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The Proceedings of the American Thoracic Society 1:231-234 (2004)
© 2004 The American Thoracic Society

Effects of Corticosteroids on Structural Cells in Asthma and Chronic Obstructive Pulmonary Disease

Reynold A. Panettieri, Jr.

Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Reynold A. Panettieri, Jr., M.D., Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, 421 Curie Boulevard, BRB II/III, Philadelphia, PA 19104-6160. E-mail: rap{at}mail.med.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
CHEMOKINE AND CYTOKINE RELEASE...
 CORTICOSTEROIDS AND CYTOKINE...
 INHIBITION OF STRUCTURAL CELL...
 REFERENCES
 
Structural cells such as airway smooth muscle, myofibroblasts, and fibroblasts play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease. Although considerable research effort has focused on the effects of steroids on leukocyte function and airway inflammation, few studies have investigated the effects of steroids on structural cell function. There is evidence that structural cells, apart from maintaining the integrity of the bronchial wall, may also participate in airway inflammatory responses. New data suggest that steroids inhibit some but not all proliferative and migratory responses in structural cells. Further, in structural cells the downstream signaling effects altered by glucocorticoids appear to differ from those observed in leukocytes. Therapeutic approaches designed to modulate chemokine and cytokine secretion by structural cells may offer new opportunities to treat diseases characterized by airway obstruction.

Key Words: airway remodeling • airway smooth muscle • fibroblasts • myofibroblasts

Asthma and chronic obstructive pulmonary disease (COPD), chronic diseases affecting millions of people worldwide, are characterized by airway obstruction, airway inflammation, and alterations in structural cell function. The role of structural cells such as airway smooth muscle (ASM), myofibroblasts, and fibroblasts was thought to be maintenance of bronchial wall integrity, but evidence suggests that these cells may be integral components of the inflammatory response as well. This review focuses on the synthetic function of structural cells, which is defined as the ability to secrete immunomodulatory cytokines and chemokines and to express cell surface receptors that are important for cell adhesion and leukocyte activation. Further, it discusses whether the effects of glucocorticoids on structural cell synthetic function could have therapeutic implications.

In diseases characterized by airway obstruction, the most common medications prescribed include antiinflammatory glucocorticoids and bronchodilators such as short-acting (albuterol) or long-acting (formoterol, salmeterol) ß2-agonists. Glucocorticoids act by binding and activating the cytosolic glucocorticoid receptor. The activated glucocorticoid receptor then undergoes nuclear translocation and interacts in either a cis- or transrepressive manner to inhibit cytokine gene expression (1). Despite considerable research effort in defining the effects of glucocorticoid receptor activation in regulating leukocyte function, little is known about the role of glucocorticoids in modulating structural cell function. Current evidence suggests that cellular responses to glucocorticoids in structural cells may differ from those observed in leukocytes. Such observations may have important clinical relevance, given the evidence that some patients with asthma or COPD appear to be glucocorticoid insensitive.


   CHEMOKINE AND CYTOKINE RELEASE BY ASM CELLS AND FIBROBLASTS
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Various cell types that infiltrate the inflamed submucosa present the potential for important cell–cell interactions. Eosinophils, macrophages, and lymphocytes initiate and perpetuate airway inflammation by producing proinflammatory mediators. Evidence also suggests that exposure of ASM to cytokines or growth factors alters contractility and calcium homeostasis (2) and induces smooth muscle cell hypertrophy and hyperplasia (3).

Studies have revealed that ASM, as well as other structural cells such as myofibroblasts and fibroblasts, secretes a number of cytokines and chemoattractants. Bronchial biopsies of ASM in subjects with mild asthma show constitutive staining for RANTES (the CCL5 chemokine regulated upon activation, normal T cell expressed and secreted) (4) and, in vitro, RANTES secretion in ASM is induced by tumor necrosis factor (TNF)-{alpha} and interferon-{gamma} (5–7). Similarly, the CXCL8 chemokine interleukin (IL)-8 is secreted by ASM in response to TNF-{alpha}, IL-1ß, and bradykinin (8–10). Other chemokines secreted by structural cells include eotaxin, an eosinophil chemoattractant, and monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 (6, 11, 12) (Table 1) (13).


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  		TABLE 1. Immunomodulatory proteins expressed by human airway smooth muscle cells

 
IL-6, a pleiotropic cytokine, induces smooth muscle cell hyperplasia (14) but also modulates B and T cell proliferation and immunoglobulin secretion. IL-6 secretion by ASM cells is inducible by multiple stimuli, including IL-1ß, TNF-{alpha}, transforming growth factor-ß, and sphingosine 1-phosphate, a mediator in asthma (7, 10, 15–17). Transgenic expression of IL-6 in the murine lung evokes a peribronchiolar inflammatory infiltrate but promotes airway hyporesponsiveness. These data suggest an intriguing role for IL-6 in controlling local inflammation and regulating airway reactivity (18, 19), consistent with the known ability of IL-6 to inhibit TNF-{alpha} and IL-1ß secretion. ASM cells may also play a role in promoting both the recruitment and survival of eosinophils by secretion of granulocyte-macrophage colony-stimulating factor and IL-5 (20–22). Additional cytokines that are secreted by human ASM cells include IL-1ß and other IL-6 family cytokines, such as leukemia inhibitory factor, IL-11, and the thymus- and activation-regulated chemokine (10, 15, 22, 23).


   CORTICOSTEROIDS AND CYTOKINE-INDUCED SYNTHETIC RESPONSES IN STRUCTURAL CELLS
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A cornerstone in the management of asthma is the control of airway inflammation. To date, one of the most effective medications for airway inflammation is inhaled corticosteroids. Despite their use for more than 25 years, the precise mechanisms by which steroids improve lung function remain unclear. Because of the therapeutic importance of inhaled corticosteroids in asthma and COPD, investigators have examined whether steroids alter immunomodulatory functions in ASM and fibroblast cells.

Current evidence suggests that chemokine and cytokine secretion induced by inflammatory mediators is inhibited by dexamethasone in human ASM cells. Cytokine-induced secretion of RANTES (5–7), MCP (6), eotaxin (24), granulocyte-macrophage colony-stimulating factor (20), and IL-6 (16) was abrogated with corticosteroids. In most of these studies, corticosteroids and agents that mobilize intracellular cyclic adenosine monophosphate ([cAMP]i) acted additively to inhibit chemokine and cytokine secretion (7). Current hypotheses suggest that steroids may directly inhibit gene expression by altering gene promoter activity and/or may abrogate critical signaling events, such as activation of nuclear factor (NF)-{kappa}B or activator protein (AP)-1, that then modulate gene expression. However, the precise mechanisms by which steroids may regulate synthetic responses in ASM cells remain unknown.

NF-{kappa}B is implicated as a pivotal transcriptional factor mediating chronic inflammatory responses in asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (25). The inhibition of activation of transcription factors, such as NF-{kappa}B or AP-1, is thought to cause many of the antiinflammatory effects of corticosteroids (25). Dexamethasone had no effect on TNF-{alpha}–induced or IL-1ß–induced NF-{kappa}B activation in human ASM cells (26). Further, cytokine-induced expression of intercellular cell adhesion molecule (ICAM)-1 in ASM cells, which is completely dependent on NF-{kappa}B activation, was not affected by dexamethasone, whereas IL-1ß–induced cyclooxygenase (COX)-2 expression was abrogated (26–28). Collectively, these data support the notion that the antiinflammatory effects of steroids in asthma or COPD may not be due to modulation of cytokine-induced NF-{kappa}B activation or ICAM-1 expression in human ASM cells. In addition, the cytokine-induced secretion of chemokines, which is exquisitely sensitive to corticosteroids, is probably regulated in part by pathways not dependent on NF-{kappa}B activation or may be influenced by the context in which the promoter, cofactor, and glucocorticoid receptor interact. Figure 1 summarizes the putative signaling pathways that regulate cytokine-induced ASM synthetic pathways and the pharmacologic agents that modulate these pathways. The inability of steroids to inhibit all cytokine-induced synthetic responses in ASM cells may have important consequences for the local inflammatory responses in the airways and for the development of airway remodeling in bronchi of some patients with chronic severe asthma.



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  		Figure 1. Putative signaling path-ways that regulate cytokine-induced synthetic responses in ASM cells. In general, [cAMP]i-mobilizing agents inhibit cytokine-induced expression of chemokines and cell adhesion molecules. IL-6 secretion, however, is augmented by agents that increase [cAMP]i. Cytokine-induced NF-{kappa}B activation in human ASM is corticosteroid insensitive. A-kinase = cAMP-dependent protein kinase A; ERK = extracellular signal-regulated kinase; Gs = guanine-nucleotide binding protein; JNK = Jun-N-terminal kinase; PDE = phosphodiesterase. Adapted by permission from Lazaar and Panettieri (13).

 
Glucocorticoids and ß2-agonists appear to act additively to inhibit structural cell synthetic responses (24, 29). For example, Pang and Knox demonstrated that glucocorticoids and ß2-agonists each partially inhibited TNF-{alpha}–induced eotaxin secretion from ASM cells and had an additive effect in combination (24). Although Pang and Knox did not examine the underlying transcriptional mechanisms, it is interesting to note that the eotaxin promoter does not contain a cAMP response element (CRE) or glucocorticoid response element (30). Although the IL-8 promoter does contain a CRE region (31), treatment of ASM cells with ß2-agonists alone only minimally induced IL-8 secretion, and ß2-agonists had no effect on IL-8 induction by TNF-{alpha} (29). TNF-{alpha}–induced IL-8 secretion was synergistically inhibited by glucocorticoid plus ß2-agonist combination treatment (29). ß2-Agonist treatment did not alter the virtually complete inhibition of TNF-{alpha}–induced RANTES expression that occurred at high glucocorticoid concentrations, but it did render low concentrations of glucocorticoids more efficacious in inhibiting TNF-{alpha}–induced RANTES expression (7). This might be interpreted as a "glucocorticoid-sparing effect" consistent with that observed in patients with asthma undergoing combination therapy with an inhaled corticosteroid and a ß2-agonist. Collectively, these studies show that the effect of glucocorticoid plus ß2-agonist combination therapy on ASM gene expression represents a complex interplay among the transcription factors controlling cytokine gene expression.


   INHIBITION OF STRUCTURAL CELL PROLIFERATION AND MIGRATION BY GLUCOCORTICOIDS
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Many of the therapies widely used to treat asthma and COPD have been examined for their ability to inhibit ASM cell proliferation in vitro. Although no systematic study of the relative efficacies has been performed, in vitro evidence suggests that antiasthma drugs may, in part, reduce airway remodeling in vivo. Furthermore, these studies provide useful clues for the design of future therapeutic agents to treat airway remodeling in asthma or COPD.

In human ASM cells, dexamethasone or fluticasone propionate arrests ASM cells in the G1 phase of the cell cycle (32). Investigators showed that corticosteroids reduced thrombin-stimulated increases in cyclin D1 protein and mRNA levels and also attenuated phosphorylation of retinoblastoma protein, via a pathway either downstream of or parallel to the mitogen-activated protein kinase pathway (32). Evidence suggests that corticosteroids may not be effective in inhibiting ASM cell mitogenesis in response to receptor tyrosine kinase–activating mitogens (33). In addition, glucocorticoid effects on ASM cell growth also are dependent on ASM–matrix interactions. Evidence suggests that ASM growth on collagen I appears resistant to glucocorticoid inhibition and may relate to integrin–matrix interactions (34). Collectively, these studies suggest that steroids inhibit some but not all growth factor–induced proliferation of structural cells.

Increased smooth muscle mass is frequently associated with diseases manifested by increased airway or pulmonary vascular resistance (35–37). Growth factors, contractile agonists, and inflammatory mediators stimulate abnormal smooth muscle growth by promoting smooth muscle proliferation (38). Histologic findings suggest that proliferating smooth muscle cells migrate along chemotactic gradients, as evidenced by the invasion of smooth muscle–like cells into the submucosa (39) and the invasion of pulmonary vascular smooth muscle (PVSM) cells into the interstitium (40). Importantly, agents that stimulate smooth muscle cell proliferation also appear capable of inducing smooth muscle cell migration (41–44).

To date, few studies have compared cell migration in both airway and vascular smooth muscle cells. Such studies will be important as researchers target therapeutic approaches to many diseases. Evidence suggests that the combination of a ß2-agonist and a steroid can be beneficial at both the organ system level (45) and the cellular level (46, 47), so investigators have examined the effect of glucocorticoids on inhibition of ASM migration as mediated by salmeterol, prostaglandin E2 (PGE2), and forskolin (an adenylyl cyclase activator). Dexamethasone or fluticasone proprionate, but not salmeterol alone, inhibited ASM cell migration stimulated by platelet-derived growth factor (PDGF), and combined treatment enhanced inhibition. Similarly, overnight pretreatment of ASM cells with fluticasone proprionate augmented the inhibitory effect of PGE2 and salmeterol on PDGF-induced migration. Also, preincubation of ASM cells with fluticasone proprionate enhanced the inhibitory effect of forskolin on PDGF-induced ASM cell migration. It is unknown whether the primarily additive effect of a glucocorticoid plus a cAMP-elevating agent represents contributions of distinct, parallel pathways or rather represents signaling cross-talk/cooperativity, perhaps at the level of cAMP production and activation of protein kinase A. These data demonstrate that pretreatment with fluticasone proprionate or dexamethasone does not alter basal cAMP production or CRE-Luc activity and fails to significantly increase acute cAMP accumulation stimulated by salmeterol. Therefore, under these conditions, glucocorticoid treatment does not enhance ß2-adrenoceptor responsiveness via mechanisms such as ß2-adrenoceptor upregulation, as described previously (47), and the inhibitory effects of glucocorticoids on migration are cAMP/protein kinase A independent. Pretreatment with fluticasone proprionate or dexamethasone does, however, promote a small but significant increase in salmeterol-stimulated CRE activity, suggesting a small measure of signaling cooperation at the level of gene transcription regulation.

These data highlight cell-specific effects of various mitogens on the migration of human ASM and PVSM cells. In addition, cAMP-generating agents inhibit ASM and PVSM cell migration, and their efficacy seems to be related to their capacity to stimulate cAMP production and protein kinase A activity. Steroids profoundly inhibit PDGF-stimulated migration of ASM and PVSM, and this inhibition is enhanced by salmeterol. Other studies have demonstrated that ß2-agonists, as well as phosphodiesterase-4 inhibitors, enhance IL-6 secretion and inhibit RANTES secretion in ASM cells (48).

CONCLUSIONS
Structural cells such as ASM, myofibroblasts, and fibroblasts, which maintain the integrity of the bronchial wall, have now been identified as serving an immunomodulatory role as well. The effects of glucocorticoids on some, but not all, of the inflammatory responses induced by structural cells pose important new research questions. Emerging evidence suggests that the combination of a glucocorticoid with an agent that increases cAMP offers great advantage in inhibiting synthetic responses in structural cells. To date, much of the research gleaned in this area has focused on in vitro cell studies, and future research efforts should be devoted to the correlation of in vitro findings with those derived from in vivo models.


   ACKNOWLEDGMENTS
 
R.A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

The author thanks Mary McNichol for assistance in preparation of the manuscript.

(Received in original form February 18, 2004; accepted in final form May 3, 2004)


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  1. Barnes PJ, Perdersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J Respir Crit Care Med 1998;157:S1–S53.[Free Full Text]
  2. Amrani Y, Panettieri RA Jr. Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists. Thorax 1998;53:713–716.[Free Full Text]
  3. Lazaar AL, Amrani Y, Panettieri RA Jr. The role of inflammation in the regulation of airway smooth muscle cell function and growth. In: Busse W, Holgate S, editors. Asthma and rhinitis, 2nd ed. Oxford: Blackwell Science; 2000. p. 1402–1413.
  4. Berkman N, Krishnan VL, Gilbey T, Newton R, O'Connor B, Barnes PJ, Chung KF. Expression of RANTES mRNA and protein in airways of patients with mild asthma. Am J Respir Crit Care Med 1996;154:1804–1811.[Abstract]
  5. John M, Hirst SJ, Jose PJ, Robichaud A, Berkman N, Witt C, Twort CHC, Barnes PJ, Chung KF. Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids. J Immunol 1997;158:1841–1847.[Abstract]
  6. Pype JL, Dupont LJ, Menten P, Van Coillie E, Opdenakker G, Van Damme J, Chung KF, Demedts MG, Verleden GM. Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells: modulation by corticosteroids and T-helper 2 cytokines. Am J Respir Cell Mol Biol 1999;21:528–536.[Abstract/Free Full Text]
  7. Ammit AJ, Hoffman RK, Amrani Y, Lazaar AL, Hay DWP, Torphy TJ, Penn RB, Panettieri RA Jr. TNF{alpha}-induced secretion of RANTES and IL-6 from human airway smooth muscle cells: modulation by cAMP. Am J Respir Cell Mol Biol 2000;23:794–802.[Abstract/Free Full Text]
  8. John M, Au B-T, Jose PJ, Lim S, Saunders M, Barnes PJ, Mitchell JA, Belvisi MG, Chung KF. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998;18:84–90.[Abstract/Free Full Text]
  9. Pang L, Knox AJ. Bradykinin stimulates IL-8 production in cultured human airway smooth muscle cells: role of cyclooxygenase products. J Immunol 1998;161:2509–2515.[Abstract/Free Full Text]
  10. Hedges JC, Singer CA, Gerthoffer WT. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol 2000;23:86–94.[Abstract/Free Full Text]
  11. Ghaffar O, Hamid Q, Renzi PM, Allahkverdi Z, Molet S, Hogg JC, Shore SA, Luster AD, Lamkhioued B. Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells. Am J Respir Crit Care Med 1999;159:1933–1942.[Abstract/Free Full Text]
  12. Chung KF, Patel HJ, Fadlon EJ, Rousell J, Haddad E-B, Jose PJ, Mitchell J, Belvisi M. Induction of eotaxin expression and release from human airway smooth muscle cells by IL-1ß and TNF{alpha}: effects of IL-10 and corticosteroids. Br J Pharmacol 1999;127:1145–1150.[CrossRef][Medline]
  13. Lazaar AL, Panettieri RA Jr. Airway smooth muscle as an immunomodulatory cell: a new target for pharmacotherapy? Curr Opin Pharmacol 2001;1:259–264.[CrossRef][Medline]
  14. De S, Zelazny ET, Souhrada JF, Souhrada M. IL-1ß and IL-6 induce hyperplasia and hypertrophy of cultured guinea pig airway smooth muscle cells. J Appl Physiol 1995;78:1555–1563.[Abstract/Free Full Text]
  15. Elias JA, Wu Y, Zheng T, Panettieri RA Jr. Cytokine- and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines. Am J Physiol Lung Cell Mol Physiol 1997;273:L648–L655.[Abstract/Free Full Text]
  16. McKay S, Hirst SJ, Bertrand-de Haas M, de Jonste JC, Hoogsteden HC, Saxena PR, Sharma HS. Tumor necrosis factor-{alpha} enhances mRNA expression and secretion of interleukin-6 in cultured human airway smooth muscle cells. Am J Respir Cell Mol Biol 2000;23:103–111.[Abstract/Free Full Text]
  17. Ammit AJ, Hastie AT, Edsall LC, Hoffman RK, Amrani Y, Krymskaya VP, Kane SA, Peters SP, Penn RB, Spiegel S, et al. Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J 2001;15:1212–1214.[Free Full Text]
  18. DiCosmo BF, Geba GP, Picarella D, Elias JA, Rankin JA, Stripp BR, Whitsett JA, Flavell RA. Airway epithelial cell expression of interleukin-6 in transgenic mice: uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest 1994;94:2028–2035.
  19. Wang J, Homer RJ, Chen Q, Elias JA. Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation. J Immunol 2000;165:4051–4061.[Abstract/Free Full Text]
  20. Saunders MA, Mitchell JA, Seldon PM, Yacoub MH, Barnes PJ, Giembycz MA, Belvisi MG. Release of granulocyte-macrophage colony stimulating factor by human cultured airway smooth muscle cells: suppression by dexamethasone. Br J Pharmacol 1997;120:545–546.[CrossRef][Medline]
  21. Hallsworth MP, Soh CPC, Twort CHC, Lee TH, Hirst SJ. Cultured human airway smooth muscle cells stimulated by interleukin-1ß enhance eosinophil survival. Am J Respir Cell Mol Biol 1998;19:910–919.[Abstract/Free Full Text]
  22. Hakonarson H, Maskeri N, Carter C, Chuang S, Grunstein MM. Autocrine interaction between IL-5 and IL-1ß mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest 1999;104:657–667.[Medline]
  23. Knight DA, Lydell CP, Zhou D, Weir TD, Schellenberg RR, Bai TR. Leukemia inhibitory factor (LIF) and LIF receptor in human lung: distribution and regulation of LIF release. Am J Respir Cell Mol Biol 1999;20:834–841.[Abstract/Free Full Text]
  24. Pang L, Knox AJ. Regulation of TNF-{alpha}-induced eotaxin release from cultured human airway smooth muscle cells by ß2-agonists and corticosteroids. FASEB J 2001;115:261–269.
  25. Barnes PJ, Karin M. Nuclear factor-{kappa}B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066–1071.[Free Full Text]
  26. Amrani Y, Lazaar AL, Panettieri RA Jr. Up-regulation of ICAM-1 by cytokines in human tracheal smooth muscle cells involves an NF-{kappa}B-dependent signaling pathway that is only partially sensitive to dexamethasone. J Immunol 1999;163:2128–2134.[Abstract/Free Full Text]
  27. Belvisi MG, Saunders MA, Haddad E-B, Hirst SJ, Yacoub MH, Barnes PJ, Mitchell JA. Induction of cyclo-oxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type. Br J Pharmacol 1997;120:910–916.[CrossRef][Medline]
  28. Pang L, Knox AJ. Effect of interleukin-1ß, tumour necrosis factor-{alpha} and interferon-{gamma} on the induction of cyclo-oxygenase-2 in cultured human airway smooth muscle cells. Br J Pharmacol 1997;121:579–587.[CrossRef][Medline]
  29. Pang L, Knox AJ. Synergistic inhibition by ß2-agonists and corticosteroids on tumor necrosis factor-{alpha}-induced interleukin-8 release from cultured human airway smooth-muscle cells. Am J Respir Cell Mol Biol 2000;23:79–85.[Abstract/Free Full Text]
  30. Hein H, Schluter C, Kulke R, Chriostophers E, Schroder J-M, Bartels J. Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene. Biochem Biophys Res Commun 1997;237:537–542.[CrossRef][Medline]
  31. Taylor CT, Fueki N, Agah A, Hershberg RM, Colgan SP. Critical role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-{alpha}. J Biol Chem 1999;274:19447–19454.[Abstract/Free Full Text]
  32. Fernandes D, Guida E, Koutsoubos V, Harris T, Vadiveloo P, Wilson JW, Stewart AG. Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle. Am J Respir Cell Mol Biol 1999;21:77–88.[Abstract/Free Full Text]
  33. Ammit AJ, Panettieri RA Jr. Signal transduction in smooth muscle. Invited review: The circle of life—cell cycle regulation in airway smooth muscle. J Appl Physiol 2001;91:1431–1437.[Abstract/Free Full Text]
  34. Bonacci JV, Harris T, Wilson JW, Stewart AG. Collagen-induced resistance to glucocorticoid anti-mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway. Br J Pharmacol 2003;138:1203–1206.[CrossRef][Medline]
  35. Panettieri RA Jr. Cellular and molecular mechanisms regulating airway smooth muscle cell proliferation and cell adhesion molecule expression. Am J Respir Crit Care Med 1998;158:S133–S140.[Abstract/Free Full Text]
  36. Black JL, Roth M, Lee J, Carlin S, Johnson PR. Mechanisms of airway remodeling: airway smooth muscle. Am J Respir Crit Care Med 2001;164:S63–S66.[Abstract/Free Full Text]
  37. Bento AM, Hershenson MB. Airway remodeling: potential contributions of subepithelial fibrosis and airway smooth muscle hypertrophy/hyperplasia to airway narrowing in asthma. Allergy Asthma Proc 1998;19:353–358.[CrossRef][Medline]
  38. Stork PJS, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 2002;12:258–266.[CrossRef][Medline]
  39. Gizycki MJ, Adelroth E, Rogers AV, O'Byrne PM, Jeffery PK. Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997;16:664–673.[Abstract]
  40. Hedges JC, Dechert MA, Yamboliev IA, Martin JL, Hickey E, Weber LA, Gerthoffer WT. A role for p38mapk/HSP27 pathway in smooth muscle cell migration. J Biol Chem 1999;274:24211–24219.[Abstract/Free Full Text]
  41. Kraemer R, Nguyen H, March KL, Hempstead B. NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses. Arterioscler Thromb Vasc Biol 1999;19:1041–1050.[Abstract/Free Full Text]
  42. Cospedal R, Abedi H, Zachary I. Platelet-derived growth factor-BB (PDGF-BB) regulation of migration and focal adhesion kinase phosphorylation in rabbit aortic vascular smooth muscle cells: roles of phosphatidylinositol 3-kinase and mitogen-activated protein kinases. Cardiovasc Res 1999;41:708–721.[Abstract/Free Full Text]
  43. Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA Jr, Krymskaya VP. Phosphatidylinositol 3-kinase is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2002;283:L354–L363.[Abstract/Free Full Text]
  44. Parameswaran K, Cox G, Radford K, Janssen L, Sehmi R, O'Byrne PM. Cysteinyl leukotrienes promote human airway smooth muscle migration. Am J Respir Crit Care Med 2002;166:738–742.[Abstract/Free Full Text]
  45. Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, Prillaman B, Shah T. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Ann Allergy Asthma Immunol 1999;82:257–265.[Medline]
  46. Eickelberg O, Roth M, Lorx R, Bruce V, Rudiger J, Johnson M, Block L-H. Ligand-independent activation of the glucocorticoid receptor by ß2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999;274:1005–1010.[Abstract/Free Full Text]
  47. Kalavantavanich K, Schramm CM. Dexamethasone potentiates high-affinity ß-agonist binding and Gs{alpha} protein expression in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2000;278:L1101–L1106.[Abstract/Free Full Text]
  48. Ammit AJ, Lazaar AL, Irani C, O'Neill GM, Gordon ND, Amrani Y, Penn RB, Panettieri RA Jr. Tumor necrosis factor-{alpha}-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and ß-agonists. Am J Respir Cell Mol Biol 2002;26:465–474.[Abstract/Free Full Text]



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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. M. Goldsmith, M. B. Hershenson, M. P. Wolbert, and J. K. Bentley
Regulation of airway smooth muscle {alpha}-actin expression by glucocorticoids
Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L99 - L106.
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