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Effects of glucocorticoids or beta 2-agonists on inflammatory responses induced by organic dust in vitro and in vivo

thesis
posted on 2024-09-03, 00:09 authored by Alexandra Ek

Exposure of healthy subjects in a swine barn causes an acute inflammatory response in the airways and an increase in bronchial responsiveness to methacholine. The aim of this thesis was to study the mechanisms by which glucocorticoids or Beta2-agonists interfere with the inflammatory response following swine house dust-exposure both in vitro and in vivo.

In the first study, the effect of fluticasone or budesonide on cytokine response in swine house dust-stimulatedA549 lung epithelial cells (IL-6 and IL-8) and in LPSstimulated human alveolar macrophages (IL-6, IIL-8 and TNF-alpha was evaluated. The glucocorticoids caused a dose-response inhibition of the cytokines and potent effects were found at concentrations that are likely to be found in the airways during inhalation therapy. Furthermore, the onset of the cytokine suppression by glucocorticoids in vitro was rapid.

In the second study, the involvement of NF-kappaB on swine house dust-mediated IL6 and IL-8 release from A549 lung epithelial cells and the influence of glucocorticoids was evaluated. By interfering with the NF-kappaB pathway at different levels, it was demonstrated that swine dust stimulation activated NF-kappaB and cytokine release. In addition, it was shown that the glucocorticoid-mediated cytokine inhibition might, in part, be explained by inhibition of NF-kappaB activation.

In the third study, the effect of treatment with fluticasone (inhalation and intranasally) on the upper airway inflammatory response, the systemic response and the increased bronchial responsiveness to methacholine induced in healthy subjects following exposure in a swine barn, was evaluated. Intranasal fluticasone attenuated plasma leakage, assessed as albumin concentrations, and cytokine concentrations in nasal lavage fluid (IL-8 and TNF-alpha). Fluticasone treatment also attenuated serum IL6 levels and body temperature increases but not the increased bronchial responsiveness following exposure.

In the fourth study, the effect of inhaled fluticasone or salmeterol on the lower airway inflammatory response induced in healthy individuals following exposure in a swine barn was evaluated. There were no effects of fluticasone or salmeterol treatment on the increase in cell concentration and cytokine release in bronchoalveolar lavage fluid following exposure. Additionally, exposure reduced the capability of alveolar macrophages to release cytokines ex vivo and pre-exposure treatment did not affect this capability.

Last, the effect of the long-acting beta2-agonist salmeterol, on the increased bronchial responsiveness to methacholine, induced in healthy subjects exposed in a swine barn, was investigated. Salmeterol inhalation did not alter the increased responsiveness to methacholine following exposure, neither when inhaled regularly during two weeks prior to exposure nor when administered as a single dose prior to exposure. However, salmeterol inhalation caused a decreased responsiveness in healthy unexposed subjects. This indicates that the lack of protective effect of salmeterol was not due to homologous beta2-adrenoceptor desensitization but rather that exposure may have altered the airway response to beta2-agonists.

In conclusion, glucocorticoids may exert anti-inflammatory effects on the organic dust induced inflammatory response. Glucocorticoid-mediated inhibition of proinflammatory cytokines, through inhibition Of NF-kappaB activation, might be an important mechanism by which these effects are exerted. On the other hand, the glucocorticoid had no effect on the inflammatory response in the lower airways or on the increased bronchial responsiveness following exposure. Salmeterol did neither influence the inflammatory response nor the increased bronchial responsiveness following exposure.

List of scientific papers

I. Ek A, Larsson K, Siljerud S, Palmberg L (1999). Fluticasone and budesonide inhibit cytokine release in human lung epithelial cells and alveolar macrophages. Allergy. 54(7): 691-9.
https://pubmed.ncbi.nlm.nih.gov/10442524

II. Liden J, Ek A, Palmberg L, Okret S, Larsson K (2003). Organic dust activates NF-kappaB in lung epithelial cells. Respir Med. 97(8): 882-92.
https://pubmed.ncbi.nlm.nih.gov/12924514

III. Ek A, Palmberg L, Larsson K (2004). The effect of fluticasone on the airway inflammatory response to organic dust. Eur Respir J. 24: 1-7.

IV. Ek A, Palmberg L, Larsson K (2000). Influence of fluticasone and salmeterol on airway effects of inhaled organic dust;an in vivo and ex vivo study. Clin Exp Immunol. 121(1): 11-6.
https://pubmed.ncbi.nlm.nih.gov/10886233

V. Ek A, Palmberg L, Sundblad BM, Larsson K (2004). Salmeterol has no effect on the increased bronchial responsiveness caused by organic dust. [Submitted]

History

Defence date

2004-10-15

Department

  • Institute of Environmental Medicine

Publication year

2004

Thesis type

  • Doctoral thesis

ISBN-10

91-7045-720-4

Number of supporting papers

5

Language

  • eng

Original publication date

2004-09-24

Author name in thesis

Ek, Alexandra

Original department name

Institute of Enviromental Medicine

Place of publication

Stockholm

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