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Migration of Airway Smooth Muscle Cells

Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts

Address correspondence to: J. Mark Madison, M.D., Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, LRB 319, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605-2324. E-mail: Mark.Madison{at}umassmed.edu

Abbreviations: airway smooth muscle cells, ASMCs • cyclic adenosine monophosphate, cAMP • extracellular signal–regulated kinase, ERK • heat shock protein 27, HSP27 • mitogen-activated protein kinase, MAPK • platelet-derived growth factor, PDGF • phosphatidylinositol 3-kinase, PI3K • vascular smooth muscle cells, VSMCs

	Introduction

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 
Airway smooth muscle cells (ASMCs) have more than a single "function." In addition to an obvious contractile function that regulates rapid changes in airway caliber, these cells have both a proliferative function that leads to hyperplasia and hypertrophy of smooth muscle in persistent asthma, and a secretory function that contributes to the extracellular matrix and modulates airway inflammation by elaboration of cytokines, mediators, and growth factors (1–3). Now, an emerging new function for these cells is cell migration—a capability of ASMCs that may have importance during the airway remodeling of persistent asthma. In this issue of the AJRCMB, Goncharova and coworkers compare cultured human ASMC migration to vascular smooth muscle cell (VSMC) migration, and test the effects that asthma medications (ß-adrenergic agonist, phosphodiesterase inhibitor, and glucocorticoids) have on migration stimulated by platelet-derived growth factor (PDGF) (4).

	Migration of VSMCs

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 
Compared with ASMCs, much more is known about the migration of VSMCs. In atherosclerosis, the intima becomes thickened due to an increase in extracellular matrix and the proliferation of a VSMC population (5, 6). These muscle cells probably are derived both from a small population of pre-existing cells in the intima and from VSMCs that have migrated into the intima from the media. According to one hypothesis, VSMCs are normally surrounded by a basement membrane and extracellular matrix that keeps the cells in a differentiated state by interacting with specific integrins expressed on the cell surface (5). In response to injury, inflammation, or wall stress, the enzymatic activity of heparanases, plasminogen activators, and matrix metalloproteinases degrade the matrix. Along with growth factors and cytokines, this stimulates phenotypic modulation of the VSMCs, directed migration (chemotaxis) into the intima, and proliferation.

Because of their importance in the pathogenesis of atherosclerosis, the intracellular mechanisms controlling migration of VSMCs have received much attention. Although important cell-specific differences are likely, many findings for vascular muscle (and other cell types) may be relevant to understanding smooth muscle migration in the airways (6–10). The process of cell migration is fundamentally one of cytoskeletal remodeling with spatially directed protrusions of filopodia and lamellipodia that are dependent on actin polymerization. Many families of proteins participate in the regulation of these dynamic processes, and these include proteins that regulate actin capping, severing, cross-linking, nucleation, and movement (10). Focal adhesions between the cell membrane and matrix are also essential elements of the migratory process, because these transmit the force of the contractile apparatus to the matrix to pull the cell forward (8). These complex processes are themselves regulated by signaling pathways that include extracellular matrix elements (e.g., fibronectin, osteopontin, and vitronectin), the integrins, and focal adhesion proteins, including focal adhesion kinase, Src family tyrosine kinases, and paxilllin. Downstream effectors include calcium signaling, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) cascades, and the Rho GTPases (7). For VSMCs, understanding the signaling underlying directed cell movement holds the promise of finding interventions to slow the progression of atherosclerosis.

	Migration of ASMCs

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 
By analogy with atherosclerosis and vascular smooth muscle, some have speculated that ASMCs have a migratory function relevant to the pathology of asthma. Although there is, as yet, no direct evidence showing that ASMCs migrate in vivo in the adult airway, it is possible that cell migration is an important aspect of the smooth muscle hyperplasia and remodeling that are recognized pathologic features of asthma. Moreover, it is also possible that migration of smooth muscle cells toward the lumen of the airway plays a role in the appearance of myofibroblasts in the lamina reticularis of the asthmatic airway (11, 12). The myofibroblast is a little-studied, but potentially important, cell type that has an ultrastructure intermediate between differentiated smooth muscle cells and fibroblasts (11). By electron microscopy, myofibroblasts of the airway are elongate cells located in the lamina reticularis, a layer of fibrillar material that lies between the true epithelial basement membrane and the airway smooth muscle layer. The cells have abundant polyribosomes, dilated rough endoplasmic reticulum, an indented nucleus, and parallel arrays or bundles of thin filaments with dense condensations consistent with a contractile apparatus. The cellular origin(s) of these myofibroblasts in the lamina reticularis has not been established, but two major possibilities are that the cells are an expansion of a small resident population of myofibroblasts and/or that smooth muscle cells actively migrate into the submucosa from the adjacent layer of smooth muscle.

In an important morphologic study, Gizycki and colleagues counted myofibroblasts in human mucosal biopsy specimens after allergen challenge (12). Twenty-four hours after allergen challenge, subjects with asthma had a dramatic increase in the number of myofibroblasts in the lamina reticularis, and this was not seen in control subjects without asthma. The myofibroblasts had the irregular cell outlines that suggest active motility, had intracellular bundles of filaments with dense condensations, and sometimes were localized in close approximation to bundles or blocks of airway smooth muscle tissue. The ultrastructural similarity of these myofibroblasts to smooth muscle cells and the location and apparent motility of the cells are consistent with some or all of the myofibroblasts being derived from smooth muscle cells that actively migrated into the lamina reticularis. This migration process could be significant for the pathogenesis of asthma, because evidence suggests that myofibroblasts secrete the collagen matrix that thickens the lamina reticularis, participate in epithelial cell–mesenchymal interactions, modulate eosinophil survival, and participate in the remodeling of smooth muscle bundles during muscle hyperplasia (11–15). Therefore, it is possible that the active migration of ASMCs, or cells closely derived from them, is central to certain aspects of airway remodeling, and, ultimately, a useful therapeutic target in asthma.

In addition to studies of airway morphology, in vitro studies of cultured ASMCs also have supported the concept that smooth muscle cells migrate. Because cell migration often is associated with proliferation, the chemotactic effects of growth factors and inflammatory cytokines on migration of cultured airway smooth muscle cells have been tested (Table 1). Studies have demonstrated chemotactic responses to PDGF, interleukin-1ß, transforming growth factor-ß, and urokinase, and have delineated some of the major signal transduction pathways involved (16–20). In addition, even though leukotriene E₄ was not a chemoattractant itself, this important inflammatory mediator did increase nondirectional cell movement (chemokinesis) and enhanced the chemotactic response to PDGF (21). In the current issue of AJRCMB, Goncharova and coworkers have extended understanding of ASMC migration by comparing the chemotactic effects of PDGF, transforming growth factor-, basic fibroblast growth factor, thrombin, and vascular endothelial growth factor on the migration of both human ASMCs and pulmonary artery VSMCs (4). Because of their important therapeutic role in asthma, the study also tested the effects of cyclic adenosine monophosphate (cAMP)-mobilizing agents and glucocorticoids on cell migration in vitro. The findings described in the study are significant because they show that stimulation of cell proliferation and cell migration are not necessarily overlapping in terms of regulation by growth factors, that there may be aspects of migration that are specific for smooth muscle cells from the airways, and that asthma medications have significant inhibitory effects on migration.

	Signaling Pathways for Migration of ASMCs

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

In one series of studies of ASMCs, PDGF both stimulated cell migration and the phosphorylation of heat shock protein 27 (HSP27), an important regulator of actin remodeling whose phosphorylation favors polymerization of F-actin (16, 18). Pharmacologic inhibition of p38^MAPK blocked cell migration in response to PDGF, and, furthermore, this was associated with inhibition of phosphorylation of HSP27 (16). Overexpression of a dominant-negative mutant of p38^MAPK and an HSP27-phosphorylation mutant dramatically blocked cell migration in response to PDGF. In a subsequent study, p21-activated kinase 1 (PAK1) was identified as a regulator of p38^MAPK because overexpression of an inactive PAK1 mutant blocked chemotactic migration to PDGF and reduced p38^MAPK phosphorylation (18). These findings are significant because the PAK family of molecules has regulatory interactions with the Rho GTPases, a family of proteins widely recognized as important in the actin polymerization–dependent appearance of filopodia and lamellipodia during cell migration (7, 23). Other studies suggest that PI3K and Rho-kinase have a role in regulating migration. Specifically for airway smooth muscle, pharmacologic inhibitors of PI3K (LY294002) and Rho-kinase (Y27632) both blocked migration in response to PDGF (20, 21).

In a different series of studies, there has been a focus on the plasminogen activator, urokinase, because it is a potent chemoattractant of ASMCs. Directed migration is stimulated by high-affinity binding of urokinase to the urokinase plasminogen activator receptor (uPAR) and low-affinity binding of the kringle domain of urokinase to an unidentified cell surface receptor (17, 19). Chemotactic signaling from uPAR may be mediated by a direct interaction with integrins. Subsequent studies showed that urokinase activated both ERK and p38^MAPK pathways for cell migration, but that binding of the kringle domain was the event specifically responsible for activating p38^MAPK to cause the phosphorylation of the actin-associated protein, caldesmon (19). Although the functional significance of caldesmon phosphorylation and the roles of p38^MAPK in regulating it are not entirely clear, pharmacologic inhibition of p38^MAPK activity did block urokinase-stimulated phosphorylation of caldesmon and the migration of ASMCs (17, 19, 24). In contrast to PDGF-stimulated chemotaxis, the migration stimulated by the kringle domain of urokinase was not associated with increased phosphorylation of HSP27 (19). This latter finding suggests that even rather distal events in these complicated signaling cascades feature important agonist-specific differences.

	Inhibition of ASMC Migration

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 
Less is known about the signaling pathways that inhibit the migration of cells, but, in many cell types, increases in cAMP are associated with inhibition of migration. Specifically in ASMCs, Parameswaran and coworkers showed that prostaglandin E₂ (PGE₂) inhibited migration in response to PDGF, and this suggested that increases in cAMP were inhibitory in this cell type (21). In the current issue, Goncharova and colleagues tested for inhibition of ASMC migration and correlated increases in cAMP and protein kinase A (PKA) activity to inhibition of chemokinesis and PDGF-stimulated chemotaxis. In other experiments, pretreatment of cells with glucocorticoids strongly inhibited migration. The implication of these new findings is that the current treatment of asthma, which routinely combines ß-adrenergic agonists and glucocorticoids, is likely to have significant inhibitory effects on the migration of smooth muscle cells and may, therefore, have significant effects on the airway remodeling processes that are dependent on smooth muscle. Observed cooperative effects between cAMP/PKA-mediated mechanisms and glucocorticoids in airway smooth muscle migration are particularly notable because synergism also has been found for inhibiting secretion of mediators and control of cell proliferation in this cell type (25, 26).

How increases in cAMP and glucocorticoids actually inhibit signaling pathways promoting directed migration of ASMCs is not yet known and may involve multiple mechanisms. cAMP and the consequent activation of PKA may modulate MAPK cascades. Of particular interest will be whether PKA has inhibitory effects on p38^MAPK signaling, because that cascade has already been implicated in the migration of these cells (16, 18, 19, 21). Of note, in VSMCs, cAMP-mobilizing agents increased the phosphorylation of HSP20, a heat shock protein that may interact with HSP27 and myosin light chains (27, 28). Although there may be species- and cell type–specific differences, this finding suggests that cAMP/PKA may act distally in the p38^MAPK cascade to modulate cytoskeletal dynamics. It is also important to recognize that ß-adrenergic agonists have both PKA-dependent and -independent effects on actin depolymerization in airway smooth muscle and, therefore, PKA may not mediate all the effects that ß-adrenergic agonists have on actin remodeling (29). Finally, even less is known about the mechanisms, probably multiple, that underlie the inhibitory effects of glucocorticoids on migration (30). However, given the evidence that p38^MAPK has a major role in regulating migration in ASMCs, it is interesting that, in HeLa cells, glucocorticoids did inhibit p38^MAPK signaling by inducing a sustained expression of MAPK phosphatase 1 (MKP-1) (31). Understanding these and other ways to inhibit cell migration will be areas of increasing importance as more is learned about airway remodeling in persistent asthma.

	Summary

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 
For ASMCs, much remains to be learned about the role of cell migration in asthma and the signaling underlying its control. Many features of this process will be shared with other cell types, but important differences are probable. Potentially, an understanding of the molecular signaling pathways controlling migration will suggest points of intervention for control of airway remodeling in asthma.

	Acknowledgments

 
This work was supported by NIH grant HL-54143.

Received in original form April 16, 2003

	References

Top Introduction Migration of VSMCs Migration of ASMCs Signaling Pathways for Migration... Inhibition of ASMC Migration Summary References

 

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Madison, J. M. Search for Related Content PubMed PubMed Citation Articles by Madison, J. M.