Airway smooth muscle: A modulator of airway remodeling in asthma
2005; Elsevier BV; Volume: 116; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2005.06.030
ISSN1097-6825
AutoresAili L. Lazaar, Reynold A. Panettieri,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoAsthma is a disease characterized, in part, by airway hyperresponsiveness and inflammation. Although asthma typically induces reversible airway obstruction, in some patients with asthma, airflow obstruction can become irreversible. Such obstruction might be a consequence of persistent structural changes in the airway wall caused by the frequent stimulation of airway smooth muscle (ASM) by contractile agonists, inflammatory mediators, and growth factors. Traditional concepts concerning airway inflammation have focused on trafficking leukocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Recent studies suggest that ASM cells might modulate airway remodeling by secreting cytokines, growth factors, or matrix proteins and by expressing cell adhesion molecules and other potential costimulatory molecules. These ASM cell functions might directly or indirectly modulate submucosal airway inflammation and promote airway remodeling. Asthma is a disease characterized, in part, by airway hyperresponsiveness and inflammation. Although asthma typically induces reversible airway obstruction, in some patients with asthma, airflow obstruction can become irreversible. Such obstruction might be a consequence of persistent structural changes in the airway wall caused by the frequent stimulation of airway smooth muscle (ASM) by contractile agonists, inflammatory mediators, and growth factors. Traditional concepts concerning airway inflammation have focused on trafficking leukocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Recent studies suggest that ASM cells might modulate airway remodeling by secreting cytokines, growth factors, or matrix proteins and by expressing cell adhesion molecules and other potential costimulatory molecules. These ASM cell functions might directly or indirectly modulate submucosal airway inflammation and promote airway remodeling. Chronic severe asthma is characterized by inflammation of the airways and growth of airway smooth muscle (ASM) cells. In patients with asthma, cytokines and growth factors promote myocyte proliferation and deposition of extracellular matrix (ECM) that, in part, constitute the process of airway remodeling. Pathologically, angiogenesis and microvascular remodeling are prominent features of chronic severe asthma, changes that are likely mediated by multiple factors. We will discuss the potential for ASM to influence the remodeling process through its ability to synthesize and secrete inflammatory mediators and ECM, as well as express adhesion molecules and other immunomodulatory proteins. ASM mitogens act through different receptor-operated mechanisms. Although growth factors induce ASM cell mitogenesis by activating receptors with intrinsic protein receptor tyrosine kinase (RTK) activity, contractile agonists released from inflammatory cells mediate their effects through activation of G protein–coupled receptors (GPCRs). Importantly, synergy can occur between RTK and GPCRs to promote human ASM mitogenesis.1Krymskaya V.P. Orsini M.J. Eszterhas A.J. Brodbeck K.C. Benovic J.L. Panettieri Jr., R.A. et al.Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle.Am J Respir Cell Mol Biol. 2000; 23: 546-554Crossref PubMed Scopus (117) Google Scholar The mechanisms regulating smooth muscle proliferation have been the subject of numerous reviews.2Hirst S.J. Martin J.G. Bonacci J.V. Chan V. Fixman E.D. Hamid Q.A. et al.Proliferative aspects of airway smooth muscle.J Allergy Clin Immunol. 2004; 114: S2-S17Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Phosphatidylinositol 3-kinase (PI3K) and extracellular signal–regulated kinase (ERK) activation appear to be the dominant signal transduction pathways for RTK-, GPCR-, or cytokine-stimulated growth of ASM cells (Fig 1). PI3K phosphorylates membrane phosphoinositides, which function as second messengers and activate downstream effector molecules to regulate cell-cycle protein expression and thus modulate cell-cycle traversal.3Cantley L.C. The phosphoinositide 3-kinase pathway.Science. 2002; 296: 1655-1657Crossref PubMed Scopus (4542) Google Scholar Activation of PI3K is critical for ASM cell-cycle progression,4Krymskaya V.P. Penn R.B. Orsini M.J. Scott P.H. Plevin R.J. 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These investigators found no evidence for ASM cell hypertrophy, although they did confirm the presence of ASM hyperplasia. More work is needed in this particular area of ASM cell biology. Hyperplasia and hypertrophy are important processes regulating increased smooth muscle mass in asthma. Analogous to vascular smooth muscle migration in atherosclerosis, however, ASM cell migration also likely promotes airway remodeling in chronic asthma. Evidence suggests that proliferating smooth muscle cells migrate along chemotactic gradients. During chronic inflammation, myocyte migration would be promoted by exposure of cells to a variety of cytokines and growth factors, as well as to an altered ECM. Structurally, myofibroblasts display a phenotype intermediate between fibroblasts and smooth muscle cells, express α-smooth muscle actin, and have the ability to secrete ECM proteins. In addition, myofibroblasts secrete chemokines and prolong eosinophil survival.29Zhang S. Mohammed Q. Burbidge A. Morland C.M. Roche W.R. Cell cultures from bronchial subepithelial myofibroblasts enhance eosinophil survival in vitro.Eur Respir J. 1996; 9: 1839-1846Crossref PubMed Scopus (35) Google Scholar Although myofibroblasts are found in the lamina reticularis, the origin of these cells remains unknown. Possibly the cells exist in small numbers within the lamina reticularis and proliferate locally after stimulation with inflammatory mediators or growth factors. Alternately, smooth muscle cells, under the influence of similar stimuli, migrate from the periphery of the smooth muscle bundle into the submucosa. A final intriguing possibility suggests that cells are recruited from a circulating pool of fibrocytes, as has recently been described.30Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar In this study CD34+ cells expressing procollagen I and α-smooth muscle actin were increased in the bronchial mucosa after allergen challenge in patients with asthma. Using a murine model of chronic allergic airway inflammation, the investigators demonstrated that these cells were recruited from a circulating population of CD34+ fibrocytes.30Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar The potential for mesenchymal cells, such as myofibroblasts, to migrate into the airway wall is well established in patients with asthma.31Brewster C.E.P. Howarth P.H. Djukanovic R. Wilson J. Holgate S.T. Roche W.R. 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Increased chemotaxis of ASM cells has been demonstrated to PDGF, TGF-β, basic fibroblast growth factor, and IL-1β. Urokinase has been shown to increase chemotaxis in some, but not all, studies.34Mukhina S. Stepanova V. Traktouev D. Poliakov A. Beabealashvilly R. Gursky Y. et al.The chemotactic action of urokinase on smooth muscle cells is dependent on its kringle domain. Characterization of interactions and contribution to chemotaxis.J Biol Chem. 2000; 275: 16450-16458Crossref PubMed Scopus (100) Google Scholar, 35Carlin S.M. Roth M. Black J.L. Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells.Am J Physiol Lung Cell Mol Physiol. 2003; 284: L1020-L1026PubMed Google Scholar Cysteinyl leukotrienes alone promote chemokinesis only; however, in combination with PDGF, increased chemotaxis is observed over that seen with PDGF alone.36Parameswaran K. Cox G. Radford K. Janssen L. Sehmi R. O'Byrne P.M. 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Extracellular matrix regulates human airway smooth muscle cell migration.Eur Respir J. 2004; 24: 545-551Crossref PubMed Scopus (60) Google Scholar recently demonstrated that ASM cells migrate more on collagen III and V and fibronectin compared with on collagen I, elastin, or laminin. Corticosteroids have been shown to inhibit ASM cell migration in vitro. Phosphodiesterase 4 (PDE4) inhibitors and β2-agonists have a more modest effect, but this can be enhanced by low concentrations of corticosteroids.37Goncharova E.A. Billington C.K. Irani C. Vorotnikov A.V. Tkachuk V.A. Penn R.B. et al.Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration.Am J Respir Cell Mol Biol. 2003; 29: 19-27Crossref PubMed Scopus (93) Google Scholar Many chemokines, which act to recruit and activate leukocytes, are found in the bronchoalveolar lavage fluid and lung tissue of patients with asthma. ASM cells have been shown to secrete RANTES, eotaxin, IL-8, monocyte chemotactic protein (MCP) 1, MCP-2, MCP-3, thymus and activation-regulated chemokine, and GM-CSF in response to TNF-α and IL-1β (Fig 2).41Howarth P.H. Knox A.J. Amrani Y. Tliba O. Panettieri Jr., R.A. Johnson M. Synthetic responses in airway smooth muscle.J Allergy Clin Immunol. 2004; 114: S32-S50Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Interestingly, polymorphisms in the IL-4 receptor on ASM might influence chemokine release.42Faffe D.S. Whitehead T. Moore P.E. Baraldo S. Flynt L. Bourgeois K. et al.IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype.Am J Physiol Lung Cell Mol Physiol. 2003; 285: L907-L914PubMed Google Scholar ASM cells might play a role in promoting both the recruitment and survival of eosinophils through secretion of GM-CSF and IL-5.43Saunders M.A. Mitchell J.A. Seldon P.M. Yacoub M.H. Barnes P.J. 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Mast-cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (1020) Google Scholar In addition to eotaxin, ASM cells secrete stem cell factor, which acts to recruit and retain mast cells within the smooth muscle layer.47Kassel O. Schmidlin F. Duvernelle C. Gasser B. Massard G. Frossard N. Human bronchial smooth muscle cells in culture produce stem cell factor.Eur Respir J. 1999; 13: 951-954Crossref PubMed Scopus (64) Google Scholar In addition to secreting chemokines that recruit leukocytes into the airways, ASM might promote leukocyte retention and activation through the expression of cell adhesion molecules. ASM cells express intercellular adhesion molecule 1 and VCAM-1, which are inducible by inflammatory mediators and constitutively express CD44, the hyaluronan receptor.48Lazaar A.L. Albelda S.M. Pilewski J.M. Brennan B. Puré E. Panettieri Jr., R.A. T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis.J Exp Med. 1994; 180: 807-816Crossref PubMed Scopus (210) Google Scholar ASM cells also express variable levels of integrin subunits, with the αv, α5, and β1 subunits predominating.49Freyer A.M. Johnson S.R. Hall I.P. Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells.Am J Respir Cell Mol Biol. 2001; 25: 569-576Crossref PubMed Scopus (128) Google Scholar The ability of ASM-associated cell adhesion molecules to directly activate T cells remains controversial. Although ASM cells express MHC class II and CD40 after stimulation with IFN-γ50Lazaar A.L. Reitz H.E. Panettieri Jr., R.A. Peters S.P. Puré E. Antigen receptor-stimulated peripheral blood and bronchoalveolar lavage-derived T cells induce MHC class II and ICAM-1 expression on human airway smooth muscle.Am J Respir Cell Mol Biol. 1997; 16: 38-45Crossref PubMed Scopus (42) Google Scholar, 51Lazaar A.L. Amrani Y. Hsu J. Panettieri Jr., R.A. Fanslow W.C. Albelda S.M. et al.CD40-mediated signal transduction in human airway smooth muscle.J Immunol. 1998; 161: 3120-3127PubMed Google Scholar and coculture of T cells with ASM appears to upregulate T-cell expression of CD25,52Hakonarson H. Kim C. Whelan R. Campbell D. Grunstein M.M. Bi-directional activation between human airway smooth muscle cells and T lymphocytes: role in induction of altered airway responsiveness.J Immunol. 2001; 166: 293-303PubMed Google Scholar the physiologic relevance of these findings remains unknown because ASM cells are unable to present antigen to CD4 T cells.50Lazaar A.L. Reitz H.E. Panettieri Jr., R.A. Peters S.P. Puré E. 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Krymskaya V.P. et al.Airway smooth muscle cells enhance C3a-induced mast cell degranulation following cell-cell contact.FASEB J. 2005; 19: 798-800PubMed Google Scholar This effect requires cell-cell contact, although the receptors mediating mast cell adhesion to ASM have not yet been identified.55Robinson D.S. The role of the mast cell in asthma: induction of airway hyperresponsiveness by interaction with smooth muscle?.J Allergy Clin Immunol. 2004; 114: 58-65Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar In contrast, coculture of activated T cells and ASM clearly induces smooth muscle cell DNA synthesis.48Lazaar A.L. Albelda S.M. Pilewski J.M. Brennan B. Puré E. Panettieri Jr., R.A. T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis.J Exp Med. 1994; 180: 807-816Crossref PubMed Scopus (210) Google Scholar, 53Ramos-Barbon D. Presley J.F. Hamid Q.A. Fixman E.D. Martin J.G. Antigen-specific CD4(+) T cells drive airway smooth muscle remodeling in experimental asthma.J Clin Invest. 2005; 115: 1580-1589Crossref PubMed Scopus (103) Google Scholar Adhesion of activated T cells also appears to alter smooth muscle cell contractility,52Hakonarson H. Kim C. Whelan R. Campbell D. Grunstein M.M. Bi-directional activation between human airway smooth muscle cells and T lymphocytes: role in induction of altered airway responsiveness.J Immunol. 2001; 166: 293-303PubMed Google Scholar potentially because of the autocrine secretion of IL-5 and IL-1β.45Hakonarson H. Maskeri N. Carter C. Chuang S. Grunstein M.M. Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle.J Clin Invest. 1999; 104: 657-667Crossref PubMed Scopus (114) Google Scholar Others have shown that ASM cells cultured with activated T cells show increased calcium mobilization responses to leukotriene D4 (LTD4) and serotonin,56Tolloczko B. Ramos-Barbon D. Martin J.G. Activated T-cells increase contractile agonist-induced calcium mobilization in airway smooth muscle cells.Proc Am Thorac Soc. 2005; 2: A27Google Scholar whereas release of lipid mediators and enzymes by activated mast cells likely promotes airway hyperresponsiveness and either inhibits (chymase) or promotes (tryptase) ASM cell proliferation.57Lazaar A.L. Plotnick M.I. Kucich U. Crichton I. Lotfi S. Das S.K. et al.Mast cell chymase modifies cell-matrix interactions and inhibits mitogen-induced proliferation of human airway smooth muscle cells.J Immunol. 2002; 169: 1014-1020PubMed Google Scholar, 58Brown J.K. Tyler C.L. Jones C.A. Ruoss S.J. Hartmann T. Caughey G.H. Tryptase, the dominant secretory granular protein in human mast cells, is a potent mitogen for cultured dog tracheal smooth muscle cells.Am J Respir Cell Mol Biol. 1995; 13: 227-236Crossref PubMed Scopus (109) Google Scholar, 59Brown J.K. Jones C.A. Rooney L.A. Caughey G.H. Hall I.P. Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L197-L206PubMed Google Scholar These studies highlight the finding that direct interactions between leukocytes and smooth muscle cells contribute to the modulation of the local milieu, resulting in smooth muscle cell activation and growth and possibly leuko
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