Methylprednisolone and isoproterenol inhibit airway smooth muscle proliferation by separate and additive mechanisms

Schramm, Craig M.; Omlor, Gregory J.; Quinn, Lisa; Noveral, James P.

doi:10.1016/0024-3205(96)00259-7

Cited by 13 publications

(6 citation statements)

References 14 publications

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“…Glucocorticoids inhibit airway smooth muscle proliferation and may therefore be beneficial in reducing the airway wall remodelling that occurs in asthma ( Schramm et al ., 1996 ; Stewart et al ., 1995a , 1995c ; Young et al ., 1995 ). Since asthma is a chronic inflammatory disease of the airways in which pro‐inflammatory cytokines are present in biologically active amounts in bronchoalveolar lavage fluid aspirated from asthmatic patients ( Broide et al ., 1992 ; Cembrzynska‐Nowak et al ., 1993 ; Mattoli et al ., 1991 ; Walker et al ., 1992 ), we re‐evaluated the anti‐proliferative effects of the glucocorticoids, dexamethasone and fluticasone propionate ( Holliday et al ., 1994 ), in the presence of a combination of the cytokines, IL‐1α and TNF‐α.…”

Section: Discussionmentioning

confidence: 99%

“…In considering the impact of IL‐1α exposure on airway smooth muscle in the asthmatic airway, predicting the outcome for remodelling is complicated by the interrelated phenomena which are elicited by IL‐1α. Thus, whilst the cytokine induction of PGE 2 is growth inhibitory, it may be that the heterologous desensitization of β 2 ‐adrenoceptors by PGE 2 is of more significance to the regulation of airway smooth muscle proliferation in asthma, since β 2 ‐adrenoceptor agonists partially inhibit airway smooth muscle proliferation ( Schramm et al ., 1996 ; Tomlinson et al ., 1994 ; Young et al ., 1995 ). Glucocorticoids reverse the desensitization of β 2 ‐adrenoceptors in airway smooth muscle ( Hauck et al ., 1997 ) and in non‐muscle cell types ( Chong et al ., 1997 ).…”

Section: Discussionmentioning

confidence: 99%

“…Studies from this and other laboratories have identified biologically diverse stimuli for proliferation of cultured human airway smooth muscle which include peptide growth factors, proteases, low molecular weight bronchoconstrictors and some pro‐inflammatory cytokines (see Stewart et al ., 1995c for review). The major anti‐asthma drug classes, β 2 ‐adrenoceptor agonists and glucocorticoids, attenuate airway smooth muscle proliferation ( Schramm et al ., 1996 ; Stewart et al ., 1995a ; 1997 ; Tomlinson et al ., 1995 ; Young et al ., 1995 ).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Vlahos

Stewart

1999

British J Pharmacology

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1 Previous studies have established that glucocorticoids inhibit airway smooth muscle DNA synthesis. The eects of a combination of the pro-in¯ammatory cytokines, interleukin-1a (IL-1a) and tumour necrosis factor-a (TNF-a) on the inhibition of DNA synthesis by glucocorticoids in human cultured airway smooth muscle have now been investigated, since these cytokines are chronically expressed in asthmatic airways. 2 Thrombin (0.3 u ml 71 ) and basic ®broblast growth factor (bFGF, 300 pM) stimulated increases in DNA synthesis which were concentration-dependently inhibited by dexamethasone (1 ± 1000 nM). 3 The cytokine mixture, comprising IL-1a (0.01 and 0.1 pM) and TNF-a (3 and 30 pM), directly evoked increases in DNA synthesis which were attenuated by dexamethasone. However, the cytokine mixture prevented responses to bFGF or thrombin. 4 Paradoxically, in the presence of the cytokine mixture and bFGF, dexamethasone (1 ± 1000 nM) concentration-dependently increased DNA synthesis. Furthermore, neither dexamethasone (100 nM) nor¯uticasone propionate (1 nM) inhibited DNA synthesized in response to bFGF/cytokine mixture combination and dexamethasone was similarly inactive against the thrombin/cytokine mixture. 5 The levels of prostaglandin E 2 (PGE 2 ), an established inhibitor of airway smooth muscle DNA synthesis, remained below the limits of assay detection (0.05 nM) under basal conditions or following stimulation with either thrombin or bFGF. In contrast, the cytokine mixture alone, and in the presence of thrombin or bFGF, induced biologically active levels of PGE 2 . Dexamethasone (100 nM), the non-selective cyclo-oxygenase (COX) inhibitor indomethacin (3 mM) or the selective COX-2 inhibitor L-745,337 (0.3 mM) completely inhibited synthesis of PGE 2 . 6 Neither indomethacin (3 mM) nor L-745,337 (0.3 mM) in¯uenced thrombin-or bFGF-induced DNA synthesis. However, each COX inhibitor enhanced DNA synthesis in cytokine-treated cells. 7 In unstimulated airway smooth muscle cells, COX-1, but not COX-2 protein was detectable by Western blotting. The induction of COX-2 protein by the cytokine mixture was attenuated by dexamethasone (100 nM), whereas the level of COX-1 protein was unaected by either the cytokines or by dexamethasone. 8 Cytokine-induced, COX-2-dependent eicosanoid production inhibits DNA synthesis. The paradoxical increase in DNA synthesis observed in glucocorticoid treated airway smooth muscle stimulated by cytokine/bFGF combinations may be explained by the ability of glucocorticoids to repress COX-2 induction and prevent cytokine-induction of the DNA synthesis inhibitor, PGE 2 .

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Vlahos

Stewart

1999

British J Pharmacology

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“…The clinical efficacy of glucocorticoids in preventing or reversing structural changes in the airways, including smooth muscle hyperplasia/hypertrophy, is undefined (reviewed in [41]). In cell culture-based systems, however, glucocorticoids inhibit mitogen-stimulated proliferation of smooth muscle derived from bovine [152], rabbit [153] and human airways [154]. A recent study by STEWART and coworkers [155] has addressed the possible molecular mechanisms by which glucocorticoids could prevent induction of DNA synthesis by a-thrombin.…”

Section: Role Of Phosphoinositide 3-kinase Activation In Proliferationmentioning

confidence: 99%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase‐, protein kinase C‐ and phosphoinositide 3‐kinase‐dependent pathways, since these appear to be the major candidate second messenger pathways for G protein‐ and tyrosine kinase‐coupled receptor‐stimulated proliferation.

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“…Glucocorticoids inhibit mitogen-stimulated proliferation of smooth muscle cells cultured from rabbit (31), bovine (32), and human airways (33). However, little is known of the particular site(s) at which glucocorticoids inhibit the mitogenic signaling pathway.…”

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confidence: 99%

Glucocorticoids Inhibit Proliferation, Cyclin D1 Expression, and Retinoblastoma Protein Phosphorylation, but Not Activity of the Extracellular-Regulated Kinases in Human Cultured Airway Smooth Muscle

Fernandes

Guida

Koutsoubos

et al. 1999

Am J Respir Cell Mol Biol

128

114

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We have previously shown that glucocorticoids inhibit mitogen-stimulated proliferation of human cultured airway smooth muscle (ASM) cells. The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 microM), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.

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Methylprednisolone and isoproterenol inhibit airway smooth muscle proliferation by separate and additive mechanisms

Cited by 13 publications

References 14 publications

Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Glucocorticoids Inhibit Proliferation, Cyclin D1 Expression, and Retinoblastoma Protein Phosphorylation, but Not Activity of the Extracellular-Regulated Kinases in Human Cultured Airway Smooth Muscle

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