Effect of an Inhaled Corticosteroid on Airway Inflammation and Symptoms in Asthma

Djukanović, Ratko; Wilson, John W.; Britten, Karen M.; Wilson, Susan J.; Walls, Andrew F.; Roche, William R.; Howarth, Peter H.; Holgate, Stephen T.

doi:10.1164/ajrccm/145.3.669

Cited by 625 publications

(320 citation statements)

References 14 publications

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“…Glucocorticoids such as budesonide are currently the most effective agents available to treat asthmatic airway inflammation. These compounds reduce the number of T cells (66,67) and the number of cells expressing mRNA for IL-4 and IL-5 (68,69) in asthmatic airways. Much of their protective activity can be explained by their suppressive effects against the processing of genes for key proinflammatory cytokines such as IL-4 and IL-5 by T cells (70).…”

Section: Discussionmentioning

confidence: 99%

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

Haddad¹,

Underwood²,

Dabrowski

et al. 2002

The Journal of Immunology

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Intratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4+ T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the αβ-TCR caused 54% depletion of total (CD2+) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.

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Section: Discussionmentioning

confidence: 99%

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

Haddad¹,

Underwood²,

Dabrowski

et al. 2002

The Journal of Immunology

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“…Anti-inflammatory glucocorticoid therapy reduces IL-5 expression and suppresses airway eosinophilia in asthma (34,52). Thus, priming of eosinophils with cytokines such as IL-5 and the increase in cysLTs production in the airways of asthmatics may contribute to eosinophil influx and activation.…”

Section: Discussionmentioning

confidence: 99%

IL-5 Up-Regulates Cysteinyl Leukotriene 1 Receptor Expression in HL-60 Cells Differentiated into Eosinophils

Thivierge

Doty

Johnson

et al. 2000

The Journal of Immunology

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The cysteinyl leukotrienes, leukotriene (LT) C4, LTD4, and LTE4, are lipid mediators that have been implicated in the pathogenesis of several inflammatory processes, including asthma. The human LTD4 receptor, CysLT1R, was recently cloned and characterized. We had previously shown that HL-60 cells differentiated toward the eosinophilic lineage (HL-60/eos) developed specific functional LTD4 receptors. The present work was undertaken to study the potential modulation of CysLT1R expression in HL-60/eos by IL-5, an important regulator of eosinophil function. Here, we report that IL-5 rapidly up-regulates CysLT1R mRNA expression, with consequently enhanced CysLT1R protein expression and function in HL-60/eos. CysLT1R mRNA expression was augmented 2- to 15-fold following treatment with IL-5 (1–20 ng/ml). The effect was seen after 2 h, was maximal by 4 h, and maintained at 8 h. Although CysLT1R mRNA was constitutively expressed in undifferentiated HL-60 cells, its expression was not modulated by IL-5 in the absence of differentiation. Differentiated HL-60/eos cells pretreated with IL-5 (10 ng/ml) for 24 h showed enhanced CysLT1R expression on the cell surface, as assessed by flow cytometry using a polyclonal anti-CysLT1R Ab. They also showed enhanced responsiveness to LTD4, but not to LTB4 or platelet-activating factor, in terms of Ca2+ mobilization, and augmented the chemotactic response to LTD4. Our findings suggest a possible mechanism by which IL-5 can modulate eosinophil functions and particularly their responsiveness to LTD4, and thus contribute to the pathogenesis of asthma and allergic diseases.

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“…It has been proposed that fluticasone propionate nasal spray may act by preventing the activation of these cells and the subsequent release of (chemotactic) inflammatory mediators and further influx of cells. Several in vitro studies have shown that corticosteroids inhibit T cell proliferation and cytokine production (Culpepper and Lee, 1985), decrease the number of cells expressing interleukin-4 and interleukin-5 mRNA in vivo (Robinson et al, 1993) and decrease the number and activation of mast cells and eosinophils in bronchial biopsies and lavages (Djukanovic et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-5 and eosinophil cationic protein in nasal lavages of rhinitis patients

Garrelds

Veld

Nahori

et al. 1995

European Journal of Pharmacology

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The production of interleukin-5 and eosinophil cationic protein (ECP) in the nasal cavity was examined in 24 patients with rhinitis who were allergic to the house dust mite. During a double-blind placebo-controlled cross-over study, fluticasone propionate aqueous nasal spray (200 tzg) was administered twice daily for 2 weeks. After four basal nasal lavages provocation with house dust mite extract was performed and nasal lavages were collected every hour for 9.5 h. Interleukin-5 was present in detectable amounts in nasal lavages from patients allergic to house dust mite. Nasal challenge with house dust mite extract caused immediate nasal symptoms and increased levels of interleukin-5. Between 3.5 and 8.5 h after the challenge symptoms recurred and interleukin-5 levels increased, reflecting a late phase reaction. Eosinophil cationic protein, a marker of activated eosinophils, was released between 6.5 and 9.5 h after challenge. Treatment with fluticasone propionate (as an aqueous nasal spray) significantly decreased the evoked interleukin-5 and ECP levels in the late phase reaction. This response was correlated with an improved symptom score. This could indicate that the number and activity of eosinophils are increased during the late phase allergic reaction, a response that is inhibited by corticosteroids.

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Effect of an Inhaled Corticosteroid on Airway Inflammation and Symptoms in Asthma

Cited by 625 publications

References 14 publications

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

IL-5 Up-Regulates Cysteinyl Leukotriene 1 Receptor Expression in HL-60 Cells Differentiated into Eosinophils

Interleukin-5 and eosinophil cationic protein in nasal lavages of rhinitis patients

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