January - March 2000: 
Volume 13, Issue 1

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Adhesion molecules and lung disease
SUMMARY: Hereby we review the role of some adhesion molecules, mainly among integrins and immumoglubulin superfamily members in patients with asthma, acute lung injury or pulmonary infections. Furthemore, we discuss the role of leukocyte adhesion molecules in lung and airways related to the above diseases.We briefly give scientific knowledge for what is known about the expression of adhesion molecules on various resident and migratory lung cells. Pneumon 2000, 13 (1): 50-56
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In multicellular organisms, the development of adhesion bonds either among cells or among cells and components of the extracellular matrix, is a crucial process. That’s why it plays a main role both at the early stage of tissue consistence and later on. This happens because this adhesive process is directly related to the differentiation, architecture and normal tissue development. The extracellular matrix consists of different proteins and various polysacharide molecules.These include collagens, laminins, fibronectins, vitronectins and proteoglycans. The interactions either among cells or among cells and substratum are mediated by some molecules, which are named adhesion molecules1-3. Nowadays, the ways that cells dissociate, migrate, arrest and reassociate with other cells are basic sections in biology and physiology. Under this approach, the histologicaI formation and function of specific cell-cell or cell-matrix functions appears very interesting.

The lung is a complex organ composed of more than twenty distinct types of cells. In addition to resident cells, the normal lung contains several types of migratory cells, principally leukocytes. Each type of cell present in the lung expresses a distinct repertoire of adhesion molecules and the repertoire of each cell type can be dramatically altered during development and in response to injury and disease. Because of this cellular complexity and the relatively recent identification of many of the known adhesion molecules, it should not be surprising that most of the details of the roles that specific adhesion molecules play in the development and progression of lung diseases remain to be elucidated. Over the past few years, information has begun to emerge on the expression of adhesion molecules on resident and migratory cells in the normal lung. A few descriptive studies have also identified changes in adhesion molecules in selected diseases of the lungs and airways.Very few experimental data are available directly addressing the functional significance of adhesion molecules expression in the lung. For this reason we briefly review what is known about expression of adhesion molecules on various resident and migratory lung cells. The discussion will be restricted to the three families of adhesion molecules that have been most intensively studied in the lung: the integrins, the immunoglobulin superfamily members and the selectins1,4,5.


Ila. Conducting airways

The conducting airways epithelium of the lungs is a pseudostratified columnar epithelium that is principally composed of ciliated cells, non-ciliated secretory cells and basal cells6. The expression of adhesion molecules is greatest in the basal cells of healthy human airways. These cells express at least five members of the integrin family7,8. The a6β4 integrin is restricted to the basal surface of the hemidesmosomes that anchor these cells to the underlying basement membrane. Of the β1 integrin subfamily, α2β1, α3β1, α9β1 integrins are all diffusely expressed around the surface at these cells, consistent with the suggested role for these molecules in cell-cell interactions between adjacent epithelial cells. These three integrins are also expressed on the surface of ciliatel and secretory cells though at extremely lower levels. The ανβ5 integrin is also expressed on basal cells in healthy adult airways. Each of these adhesion molecules can recognise components of the extracellular matrix as ligands9. Airway epithelial cells also express ICAM-1 (intercellular adhesion molecule-1), a member of the immunoglobulin family which binds as ligand for the β2 integrins expressed on leukocytes, and E-cadherin (epithelial cadherin) which interacts in cell-cell homotypic attachment and serves as a ligand for the αEβ7 Integrin that is expressed on T lymphocytes10,11. ICAM-1 is expessed principally on basal cells, whereas E-cadherin is expressed at the lateral margins of all airway epithelial cells. During airway development and in response to injury and inflammation, airway epithelial cells can be induced to express one other integrin, ανβ6, which is a receptor for fibronectin and tenascin12.

Ilb. Airway smooth muscle

Airway smooth muscle cells express several members of the integrin family, such as α1β1, α2β1, α3β1, α6β1, α8β1, α9β1 and ανβ3, ανβ5 (table 1). The specific roles these integrins play in contraction and/or proliferation of airway smooth muscle cells have not yet been examined13. However, the proliferative response of vascular smooth muscle to stretch has been clearly shown to require the participation of integrins. Since airway smooth muscle cells have also been shown to proliferate in response to stretch, it is likely that integrins are at least participants in the regulation of airway smooth muscle proliferation. Airway smooth muscle cells can be induced to express both ICAM-1 and VCAM-1 (vascular cell adhesion molecule-1), and these molecules may mediate interactions between smooth muscle and leukocytes during inflammation14.

Ilc. Glandular and alveolar epithelial cells

Airway submucosal glands are primarily composed of two cell types: Mucous cells that produce the bulk of the mucous glycoproteins present in human airways and serous cells that secrete a variety of protein constituents of the airway lining fluid15. It has been shown that serous cells require components of the extracellular matrix for full expression of their secretory phenotype. This effect of the matrix is clearly mediated by integrins since secretory differentiation can be inhibited by anti-integrin antibodies9.

Surprisingly, little is known about the distribution of adhesion molecules in the normal healthy alveolar epithelium12. These cells probably express α3β1, α6β1 and at least one αν integrin. Also, they can be induced to express ανβ6 integrin during development and in response to injury and inflammation16. Integrin α8β1 is intensely expressed in healthy alveoli, but the distribution of expression suggests that this integrin is principally in alveolar myofibroblasts rather than epithelial cells. Table 2 shows integrins and their ligands expressed on airway epithelial cells.


Ila. Airway diseases

Patients with asthma have extensive remodeling of the airway wall. Anatomic abnormalities seen in asthma include deposition of excess extracellular matrix beneath the airway epithelium, hyperplasia of epithelial secretory cells, hypertrophy of submucosal glands, and an increase in the mass of airway smooth muscle. Some of these abnormalities are also seen in other chronic airway diseases such as chronic bronchitis and cystic fibrosis17. All these anatomic changes are likely to involve signals from adhesion molecules present on resident airway cells. Singals initiated by integrins have been shown to be capable of inducing cellular proliferation and altering secretory cell phenotype in a number of experimental systems. Integrins could express on resident cells, as a result of changes in the activation state of constitutively expressed integrins or because of signals resulting from a change in the composition of the extracellular matrix present in the airway wall. It is likely that all three of these pathways work in parallel. The airway wall in patients with asthma includes an excess of type III collagen, tenascin and fibronectin. At least one integrin, ανβ6, that is not generally expressed on airway epithelial cells in healthy adult airways, is commonly expressed on epithelial cells of patients with asthma or chronic bronchitis16. This integrin is a receptor for fibronectin and tenascin and contribute to epithelial cell proliferation. Thus, it is biologically plausible that both, the alteration in extracellular matrix and the alteration in integrin expression seen in chronic airway diseases, contribute to the hyperplasia of secretory cells in the glands and/or surface epithelium.

IIlb. Acute lung injury

Bacterial sepsis, toxic gas inhalation, narcotics, acute pancreatitis and hypovolemic shock as well as other causes, can all produce a pattern of diffuse lung injury that has been called adult respiratory distress syndrome (ARDS)18. This syndrome is characterized by injury to alveolar type I cells and proliferation of alveolar type II cells that subsequently spread and differentiate into type I cells, a process that is critical to restoration of a functioning gas exchange unit. Soon after the acute injury, the alveolus is flooded with protein-containing fluid, and during the repair phase the alveolar fluid is rich in extracellular matrix proteins including fibronectin and tenascin. Alveolar epithelial cells do not normally express the integrin ανβ6, but expression is dramatically and selectively induced in alveolar type II cells within a few hours of injury in animal models of ARDS16.

IIlc. Pulmonary infections

A number of microorganisms utilize host cell adhesion receptors for attachment and infection19. In the lung, both integrins and immunoglobulin family members are probably important in this regard. At least three viruses that infect the respiratory tract infect airway cells in this fashion. Rhinoviruses, the most frequent causative agent in the common cold, infect host cells by attaching to the immunoglobulin family member ICAM-1. Experimental infection with rhinovirus is known that can induce airway hyperresponsiveness, a central feature of asthma, suggesting a role for this viral infection in lung disease. Chronic diseases of the airway, in particular asthma, are associated with increased expression of ICAM-1 on the airway epithelium, suggesting a possible mechanism for virus-induced exacerbations of these diseases. Echoviruses have also been implicated in respiratory infections. These viruses utilize an integrin, α2β1, to infect mammalian cells and α2β1 is constitutively expressed at high level on the normal airway epithelium. Adenoviruses cause infections of the lungs and airways and have been implicated as causative agents of chronic bronchitis. Several adenoviruses utilize αν integrins for infection of mammalian cellis, an effect that has been most clearly demonstrated for ανβ5 integrin20. Since αν integrins are not normally present on the luminal surface of the intact airway epithelium, efficient infection with these viruses may require prior injury or inflammation. These findings are relevant not only to spontaneous infection with adenoviruses, but also to the possible use of adenovirus vectors for pulmonary gene therapy. Recent evidence suggests that efficient transfer of genes contained in adenovirus vectors is greatly facilitated by mechanical injury to the epithelium, an effect that is most likely explained by the constitutive expression of ανβ5 on basal cells, but not on the cells that are normally in contact with the airway lumen.

Another pulmonary pathogen that utilizes host cell adhesion receptors is pneumocystis carinii, a common cause of pneumonia in immunosupressed patients. The attachment of pheumocystis to alveolar epithelial cells requires the presence of either fibronectin or vitronectin. These proteins apparently serve as bridges between specific binding proteins present on the surface of the organism itself and integrins present on the alveolar epithelium. Antibolies directed against integrins or against fibronectin or vitronectin can inhibit both attachment of the organism and the subsequent cytotoxic effect of the organism on the epithelial cells.


The lung and airways are populated by a large numbers of leukocytes that help defend against infection and play crucial role in the pathogenesis of a wide variety of diseases, including asthma, acute lung injury, emphysema and pulmonary fibrosis. The recruitment of leukocytes into the lung and airways clearly involves many of the same selectin and integrin mediated events as occur during recruitment of leukocytes into other organs. However, there are some aspects of leukocyte recruitment into the lung that are unique. The lung differs from all other organs in that it is supplied by both the high pressure systemic circulation and the low pressure pulmonary circulation. Many pulmonary capillaries are narrower than spherical neutrophils, forcing neutrophils to deform in order to transit the pulmonary circulation. Whereas neutrophils leave the systemic circulation primarily by transmigrating across postcapillary venules, neutrophils in the pulmonary circulation can emigrate efficiently through the capillary wall itself. The pulmonary circulation also features a large pool of marginated leukocytes. The mechanisms that allow these cells to remain associated with the luminal surface of the endothelium are not known. There is also evidence that the lung contains populations of lymphocytes with distinctive adhesion molecule repertoires. The lung can be divided into many anatomically and functionally distinct compartments, including the interstitium, the alveolar spaces, the epithelium and lamina propria of the airways and various lung associated lumphoid tissues, each of which has different populations of lumphocytes. T lumphocytes recovered from the epithelial lining fluid of the alveoli and airways by bronchoalveolar lavage express a different repertoire of integrins than do T lymphocytes in other tissues. A large fraction of these T cells express integrin αEβ7, a receptor for the epithelial cell surface molecule E-cadherin, indicating that these cells may have specialized interactions with the epithelium15. Although the immune systems of the gut and lung have some striking similarities, the mucosal addressin (MadCAM-1, mucosal addressin cell adhesion molecule-1) is expressed in the gut but not in the lung, indicating that lumphocytes probably use different combinations of adhesion molecules to migrate into these two organs.

IVa. Asthma

Airway inflammation is a hallmark of asthma. While asthma is still poorly understood, a substantial body of evidence suggests that T cells, eosinophils, mast cells, and perhaps other types of airway leukocytes do play a critical role in the pathogenesis of this disease21. There is now substantial interest in defining the roles of leukocyte adhesion molecules and their ligands in asthma. Two major approaches have been taken to the problem. First, several studies have examined the expression of leukocyte adhesion molecules and their ligands in human subjects with asthma22. Second, the effects of anti-adhesion molecules antibodies have been analyzed in animal models that reproduce certain features of asthma.

These studies indicate that the influx of leukocytes into the airway is likely be mediated, at least in part, by changes in the expression of adhesion molecules important in leukocyte-endothelium interactions. More remarkably, animal studies suggest that leukocyte adhesion molecules have other functions crucial for the development of asthma and that adhesion molecule agonists may be useful for the treatment of this disease.

In some studies, subjects with stable mild asthma have been compared with subjects without asthma, while others examined subjects with exacerbations induced by administration of allergen or by withdrawal of corticosteroid therapy. Because of the nature of these studies, most of them involve small numbers of subjects and this may partially account for apparent inconsistencies among them. For example, one report indicates that the expression of ICAM-1 and E-selectin is increased on airway wall endothelium from subjects with intrinsic (non allergic) asthma, whereas subjects with extrinsic (allergic) asthma and control subjects without asthma did not differ in their expression of these molecules. Controversely, other studies indicate that ICAM-1 and E-selectin expression are increased only on endothelium from subjects with extrinsic asthma. By 6 h after bronchoscopic instillation of antigen into airway segments, there are increased numbers of neuthophils, eosinophils cells and T cells in the airway wall. This coincides with increases in airway wall endotheliaI cell ICAM-1 and E-selectin expression. Levels of soluble ICAM-1 and E-selectin in the blood and in bronchoalvolar lavage fluid are elevated in asthma23. Some studies find elevations present only during exacerbations, whereas other detect elevations even in stable asthma as compared with non-asthmatic controls. Some studies have found higher levels of ICAM-1 expression in airway endothelium from subjects with asthma, while other have not detected a difference. Much less is known about the expression and function of leukocyte adhesion molecules in asthma. There is evidence of activation of circulating leukocytes in asthma, but it is not known whether integrins and other adhesion molecules are affected. While the level of expression of LFA-1 on blood T cells is similar in asthmatics and non-asthmatics, T cell expression of the LFA-1 ligand ICAM-1 may be increased in asthma. Of note is the fact that this increase is apparently limited to asthmatics who had bronchoconstriction both early (1 h) and late (3h-10h) after allergen challenge; asthmatics who had only an early response had normaI T cell ICAM-1 expression. It is not clear yet whether the increase in T cell ICAM-1 expression is merely serving as a marker of increased T cell activation, or whether ICAM-1 mediated T cell interactions may actually be important in triggering the late asthmatic response.

IVb. Acute lung injury

Acute lung injury is accompanied by an influx of neutrophils and other leukocytes into the interstitium and the alveoli and these inflammatory cells clearly play a major role in initiating tissue damage24. In humans, acute lung injury often results in profound abnormalities in gas exchange (adult respiratory distress sydrome, ARDS). Because these patients are critically ill, and lung tissue is generally unobtainable, studies of adhesion molecule expression have been somewhat limited. Analyses of blood samples from at risk patients who went on to develop ARDS revealed an increase in neutrophil expression of αMβ2 intregrin (Mac-1) and a decrease in soluble L- selectin, compared with other at risk patients who did not develop ARDS or with healthy control subjects. These data suggest that changes in adhesion molecule function may be inportant in the development of ARDS, a suggestion which is reinforced by a much more extensive collection of animal studies.

Many different animal models have been used to study the role of selectins and integrins, and their ligands, in the pathogenesis of acute lung injury. In most of these models, lung injury is dependent upon the activity of neutrophils. The results of these studies have several important implications, and namely:
• Mechanisms of neutrophil recruitment into the lung are often different from mechanisms involved in recruitment to other organs. While neutrophil migration into other tissues is commonly found to be largely dependent on β2 integrins, migration into the lung parenchyma is often relatively (or even completely) β2 integrin independent. These experimental data are supported by the observation that patients with β2 integrin deficiency (leukocyte adhesion deficiency, LAD) rarely have neutrophil extravasation except in the lung25.
• Different adhesion molecule combinations are important in different types of lung injury. Many adhesion molecules have been shown to play a role in one or more models of acute lung injury. However, it is clear that the importance of specific molecules differs considerably in different models. For example, the influx of neutrophils into rabbit lung following instillation of E. Coli endotoxin is mostly dependent on β2 integrins, whereas neutrophil influx triggered by instillation of s. pneumoniae or hydrochloric acid is largely β2 independent. The role of specific selectins also differs in different model systems.
• Adhesion molecule antagonists often prevent physiologic changes that accompany acute lung injury. Many studies have measured the effect of adhesion molecule antagonists on physiologic parameters such as lung vascular permeability and gas exhange. In various models, antibodies against selectins or integrins have been shown to attenuate physiologic abnormalities. While these changes correlate with a reduction in lung leukosequestration, this is not always the case. For example, in lung injury induced by intestinal ischemia and reperfusion, antibodies against p-selectin or integrin αMβ2 (Mac-1) block changes in lung vascular permeability without altering the sequestration of neutrophils in the lung. In some cases, adhesion molecules administrated intratracheally can attenuate lung injury. For example, lung injury induced by intrapulmonary deposition of IgG immune complexes is inhibited by intratracheal anti-aM antibody, but is unaffected by the same antibody given intravenously. In this case, the antibody apparently acts to prevent the induction of macrophage TFNa (tumor necrosis factor alpha) production and the subsequent induction of ICAM-1 and recruitment of neutrophils and other leukocytes into the lung. These findings again highlight the importance of these adhesion molecules both in leukocyte recruitment and in the function of leukocytes after migration into the lung.


1. Hynes RQ. Integrins: Versatility, modulation and signalling in cell adhesion. Cell 1992, 69:11-25.
2. Eidelman GM, Crossin KL. Cell adhesion molecules: Implications for a molecular histology. Annu Rev Biochem 1991, 60:155-161.
3. Takeichi M. Cadherin cell adhesion receptors as morphogenetic regulator. Science, 1991, 251:1451-1459.
4. Hunkapiller TH, Hood L. Diversity of the immunoglobulin superfamily. Adv Immunol 1989, 44:1-63.
5. Bevilaqua M, Butcher E, Furie B, et al. Selectins: a family of adhesion receptors. Cell 1991, 67:233.
6. Davidson JM. Biochemistry and turnover of lung interstitium. Eur Resp J 1990, 3(9):1048-1063.
7. Abraham MWM, Sielczak MW, Ahmed A, et al. a4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. J Clin Invest 1994, 94:776-187.
8. Damjanovich L, Albelda SM, Mefte SA, et al. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am J Respir Cell Mol Biol 1992, 6(2):197-206.
9. Damsky CH, Werb Z. Signal transduction by integrin receptors for extacellular matrix: Cooperative processing of extracellular information. Curr Opin Cell Biol 1992, 4(5):772-781. 10. Bacnato G, Gulli S, Altavilla P, et aI. Circulating adhesion molecules in bronchial asthma. J Investing Allergol Clin Immunol 1998, 8(2):105-108.
11. Taceichi M. Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 1993, 5, 806-812.
12. Erikson HP. Tenascin C, tenascin-R and tenascin-a family of talented proteins inx: search of functions. Curr Opin Cell Biol 1993, 5:869-876.
13. Panettieri RA. Cellular and molecular mechanisms regulating airway smooth muscle proliferation and cell adhesion molecules expression. Am J Respir Crit Care Med 1998, 158(3):33-40.
14. Elices MJ, Osborn L,Takada Y, et al. VCAM-1 on activated entothelium interacts with the leucocyte integrin VLA-4 at a site distinct from VLA-4/fibronectin binding site. Cell 1990, 60:577.
15. Erle DJ, Brown T, Christian D, et al. Lung epithelial lining fluid T cell subsets defined by distinct patterns of β7 and β1 integrin expression. Am J Respir Cell Mol Biol 1994, 10:237-244.
16. Breus JM, Gallo J, DE-Lisser HM, et aI. Expression of the β6 integrin in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 1995, 108:2241-2251.
17. Grubb BR, Rickles RJ, Ye H, et al. Inefficient gene transfer by adenovirus vector to cystic fibrosis airways epithelia of mice and humans. Nature 1994, 371:802-804.
18. Rostagno C, Felici M, Gensimn GF. Hemostatic vascular interactions in the pathogenesis and the treatment of adult respiratory distress syndrome. Ann Hal Med Int 1994, 9(4):236-242.
19. Mullican MS, Varorciyan AA, Warner RL. Compartmentalized roles for leukocytic adhesion molecules in lung inflammatory injury. J lmmunol 1995, 154:1350-1363.
20. Wickham TJ, Filardo EJ, Cheresh DA, et al. GR. Integrin ανβ5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol 1994, 127:257264.
21. Lazarus SC. Inflammation, inflammatory mediators, and mediator antagonists in ashtma. J Clin Pharmacol 1998, 38(7):577-582.
22. Schleimer RP, Bochner BS. The role of adhesion molecules in allergic inflammation and their suitability as targets of antiallergic therapy. Clin Exp AIlergy 1998, suppl 3:15-23.
23. Stanciv LA, Djukanovic R. The role of ICAM-1 on T-cells in the pathogenesis of asthma. Eur Respir J 1998, 11(4):949-957.
24. Lesur O, Arsalane K, Lane D. Lung alveolar epithelial cell migration in vitro: modulators and regulation processes. Am J Physiol 1996, 270(3):311-319
25. Etzioni A, Frudman M, Pollak S, et al. Recurrent severe infections caused by a novel leukocyte adhesion deficiency. N EngI J Med 1992, 327:1787-1792.