The Effects of Regular Inhaled Formoterol, Budesonide,  and Placebo on Mucosal Inflammation and Clinical  Indices in Mild Asthma

Wallin, Annika; Sandström, Thomas; Söderberg, Margaretha; Howarth, Peter H.; Lundbäck, Bo; Della-Cioppa, Giovanni; Wilson, Susan J.; Djukanović, Ratko; Holgate, Stephen T.; Lindberg, Anne; LARSSEN, LARS; Judd, M.; Melander, B

doi:10.1164/ajrccm.159.1.9801007

Cited by 111 publications

(62 citation statements)

References 25 publications

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“…It is clear that b 2 -agonists, through elevations in cellular cAMP, can reduce recruitment and activity of some types of proinflammatory cells. Lavage/biopsy studies have documented that formoterol inhalation reduces the number of mast cells and eosinophils in the airways of asthmatics [19], and that salmeterol can decrease the neutrophil number [20]. These sustained in vivo effects exclude the possibility that there is a complete tachyphylaxis for this type of anti-inflammatory activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells

2001

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The effect of formoterol, alone and in combination with budesonide, upon tumour necrosis factor-a stimulated (10 ng?mL -1 ) human bronchial epithelial cells was investigated.Addition of formoterol (¢10 -10 M) reduced granulocyte macrophage-colony stimulating factor (GM-CSF) levels, as assessed by enzyme-linked immunosorbent assay, by 40 -50% and increased interleukin (IL)-8 levels by y50%. The effects of formoterol were long lasting (23 h). Budesonide (10 -8 M) reduced the amounts of both cytokines (GM-CSF and IL-8) by 40%. Simultaneous addition of formoterol and budesonide reduced GM-CSF levels y75%, while IL-8 levels were decreased y40%, similar to the reduction obtained with budesonide alone. The glucocorticoid receptor (GR) antagonist RU486 did not influence the effect of formoterol, suggesting no involvement of the GR. Formoterol rapidly induced an elevation in intracellular cyclic adenosine monophosphate, which was reduced in the presence of propranolol. In addition, the alterations in cytokine secretion induced by formoterol could be fully blocked by propranolol, demonstrating that these effects are b 2 -receptor mediated.In conclusion, the combination of budesonide and formoterol reduces the secretion of granulocyte macrophage-colony stimulating factor to basal levels and counteracts the capacity of formoterol alone to induce interleukin-8 production, modulations which may facilitate improved asthma control.

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Section: Discussionmentioning

confidence: 99%

Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells

2001

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“…In guinea-pig models, eosinophil influx into the lungs after challenge was inhibited by formoterol [11,16]. In humans, there is also evidence for direct inhibitory effects on mast cell and eosinophil infiltration in vivo after inhaled formoterol therapy [15]. This could be due, in part, to decreased expression of adhesion molecules by lung fibroblasts, thus contributing to the reduction in asthmatic inflammation.…”

Section: ±10mentioning

confidence: 99%

“…Some in vivo studies in humans show inhibitory effects of formoterol on the late asthmatic response (LAR), but do not show decreased eosinophil numbers in blood and sputum [13,14]. However, WALLIN et al [15] found a reduced number of submucosal eosinophils in patients with more severe airway inflammation after treatment with inhaled formoterol. In guinea-pigs, formoterol inhibits the LAR as well as the eosinophilic influx [16].…”

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confidence: 99%

Budesonide and formoterol inhibit ICAM-1 and VCAM-1 expression of human lung fibroblasts

Spoelstra¹,

Postma²,

Hovenga³

et al. 2000

Eur Respir J

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The glucocorticoid budesonide and the long-acting b 2 -adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated.Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1b, tumour necrosis factor-a (TNF-a), interferon gamma (IFN-c) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA).It was found that both budesonide and formoterol significantly inhibited (p<0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1b (maximal inhibition (median (25±75% percentiles) 50 (48±52) and 61% (42±69), respectively, with budesonide and 55 (50±73) and 86% (64±94), respectively, with formoterol (10 -7 M)), TNF-a (maximal inhibition 49 (46±57) and 57% (44±68), respectively, with budesonide and 44 (40±75) and 62% (52±83) respectively, with formoterol), IFN-c (maximal inhibition 64% (41±67) with budesonide and 39% (29±49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69±92) with budesonide and 43% (33±67) with formoterol for VCAM-1) in a dose-dependent manner.The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10 -9 M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma. Eur Respir J 2000; 15: 68±74.

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“…A study of formoterol, another long-acting b 2 -agonist, in asthmatics, even demonstrated a reduction in the number of biopsy mast cells [13]. Moreover, addition of inhaled salmeterol to the treatment of asthmatics who continued to show symptoms despite current treatment with inhaled corticosteroids resulted in a reduction in airway tissue eosinophil number compared to using an increased dose of inhaled steroid alone [14].…”

mentioning

confidence: 99%

Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study

Jeffery

Venge²,

Gizycki³

et al. 2002

Eur Respir J

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Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established, the effects of long-acting b 2 -adrenergic receptor agonists on inflammation are the subject of debate. The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy samples of distinct immunophenotype and those expressing the genes for interleukin-4 and -5, regulatory cytokines particularly relevant to asthma.Twenty patients (aged 18-55 yrs) with mild stable asthma were randomised in a three-way crossover study to 6 weeks of treatment with: 1) salmeterol (50 mg b.d.; SM50); 2) fluticasone propionate (250 mg b.d.; FP250), or 3) placebo.Compared with placebo, SM50 significantly reduced the numbers of neutrophils in bronchial biopsy samples and the concentrations of myeloperoxidase and soluble E-selectin in serum, each of which reflect neutrophil involvement. Compared with FP250, SM50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid. Compared with placebo, FP250 significantly reduced the numbers of (CD3z) T-lymphocytes, (CD4z) T-helper cells, (CD45ROz) activated T-helper cells and eosinophils in the biopsy samples; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum. The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM50 compared to both placebo and FP250.In conclusion, a novel antineutrophilic effect of the inhaled long-acting b 2 -adrenergic receptor agonist, salmeterol, in mild asthma is reported.

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The Effects of Regular Inhaled Formoterol, Budesonide, and Placebo on Mucosal Inflammation and Clinical Indices in Mild Asthma

Cited by 111 publications

References 25 publications

Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells

Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells

Budesonide and formoterol inhibit ICAM-1 and VCAM-1 expression of human lung fibroblasts

Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study

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