,000 as opposed to over 300,000 on memory cells and natural killer cells [103] . Probably more important than quantitative receptor density, due to increased recruitment of molecules to the cell surface, is the above-described higher affinity of the receptors in the sense of an activation or functional upregulation of adhesions molecules [27, 148] . Subtle regulatory mechanisms recruit and activate the white blood cells required for the defense reaction and attract them to the site of injury. Endothelial cells, whose surfaces are enlarged by furrowing [120] , have a fundamental regulatory role due to their strategic position and omnipresence at the interface between blood or lymph and tissue. This role has been demonstrated not only for inflammatory and immunologic processes but also for the regulation of vascular tone, hemostasis, and fibrinolysis, as well as for cell growth and differentiation [53, 87, 120, 144] . In accordance with the concentration gradient of chemotactic substances, leukocytes can adhere to endothelial cells at the nearest vessel wall and transmigrate through the basement membrane between the endothelial cells to reach the effector site in the tissue matrix [100, 131, 135] . The specific expression of proteoglycans on different endothelial cells is assumed to codetermine the type of cytokines bound on the cell surface, and this probably is an additional regulatory component [84] . In the systemic circulation, leukocyte passage into the tissue occurs in the postcapillary venules, where the flow rate of the blood is lowest and is even further reduced by the dilatation of vessels in the presence of inflammation [120] . The adhesion cascade, in which all three of the above families of adhesion molecules are involved, can be subdivided into three steps (Fig. 2 ). In the first step, the selectins induce rolling of the leukocyte; it touches the vessel wall under flow conditions and is slowed down by the combined effect of transient binding and shearing forces, and thus rolls along the endothelial cells [56, 64] . The second step, firm attachment of the leukocyte to endothelial cells, is induced by the transient activation of the/32-integrins on the leukocyte. This is followed by transmigration of the leukocyte through the basement membrane between the endothelial cells into interstitial tissue [148] , which is associated with a change in the shape of the cell (polarization of the neutrophils, formation of pseudopods, or a local increase in the density of receptors for CD1 lb/CD18 on lymphocytes [74, 79, 84, 104] . The further course of cell migration is dominated by adhesion to the extracellular matrix, e.g., to the glycoproteins fibronectin and vitronectin. There are five possible mechanisms by which the recruitment of inflammatory cells can be increased: a change in the number or affinity of leukocytic molecules, increased supply in the circulation, and an increase in the number or affinity of endothelial ligands on capillary endothelial cells (Fig. 3 ). The lung is the only organ in which all white blood cells pass the capillary network [88] . Only little is known about the regulation of neutrophil transit through pulmonary microcirculation, but it is clearly different from that of systemic circulation. In the pulmonary circulation, leukocytes enter the tissue only in the capillary bed [85] . Intravascular pressure in the pulmonary circulation is markedly lower than in the systemic circulation, and the flow is pulsatile rather than constant. The pulmonary capillary bed is the most important store of intravascular neutrophilic granulocytes [85, 88] . There is presumably a dynamic equilibrium between the circulating and the non-circulating neutrophil pool in the pulmonary capillaries. This factor may play an important role in the development of adult respiratory distress syndrome (ARDS) in cases of shock associated with reduced blood flow [42, 85, 132] . Videomicroscopic studies suggest that the neutrophils are sequestered exclusively in the pulmonary capillaries; margination or rolling has been observed neither in the arterioles nor in the venules. In vitro studies have demonstrated that there is a clear correlation between the reduced deformability of neutrophils upon activation and their sequestration in the pulmonary capillaries [85, 135, 144] . Though CD 11/18 seems not to be required for the sequestration of normal neutrophils in the normal vascular bed of the lungs, it mediates neutrophil migration in case of inflammation [27, 41, 145] . The recruitment processes in the pulmonary circulation described here for neutrophils are similar for monocytes, to which we will return later. In the following, we present some of the results obtained in studies investigating the role of adhesion molecules in pulmonary diseases. We will focus on those disorders in which leukocyte integrins (LeuCAM) appear to play an important pathogenetic role: pulmonary diseases caused by smoking, bronchial asthma, pulmonary infections, acute and chronic damage to the lung parenchyma, and malignancies. Inhalation smoking can lead to the development of pulmonary obstruction, which begins in the small airways and later extends to the large bronchi when smoking is continued [96, 128] . Smoking also causes pulmonary emphysema, with destruction of the architecture of the alveolocapillary units [34] . These changes are the result of inflammatory processes, since smoking is associated with the accumulation of inflammatory cells in the lung. This accumulation is regulated by adhesion molecules. While there are many studies in the literature on the pathogenetic role of neutrophils in inhaling smokers [26, 28, 44, 69, 86, 126] , little is known about the contribution of alveolar macrophages. The pool of alveolar macrophages is two to three times larger in smokers than in nonsmokers [18, 144] . The expression density of the receptors CD11/ CD18 varies on human alveolar macrophages from nonsmokers [19, 66, 114] . The alveolar macrophages of nonsmokers show a relative decrease in CD1 la expression and a relative increase in CD1 lc and CD1 lb expression compared to peripheral blood monocytes, which is similar to the expression described for other resting tissue macrophages [51]. Since a quantitative difference in the mRNA coding for these molecules was not found, the regulatory mechanisms can be assumed to be posttranslational [5] . There are no uniform data in the literature on the effect of inhalation smoking on the expression of LeuCAM molecules on human alveolar macrophages. Some investigators have reported an increased expression of adhesion molecules as well as changes in their expression pattern [19, 114] . It was found that inhalation smoking leads to a relative increase in CDllb expression and a decrease in CD1 la expression, which results in an expression pattern indicative of a higher activation level of alveolar macrophages. Possible explanations for the increased expression are a higher influx of monocytes into the lungs or changes in the expression or affinity of the receptors induced by proinflamma-tory stimuli. Another study, using a different method, only demonstrated an increase in the absolute number of CD11/CD18-positive alveolar macrophages in smokers [66] , while the relative expression was reduced compared to nonsmokers. Interestingly, the expression of CDI 1/CD18 receptors has different effects on the functional repertoire of alveolar macrophages in smokers and nonsmokers. It was shown, for instance, that the adhesive propensity of alveolar macrophages on ICAM-l-expressing endothelial cells is markedly higher in smokers than in nonsmokers and that this is at least partly due to the binding of CD11/ CD18 to ICAM-1 [114] . Since receptor-ligand binding of/~2-integrins leads to an activation of the cell, which is reflected in an increase in intracellular free calcium and a higher translocation rate of protein kinase C [136] , altered adhesive propensity may be important in the activation of alveolar macrophages. As for neutrophils [99] , there is obviously also a close relationship between the induction of a respiratory burst and adhesion molecules on human alveolar macrophages. The increased spontaneous production of superoxide anions by smoker as opposed to nonsmoker alveolar macrophages [20, 65] can be markedly reduced by blocking the/3-chain of the CDll/CDI8 receptors [114] . It has been demonstrated in a primate model in 1990 that the intravenous administration of an antibody directed against ICAM-1, the ligand of CDll/ CD18 receptors, can prevent the development of experimentally induced bronchial hyperreactivity [142] . In asthma, this effect depends on the LFA-1/ICAMl-mediated adhesion of eosinophils to the endothelial cells in the pulmonary vessels [13, 23, 31]. Stimulation with proinflammatory stimuli such as tumor necrosis factor alpha (TNF-o0, y-interferon, and interleukin-lfi was found to enhance the expression of ICAM-1 on bronchial mucosa and vascular endothelial cells in bronchial vessels [142] . However, the effect of an anti-ICAM-1 antibody on the accumulation of inflammatory cells was seen in this primate model only when recently sensitized animals were used. Proinflammatory cytokines such as interleukin-1 or TNF-o~ have also been shown to markedly enhance the expression of ICAM-1 on human epithelial cells of the trachea [133] . This enhancement is associated with an increased adhesion of human neutrophilic granulocytes, which can be reduced by the administration of antibodies directed against both CDll/CDI8 and ICAM-1. But there are also studies that did not find a difference in the expression of ICAM-1 and ELAM-1 in bronchial mucosa of clinically stable asthmatics and control subjects [92] . Following segmental bronchial antigen expression, there is an increase in the expression of CD1 lb on alveolar granulocytes [52], which is accompanied by an intra-alveolar increase in lymphocytes, neutrophils, and eosinophils in the involved segments of the bronchial tree. Severity of asthma correlates with the number of eosinophils in the bronchial mucosa [25] . It is important, in connection with the increased number of eosinophils in the bronchial mucosa of patients with asthma, that the transendothelial migration of eosinophilic cells through human endothelial cells appears to be dependent on the expression of CD11/CD18 on eosinophilic granulocytes and of ICAM-I on endothelial cells [45] . The markedly increased expression of ICAM-1 seen in allergic patients was also demonstrated on mucosal cells of the nasal mucosa in allergic rhinitis [91] . The latter is also associated with an increase in the number of CD1 la-positive leukocytes in the nasal mucosa. Of particular interest for the pathogenesis of asthma is the interaction between CD11/CD18 receptor expression and platelet-activating factor (PAF), a proadhesive phospholipid that is released by eosinophilic granulocytes and endothelial cells [75, 147, 148] . It has been shown that the permeability of the intestinal mucosa following stimulation of the tissue with PAF can be markedly reduced by administration of anti-CD 11/CD 18 antibodies. This effect is probably due to granulocyte depletion of the mucosa induced by administration of the anti-LeuCAM antibodies [75] . The fact that the migration of eosinophilic cells through endothelial cells can be blocked by selective PAF antagonists such as WEB-2086 [29] suggests that PAF stimulates or costimulates the expression of these molecules, or that PAF influences the affinity of the receptors by means of an intracellular regulatory mechanism [147, 148] . The effect of glucocorticoids in inflammatory processes is probably due mainly to their antiinflammatory action such as reduction of cytokines and lipid mediators [56, 121, 122] . It is controversial whether glucocorticoids can reduce the in vitro expression of ICAM-1 on endothelial cells and bronchial epithelial cells [53, 137] . Glucocorticoids suppress the production and release of granulocytes from the bone marrow, as well as leukocyte activation and their adhesionmolecule-mediated passage through the vessel wall [32, 53, 55, 95] . The inhibition of cytokines probably also reduces the survival time of eosinophils in the lung, which is assumed to play a role in allergic diseases [56] . The biological significance of adhesion molecules in the defense against infection is impressively demonstrated by cases with hereditary "leukocyte adhesion deficiency" (LAD), of which more than 50 cases have been described in the literature [9, 10, 11, 24, 37, 39, 63] . LAD is inherited as an autosomal recessive disorder assumed to be caused by a point mutation within the gene region coding for CD18 on chromosome 21 in band q22. 3 [17, 74] . This genetic disorder is associated with a defective production of the beta-chain of LeuCAM receptors, resulting in a low number or absence of normal receptors on the cell surface [15] . Patients with LAD develop severe bacterial infections of the body surfaces, especially of the skin, in the oral and urogenital area, the intestine, and the respiratory tract. The fact that LAD, unlike neutropenia, can also be associated with defective wound healing, i.e., the formation of peculiar, paper-thin or dysplastic scars and characteristic peridontal defects, indicates that the CD11/ CD18 integrins have an important biological role in the formation and repair of connective tissue, a function that, under normal conditions, is assumed to be fulfilled by the influx of monocytes and other inflammatory tissue reactions [119, 124] . Infected tissue shows dense infiltrates of eosinophils, lymphocytes, plasma cells, and some macrophages, but is totally devoid of neutrophils and monocytes. These histologic features suggest adhesion mechanisms that are independent from CDI 1/CD18. VCAM-1 and the corresponding integrin, VLA-4, which are important in accumulation of eosinophils in allergic and parasitic disease, are supposed to compensate for the lacking CDll/CD18 adhesion molecules [11, 50, 57, 135] . Blood granulocyte counts are fivefold to twentyfold the normal count; in case of infection, the number rises up to 100,000/liter [9, 50] . Adhesion-dependent cellular functions such as chemotaxis and aggregation are disturbed in proportion to the extent of receptor deficiency. Phagocytosis ofiC3b-opsonized particles, which is another function of Mac-1 (CDI Ib/CD18), does not occur due to the absence of the CR3 receptor, and there is no induction of a respiratory burst [99] . Lymphocyte function is preserved, probably because of a possible compensation by lymphocyte receptors [14] . The genetic defect has been successfully repaired in vitro by transfection of the granulocytic stem cell with a CD 18-encoding sequence [62] . After successful transfection, the cells express functionally normal CD1 la/CD18 molecules and show a restitution of their functional properties. So far only two patients have been described who lack the carbohydrate ligand Sialyl-Lewisx as a binding site for E-selectin. The clinical picture is nearly identical to that of the above-described LAD [47] , which suggests that selectins and integrins are indispensible for leukocyte function in common biological processes. Adhesion molecules are also involved in other infectious diseases of the respiratory tract, since they are ligands for viral and bacterial pathogens. This is by no means accidental, since various similarities have been described to exist between cell-cell adhesion and cell-virus, cell-bacterium, or cell-protozoan adhesion [124] . Recent studies have demonstrated the N-terminal region of the ligand ICAM-1 to be a high-affinity receptor for rhinoviruses [54, 125] . Bordetella pertussis also binds to the CD1 Ib/CD18 receptor of bronchial ciliated cells and macrophages by means of a bacterial adhesion that contains the RGD sequence of the LeuCAM receptor binding domain consisting of the three amino acids Arg, Gly, and Asp [109, 113] . Consideration of adhesion molecules also sheds light on the pathophysiologic relationship between respiratory viral infections and compromised cellular defense. The infection of mononuclear cells with respiratory syncytial virus (RSV) reduces CDI la and ICAM-1 expression by these cells [112] . However, the effects of viral infection on the expression of adhesion molecules are dependent on the type of virus used in the experiments. It has recently been shown that the infection of human epithelial tracheal cells with parainfluenza 2 virus markedly enhances the expression of ICAM-1 on these cells, which appears to be functionally significant, since the affected cells were able to bind more neutrophils [1341. Chronic bacterial inflammatory diseases of the lungs are associated with an increased influx of mononuclear cells into the bronchial system. Monocytes from patients with bronchiectasis adhere more readily to surfaces coated with fibronectin, and their adhesion can be further increased by stimulation with lipopolysaccharides or proinflammatory cytokines [102] . Preincubation with an antibody directed against CD18 reduces the adhesion of monocytes from these patients by more than 50%. But the adhesion mechanism mediated by CDll/ CD18 is not the only one, since a synthetic peptide containing the RGDS sequence instead of RGD was also shown to reduce the enhanced adhesion of these monocytes [102] . Antibodies directed against CDll/CD18 or ICAM-1 antigens can influence or even prevent experimentally-induced parenchymal damage of the lung. It was shown in guinea pigs that the intrapulmonary infusion of neutrophilic granulocytes and opsonized zymosan induces the development of pulmonary edema, which can be considerably reduced after in vitro treatment of the neutrophils with an antibody to CD18 [73] . In vitro experiments with endothelial cells have shown that this effect of anti-CDl8 is based on a markedly reduced adhesive propensity of neutrophils and a markedly lower albumin permeability of the endothelial layer following incubation of the neutrophils with anti-CD18. The effect of antibodies directed against CDll/CD18 and anti-ICAM-1 on oxygen-induced pulmonary toxicity was studied in the mouse [143] . After hyperoxia for 48 h, the alveolar structures of the animals showed a markedly increased expression of ICAM-1. The injection of an anti-ICAM-1 antibody significantly reduced neutrophil infiltration of the pulmonary parenchyma and the number of neutrophils in bronchoalveolar lavage and improved the pulmonary function of the mice. An antibody directed against the CD 1 lb epitope appears to be able to reduce the toxic effect of intravenously administered TNF-o~ in dogs [46] . Although the mortality within the first 10 days after intravenous injection of a high dose of TNF-o~ did not differ, analysis of mortality within the first 30 h revealed a clear advantage for those dogs that had received an intravenous injection of an anti-CD1 lb antibody. In another animal model, it was shown that the administration of IgA complexes induces parenchymal damage in the lung of rats, which is assumed to result from a pronounced increase in the production of oxygen radicals by alveolar macrophages [97] . These experiments also demonstrated that the intravenous administration of an anti-CD 18 antibody but not of anti-CD 11 nearly normalized the increased permeability of intrapulmonary vessels and markedly reduced the number of alveolar macrophages in bronchoalveolar lavage (BAL). Similar results were obtained in rats after intravenous administration of a snake venom. In these experiments, both anti-CD1 lb and anti-CD18 antibodies significantly reduced the extent of acute parenchymal damage of the lung [98] . Studies in different animals and investigations in humans have elucidated the role of adhesion molecules in chronic inflammatory processes. It was shown that the administration of anti-CDlla or anti-CDllc antibodies almost completely prevents pulmonary fibrosis inducible by the intratracheal application ofbleomycin [107] . For anti-CD 1 la, this effect was seen even when the antibody was administered 3 weeks after bleomycin application. The accumulation of platelets and alveolar macrophages was markedly lower in the antibody-treated animals. These two mechanisms might be responsible for the reduced locoregional release of platelet-derived growth factor (PDGF) and the ensuing decrease in fibroblast activation [118] . It remains open whether this therapeutic effect can also be achieved in man, since platelets in humans, unlike those in rodents, do not express leukocyte integrins. In sarcoidosis, the total number of alveolar macrophages correlates with the number of CD 11/CD 18-positive macrophages [ 115] . This correlation is probably due to a compartment effect of pulmonary macrophages, since a parallel increase in CD11/CD18-positive peripheral monocytes is not seen in these patients. In another study investigating monocytes by laser flow cytometry, sarcoidosis patients had fairly similar proportions of CDll/CD18-positive monocytes, but a markedly higher expression density of the epitopes on these cells [117] , which might be explained by methodologic differences. The data on the expression of individual epitopes on alveolar macrophages are contradictory. While some investigators reported an increased expression of CDll/CD18 [115] , others found an increase only for CDlla, CDllb, and CD54 (ICAM-1) [89] , or for CDllb and CD54 [127] . There is also one study in which the expression of CDll/CD18 was not found to be different in patients with sarcoidosis [67]. The increased expression of CDll/CD18 epitopes on the alveolar macrophages of patients with sarcoidosis is likewise accompanied by changes in alveolar cell function. It has been shown that the C3bi-mediated phagocytosis of agarose beads is dependent on CD1 lb [105] . The enhanced respiratory burst of the alveolar macrophages seen in sarcoidosis also depends on the expression of CDll/CD18 epitopes [115] . Since the interaction of alveolar macrophages and T cells appears to be an important pathomechanism of sarcoidosis, the expression of CD11/CD18 receptors on alveolar macrophages should also play an important role in this disorder [38] . In the case of accumulation of alveolar macrophages, there might be a marked increase in the locoregional secretion of lymphotactic cytokines and lymphocyte-activating substances from alveolar macrophages, which in turn might be responsible for the accumulation of lym-phocytes in the alveolar space. The expression of ICAM-1 and LFA-1 on antigen-presenting alveolar macrophages is also required for the binding of specific T-cell clones (CD4-positive T cells) [8, 71, 83] . Only few data are available on the behavior of alveolar macrophages and their expression of CD 11/CD 18 epitopes in patients with idiopathic pulmonary fibrosis [67, 115] . A correlation between the number of alveolar macrophages and the expression of CDll/CD18 epitopes has been described [!15], and these receptors also appear to be involved in the enhanced respiratory burst of alveolar macrophages [115] . A contribution of CD11/CDI8-and ICAM-l-positive alveolar macrophages to the pathogenesis of idiopathic pulmonary fibrosis is possible, since these receptors play an important role in the chemotaxis and activation of neutrophilic granulocytes [21, 35] . While neoplastic processes, now regarded as multi-step disorders, are characterized by a loss of growth control, malignant transformation additionally involves invasive and metastatic capacity [6] . Depending on the cell type, differentiation and adhesion are coregulated by 2-10 different adhesion molecules [111] . A transient loss of cell-cell and cell-matrix adhesion, and rearrangement of cell-cell and cell-matrix contact is also required for the incorporation of the daughter cells into the tissue in normal cell division [6] . Binding to the basement membrane and to extracellular matrix proteins is mediated primarily by the integrins of the/31 and/~4 groups [68] , and by cadherines. The latter regulate extracellular cell-cell binding and, via the cytoplasmic protein catenin, the stable connections between the cytoskeleton and adjacent cells as well [82] . They are found in the zonula adherens and are involved in the formation and stabilization of cell binding [3, 82] . The role of adhesion molecules in the development of tumors may be complex. On one hand, upregulation can affect the growth, differentiation, and proliferation of cells and thus directly promote or induce tumor genesis [4, 116] . On the other hand, downregulation can reduce cell binding and thus facilitate metastasis formation, which depends on the loss of normal cell-cell and cell-matrix adhesion [3, 108, 129] . In addition, adhesion molecules are also involved in the pathomechanisms of hematogenic and lymphogenic metastatic spread (Fig. 4) . The mechanisms involved in hematogenic spread are cell-cell and cell-matrix interactions with endothelial cells, and the capacity for transendothelial migration with diapedesis into the interstitial stroma through the basement membrane [30, 80] , while the adhesion molecules of the CD44 family seem to be involved in lymphogenic spread [130] . Macrophages and T and B lymphocytes transiently express molecules of the CD44 family to achieve tolerance in the lymph nodes and lymphatic tracts. Tumor cells possibly express variants of the CD44 molecule and thus evade the lymphatic immune defense, with exprimation of splice variants of the adhesion molecule CD44, possibly mimicking a lymphocyte in lymphatic tissue, or by important regulatory mechanisms, e.g., specific activation processes, associated with its expression on the cell surface. In hematogenous spread, which is often tissuespecific, specific "vascular addressins" might regulate adhesion of neoplastic cells, and therefore tissue-specific metastatic spread. For further explanation see text. while they are recognized as developing cells in the lymph nodes [12, 72] . On the other hand, they might interact with adhesion processes, as a modulation of CD2 and LFA-1 by antibodies to CD44 has been found [60] . The organotropism of metastatic spread is presumably determined by organ-specific endothelial adhesion molecules, termed "vascular addressins" [1, 3, 146] . Endothelial and epithelial cell adhesion molecules The alveolar-capillary barrier in the adult respiratory distress syndrome Role of integrins and other cell adhesion molecules in tumor progression and metastasis Integrins and other cell adhesion molecules Expression and function of beta-2 integrins on alveolar macrophages from human and nonhuman primates Cell growth and division Occupancy of CDllb/CD18 (Mac-l) divalent ion binding site(s) induces leukocyte adhesion Coinfection of ICAM-1 and HLA-DR reconstitutes human antigen presenting cell function in mouse T cells Leukocyte adhesion deficiency: an inherited defect in the Mac-l, LFA-1, and p 150,95 glycoproteins Abnormalities of polymorphonuclear leukocyte function associated with a heritable deficiency of high molecular weight surface glycoproteins (gp138): common relationship to dimished cell adherence The severe The major human rhinovirus receptor is ICAM-1 Antigen-induced mediator release in primates The role of intercellular adhesion molecule-1 in chronic airway inflammation In vivo models of leukocyte adherence to endothelium VLA proteins in the integrin family: structures, functions, and their role on leucocytes The VLA protein family CD44 splice variants: metastasis meet lymphocytes Endothelial leukocyte adhesion molecule-l: direct expression cloning and functional interactions Transfection of cells from patients with leukocyte adhesion deficiency with an integrin beta subunit (CD 18) restores lymphocyte function-associated antigen-1 expression and function The leukocyte integrins Roll, roll, ioll you leukocyte gently down the v e i n Altered oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic cigarette smokers Expression of the CD11/CD18 cell surface adhesion glycoprotein family on alveolar macrophages in smokers and nonsmokers Expression of the CD11/CD18 cell surface adhesion glycoprotein family and MHC class II antigen on blood monocytes and alveolar macrophages in interstitial lung diseases Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers Integrins: versatility, modulations, and signalling in cell adhesion Antigen-presenting capacity in patients with sarcoidosis Adhesion protein studies provide new clue to metastasis Pulmonary edema induced by phagocytosing neutrophils. Protective effect of monoclonal antibody against phagocyte CD18 integrin The leukocyte integrins Platelet-activating factor-induced mucosal dysfunction: role of oxidants and granuloeytes Platelet membrane glycoproteins and their function: an overview Structure and function of leukocyte integrins The homing receptor (LECAM-1/L Selectin): a carbohydrate binding mediator of adhesion in the immune system Leukocytes roll on a selectin at physiologic flow rates. Distinction form and prerequisite for adhesion through integrins Tumor invasion and metastases--role of the extracellular matrix Integrin-immunoglobulin superfamily interactions in endothelial-leukocyte adhesion Cytoskeleton-plasma membrane interactions Inability of human alveolar macrophages to stimulate resting T ceils correlates with decreased antigenspecific T cell-macrophage binding Cell adhesion in the immune system Neutrophil traffic in the lungs: role of haemodynamics, cell adhesion, and deformability The effect of cigarette smoking on neutrophil kinetics in human lungs Cytokine regulation of endothelial cell function Effect of raised alveolar pressure on leukocyte retention in the human lung Increased expression of leukocyte function associated antigen-I (LFA-1) and intercellular adhesion molecule-1 ICAM-1) by alveolar macrophages of patients with pulmonary sarcoidosis Distribution of integrin cell adhesion receptors in normal bronchial epithelial cells and lung cancer cells in vitro and in vivo The expression of leukocyte-endothelial adhesion molecules is increased in perennial allergic rhinitis Intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule (ELAM-1) expression in the mucosa of normal and asthmatic subjects Leukocyte-endothelial adhesion molecules and their role in bronchial asthma and allergic rhinitis Alternative splicing of neural-cell adhesion molecule mRNA in human small-cell lung-cancer cell line H69 Immunopharmacology of asthma Reassessment of inflammation of airways in chronic bronchitis Lung injury after deposition of IgA immune complexes Roles of beta-2 integrins of rat neutrophils in complement and oxygen radicalmediated acute inflammatory injury Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CDll/CD18 integrins Leukocyte adhesion to endothelium in inflammation Increased adherence of monocytes to fibronectin in bronchiectasis Regulatory mechanisms in leukocyte adhesion: flexible receptors for sophisticated travelers Selectin/carbohydrate-mediated adhesion of leukocytes Phagocytosis of agarose beads by receptors for C3b (CR1) and iC3b (CR3) on alveolar macrophages from patients with sarcoidosis The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140 Effective treatment of the pulmonary fibrosis elicited in mice by bleomycin or silica with anti-CDll antibodies A metastatic tumor cell line has greatly reduced levels of a specific homotypic cell adhesion activity Recognition of a bacterial adhesin by an integrin: macrophage CR3 (CD1 lb/CD18) binds filamentous hemagglutinin of Bordetella pertussis New perspectives in cell adhesion: RGD and integrins Suppressed expression of ICAM-1 and LFA-1 and abrogation of leukocyte collaboration after exposure of human mononuclear leukocytes to respiratory syncytial virus in vitro Integrin-mediated localization of Brodetella pertussis within macrophages: role in pulmonary colonization Increased number of alveolar rnacrophages expressing adhesion molecules of the leukocyte adhesion molecule family in smoking subjects: association with cell-binding ability and superoxide anion production Increased number of alveolar macrophages expressing surface molecules of the CD11/CD18 family in sarcoidosis and idiopathic pulmonary fibrosis is related to the production of superoxide anions by these cells Increased tumorigenicity of fibronectin receptor deficient chinese hamster ovary cell variants Increased CD11/CD18 expression on periphereal blood leukocytes of patients with sarcoidosis Pathogenesis of pulmonary fibrosis in interstitial lung disease Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis Lymphocyte interactions with endothelial cells Effect of prednisone on monocyte-derived tumor necrosis factor and interleukin-1 in acute asthma Detection of GM-CSF in asthmatic bronchial epithelium and decrease by inhaled corticosteroids Leukocyte adhesion molecule 1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion Adhesion receptors of the immune system A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses Cytokines and lung inflammation: mechanisms of neutrophil recruitment to the lung Expression of alveolar maerophage adhesion molecules in pulmonary sarcoidosis Hydrogen peroxide-induced potentiation of contractile responses in isolated rat airways Cadherin cell adhesion receptors as a morphogenetic regulator Expression of CD44R1 adhesion molecule in colon carcinomas and metastases Proteoglycans on endothelial cells present adhesioninducing cytokines to leukocytes Transient leukopenia associated with adult respiratory distress syndrome Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines: effects on neutrophil-epithelial cell adhesion Intercellular adhesion molecule-1 (ICAM-D-dependent and ICAM-l-independent adhesive interaction between polymorphonuclear leukocytes and human airway epithelial cells infected with parainfluenza virus type 2 Regulation of myeloid blood cell-endothelial interaction by cytokines Phosphorylation of the beta-subunit of CD11/CD18 integrins by protein kinase C correlates with leukocyte adhesion Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial lines Cloning and characterization of a new intercellular adhesion molecule ICAM-3 Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte/3 z integrins in vivo Recognition by ELAM-1 of the sialyl-LeX determinant on myeloid and tumor cells Adhesion molecules and inflammatory lung disease Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma Intercellular adhesion molecule-1 contributes to pulmonary oxygen toxicity in mice: role of leukocytes revised Endothelial cell biology: adhesion molecules involved in the microvascular inflammatory response Pulmonary microcirculatory kinetics of neutrophils deficient in leukocyte adhesionpromoting glycoproteins Mediation of lung metastases of murine melanomas by a lung-specific endothelial cell adhesion molecule Endothelial cell-associated platelet-activating factor: a novel mechanism for signaling intercellular adhesion Endothelial cell interactions with granulocytes: tethering and signaling molecules Accepted for publication gemeinschaft.