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Inflammation and cell migration in chronic obstructive pulmonary disease (COPD)

thesis
posted on 2024-09-03, 00:03 authored by Kristin Blidberg

Chronic obstructive pulmonary disease (COPD), the fourth most common cause of death worldwide, is characterised by chronic airflow obstruction and chronic inflammation which affects large and, especially, small airways. There is an accumulation of inflammatory cells in the airways in COPD, in particular neutrophils, macrophages and CD8+ T-cells. Neutrophil numbers correlate with disease severity and neutrophils have been attributed a central pathophysiological role in COPD. The overall aim of this thesis was to elucidate how neutrophil function is altered by the inflammation observed in COPD. Thus, study I, II and IV were all performed on three groups of subjects, healthy non-smoking controls, smokers without COPD and smokers with COPD.

In paper I neutrophil release of CXCL8, MIP-1α and MCP-1 in response to different stimuli were studied. Also the role of TNF-α in regulating these responses was studied by inhibition of endogenous TNF-α with an anti-TNF-α antibody (infliximab). Neutrophil derived TNF-α contributed to the release of these chemokines after stimulation with LPS and organic dust as the response was inhibited by infliximab. In the COPD group infliximab did not inhibit the release of CXCL8 suggesting that the role of TNF-α is somehow altered in COPD.

In paper II chemotaxis towards CXCL8 was increased in smokers with and without COPD and migration towards LTB4 was increased in smokers without COPD compared to healthy controls. In the smoker groups serum TNF-α and migration induced by CXCL8 and LTB4 correlated. Thus chemotaxis of circulating neutrophils towards CXCL8, and partly towards LTB4, is increased in smokers. Hence smoking may cause neutrophil activation and pro- inflammatory stimuli, such as TNF-α, may be central in this activation. The enhanced migration could to some degree explain the increase in neutrophil numbers observed in the COPD lung.

In paper III we studied the influence of a β2-agonist (formoterol) and a glucocorticoid (budesonide) on circulating neutrophils isolated from healthy subjects. Budesonide inhibited and formoterol enhanced LPS-induced release of IL-6, CXCL1 and CXCL8. Moreover, formoterol up-regulated the chemokine receptors CXCR1 and CXCR2, while budesonide up-regulated CXCR2. However, the drugs did not affect the chemotactic response. Thus budesonide and formoterol, which are often used in the treatment of COPD, affect chemokine release and receptor expression, but the functional consequences of these findings are unclear.

In paper IV T-cell and alveolar macrophage (AM) interaction in COPD was examined by investigating if the production of CXCR3 binding chemokines (CXCL9, -10, -11) by AMs is enhanced in COPD. The macrophage product was also assessed for its chemotactic effects on CXCR3 expressing T-cells. No difference in chemokine release by AMs was detected and while the AM supernatant induced migration in CXCR3 expressing T-cells there was no difference between the groups. We thus conclude that the increase of CXCR3 expressing T-cells, which has been observed in the COPD lung, is not caused by the CXCR3 binding chemokines released by AMs.

Taken together these studies show an alteration in different aspects of neutrophil function in smokers with COPD but also in smokers without COPD.

List of scientific papers

I. K Blidberg, L Palmberg, B Dahlén, AS Lantz, K Larsson. Chemokine release by neutrophils in chronic obstructive pulmonary disease. Innate Immunity. 2011 Oct 13.
https://doi.org/10.1177/1753425911423270

II. K Blidberg, L Palmberg, B Dahlén, AS Lantz, K Larsson. Increased Neutrophil Migration in Smokers with and without Chronic Obstructive Pulmonary Disease (COPD). [Manuscript]

III. K Strandberg, K Blidberg, K Sahlander, L Palmberg, K Larsson. Effects on formoterol and budesonide on chemokine release, chemokine receptor expression and chemotaxis in human neutrophils. Pulm Pharmacol Ther. 2010 Aug;23(4):316-23.
https://doi.org/10.1016/j.pupt.2010.03.004

IV. K Blidberg, L Palmberg, AS Lantz, B Billing, B Dahlén, K Larsson. No alteration of production and activity of CXCR3-binding chemokines from alveolar macrophages in smokers with and without COPD. [Manuscript]

History

Defence date

2012-02-10

Department

  • Institute of Environmental Medicine

Publisher/Institution

Karolinska Institutet

Main supervisor

Larsson, Kjell

Publication year

2012

Thesis type

  • Doctoral thesis

ISBN

978-91-7457-641-2

Number of supporting papers

4

Language

  • eng

Original publication date

2012-01-20

Author name in thesis

Blidberg, Kristin

Original department name

Institute of Environmental Medicine

Place of publication

Stockholm

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