A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: A randomized, double-blind, parallel-group controlled trial

Laitinen, Lauri A.; Laitinen, Annika; Haahtela, Tari

doi:10.1016/s0091-6749(06)80008-4

Cited by 555 publications

(308 citation statements)

References 20 publications

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“…The overall effectiveness of the algorithm was demonstrated by the fact that symptoms, b 2 -agonist use and AHR continued to improve during budesonide dose-reduction long after maximal improvement had been achieved in lung function. This suggests the possibility that the initial marked improvement in AHR and lung function may have been associated with a reduction in the amount of inflammatory infiltrate [39], but that later improvement in AHR may have been related to reversal of airway wall remodelling [7] which, in the context of substantially reduced inflammation, may not have required such high budesonide doses. On entry into the study, the subjects demonstrated characteristics of moderate or severe persistent asthma, for which the treatment recommended in international guidelines is high-dose inhaled corticosteroids plus long-acting b 2 -agonists, with long-term oral corticosteroids also indicated for more than half of the subjects [1].…”

Section: Discussionmentioning

confidence: 99%

Optimal asthma control, starting with high doses of inhaled budesonide

et al. 2000

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The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines.The study had a parallel-group design and included 61 subjects with poorly controlled asthma, randomized to receive 3,200 mg or 1,600 mg budesonide daily by Turbuhaler1 for 8 weeks (double-blind), then 1,600 mg . day -1 for 8 weeks (single-blind), followed by 14 months of open-label budesonide dose down-titration using a novel algorithm, with a written asthma crisis plan based on electronic peak expiratory flow monitoring. The primary outcome variable for weeks 1±16 was change in airway hyperresponsiveness (AHR), and, for the open-label phase, mean daily budesonide dose.By week 16, there were large changes from baseline in all outcomes, with no significant differences between the 3,200-and 1,600-mg . day -1 starting dose groups (AHR increased by 3.2 versus 3.0 doubling doses, p=0.7; morning peak flow increased by 134 versus 127 L . min -1 , p=0.8). Subjects starting with 3,200 mg . day -1 were 3.8 times more likely to achieve AHR within the normal range, as defined by a provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) of $3.92 mmol by week 16 (p=0.03). During dose titration, there was no significant difference in mean budesonide dose (1,327 versus 1,325 mg . day -1 , p>0.3). Optimal asthma control was achieved in the majority of subjects (at completion/withdrawal: median symptoms 0.0 days . week -1 , b 2 -agonist use 0.2 occasions . day -1 , and PD20 2.4 mmol).In subjects with poorly controlled asthma, a starting dose of 1,600 mg . day -1 budesonide was sufficient to lead to optimal control in most subjects. The high degree of control achieved, compared with previous studies, warrants further investigation. Eur Respir J 2000; 15: 226±235.

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Section: Discussionmentioning

confidence: 99%

Optimal asthma control, starting with high doses of inhaled budesonide

et al. 2000

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Section: -Although Staphylococcus Aureusmentioning

confidence: 99%

“…Moreover, it has been clearly demonstrated that corticosteroids control genes encoding inflammatory cytokines and adhesion molecules in respiratory epithelial cells (3,7,16,26). Fluticasone propionate (FP) attenuates airway epithelial inflammation through its capacity to reduce NF-B deoxyribonucleic binding, activated by Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation (13), but it is not known whether this is also the case for S. aureus.…”

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confidence: 99%

Downregulation by a long-acting β₂-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production

Fragaki

Kileztky²,

Trentesaux³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Although Staphylococcus aureusis a major cause of pulmonary infection, the role played by this bacterium in the induction of inflammation of human airway epithelial cells (HAEC) is poorly understood. In this study, we investigated the inflammatory response of HAEC to S. aureus soluble virulence factors and demonstrate that the combination of a long-acting ␤ 2-adrenergic receptor agonist (salmeterol) with a glucocorticoid (fluticasone propionate) has an anti-inflammatory effect on HAEC. First, we demonstrate increased expression at both the mRNA and protein levels of interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)-␣ following incubation of HAEC in the presence of S. aureus soluble virulence factors and the increase of 1) the free nuclear factor-B (NF-B) and activator protein-1 (AP-1) activities and 2) the phosphorylated (P-) extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2), the P-c-Jun NH 2-terminal kinase (JNK), and the P-isoform-␣ of the NF-B inhibitor (I B␣). Next, when HAEC were preincubated with the combination of salmeterol and fluticasone propionate, the inflammatory response of HAEC was markedly attenuated in that levels of IL-8, IL-6, TNF-␣, NF-B, AP-1, P-ERK1/ERK2, P-JNK, and P-I B␣ decreased significantly. These data emphasize the deleterious effect of S. aureus soluble virulence factors and suggest that the combination of a ␤2-adrenergic receptor agonist with a glucocorticoid may attenuate the associated airway epithelial inflammation. airway inflammation; proinflammatory cytokines; nuclear fator-B and activator protein-1 activation; glucocorticoid; bacterial virulence factors STAPHYLOCOCCUS AUREUS is one of the most common grampositive bacterial pathogens, involved in airway infections, either primary or subsequent to viral diseases (17). S. aureus is also a major cause of hospital-acquired lower respiratory tract infections and is often implicated in early infectious airway disease in cystic fibrosis patients (2, 5, 6, 22). S. aureus expresses several potential virulence factors (VF) that may induce airway epithelial injury, inactivate host defense mechanisms, and impair the epithelial wound/repair process. The increasing emergence of methicillin-resistant S. aureus requires a better understanding of staphylococcal pathogenesis in infectious and inflammatory airway diseases. S. aureus surface proteins such as adhesins and protein A are produced during exponential growth phase, whereas most exoproteins, including toxins, hemolysins, and tissue-degrading enzymes, are secreted during the stationary phase. Alpha-toxin, one of the major soluble VF of S. aureus, is able to induce transient apoptosis followed by the necrosis of human airway epithelial cells (HAEC) (9). We have also recently shown that live S. aureus and more predominantly soluble VF in contact with HAEC induce marked alterations in the transcriptional expression profile of HAEC associated with activation of the NF-B and activator protein (AP)-1 pathway, upregulation of PGE 2 and cyclooxygenase (COX)-2 expression and pr...

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“…Increased numbers of polymorphonuclear cells (mainly eosinophils) and mononuclear cells (mainly lymphocytes) have been identified at autopsy in the airways of patients dying of asthma [1][2][3] and in patients with less severe asthma, by use of bronchoalveolar lavage (BAL) [4][5][6][7] and biopsy of proximal airways [7][8][9][10][11][12][13][14][15]. Immunohistochemical techniques have identified the CD4+ subset of T-lymphocytes in the airways of patients with asthma, and have demonstrated that these lymphocytes and eosinophils express markers of functional activation to a greater extent than those from nonasthmatic subjects [11,12,15,16].…”

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confidence: 99%

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

Carroll

Cooke²,

James³

1997

Eur Respir J

246

163

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Airway inflammation in asthma consists of variably increased numbers of mononuclear and polymorphonuclear cells, and there is a growing body of evidence to suggest a primary role for lymphocytes and eosinophils in the pathogenesis of asthma. The aim of this study was to examine the distribution of lymphocytes and eosinophils in the bronchial tree of cases of mild and severe asthma.In cases of fatal asthma (n=10), nonfatal asthma (sudden nonrespiratory death with a history of asthma n=10), and control cases (sudden death with no history of respiratory illness, n=10), lymphocytes and eosinophils were counted in transverse sections of large and small airways stained with haematoxylin and eosin.Cases of fatal asthma had longstanding severe asthma and nonfatal cases generally had mild asthma. Lymphocytes were increased in all airway size groups both in fatal and nonfatal cases of asthma compared to control cases (p<0.001). Eosinophils were increased (p<0.001) in all airway size groups in the cases of fatal asthma compared to the nonfatal asthma and control groups, which were similar. These differences between case groups were of similar magnitude, when only a random single airway section from each case in each size group was examined. The numbers of lymphocytes correlated with the number of eosinophils in the fatal asthma group (r=0.60; p<0.0001), and to a lesser extent in the nonfatal (r=0.34; p=0.001) and control groups (r=0.32; p=0.001).These findings suggest that increased numbers of lymphocytes are uniformly distributed in the large and small airways in cases of asthma, independently of asthma severity, and that eosinophil recruitment may be related to asthma severity. Hence, biopsy specimens of the proximal airways are likely to be representative of the cellular infiltrate in large and small airways in mild and severe asthma.

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A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: A randomized, double-blind, parallel-group controlled trial

Cited by 555 publications

References 20 publications

Optimal asthma control, starting with high doses of inhaled budesonide

Optimal asthma control, starting with high doses of inhaled budesonide

Downregulation by a long-acting β₂-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

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A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: A randomized, double-blind, parallel-group controlled trial

Cited by 555 publications

References 20 publications

Optimal asthma control, starting with high doses of inhaled budesonide

Optimal asthma control, starting with high doses of inhaled budesonide

Downregulation by a long-acting β2-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

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About

Downregulation by a long-acting β₂-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production