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. 2010 Jun 7;11(1):71.
doi: 10.1186/1465-9921-11-71.

Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma

Pankaj K Bhavsar  1 , Bruce D Levy, Mark J Hew, Michael A Pfeffer, Shamsah Kazani, Elliot Israel, Kian Fan Chung
Affiliations

Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma

Pankaj K Bhavsar et al. Respir Res. .

Abstract

Background: An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.

Methods: AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 microg/ml) with or without dexamethasone (10(-6)M). LTB4 and LXA4 were measured by enzyme immunoassay.

Results: LXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (r(s) = 0.60; p < 0.01).

Conclusions: Decreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma.

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Figures

Figure 1
Figure 1
Panel A: Individual levels of LXA4 in supernatants of alveolar macrophages before and after lipopolysaccharide (LPS) from normal subjects (n = 14), non-severe asthmatics (n = 12) and severe asthmatics (n = 11). In the asthmatic groups, closed symbols indicate those on regular treatment with inhaled and/or oral corticosteroids. Panel B: Mean levels of LXA4 induced by LPS (level after LPS minus basal level) in the 3 groups. Data shown as mean ± SEM.
Figure 2
Figure 2
Panel A: Individual levels of LTB4 in supernatants of alveolar macrophages before and after lipopolysaccharide (LPS) from normal subjects (n = 9), non-severe asthmatics (n = 9) and severe asthmatics (n = 8). In the asthmatic groups, closed symbols indicate those on regular treatment with inhaled and/or oral corticosteroids. Panel B: Mean levels of LPS-stimulated LTB4 represented by the difference between LTB4 levels with LPS and the basal level of LTB4 in the 3 groups. Data shown as mean ± SEM.
Figure 3
Figure 3
Individual levels of LXA4 measured after LPS in the absence or presence of dexamethasone (10-6 M) from alveolar macrophages stimulated by LPS from normal subjects (n = 14), non-severe asthmatics (n = 12) and severe asthmatics (n = 11). In the asthmatic groups, closed symbols indicate those on regular treatment with inhaled and/or oral corticosteroids. Data shown as mean ± SEM.
Figure 4
Figure 4
Individual levels of LTB4 measured after LPS in the absence or presence of dexamethasone (10-6 M) from alveolar macrophages stimulated by LPS in normal subjects (n = 9), non-severe asthmatics (n = 9) and severe asthmatics (n = 8). In the asthmatic groups, closed symbols indicate those on regular treatment with inhaled and/or oral corticosteroids. Data shown as mean ± SEM. Panel C. Mean degree of suppressibility of LXA4 and LTB4 release by dexamethasone. Data is expressed as % of LXA4 or LTB4 release after exposure to LPS (level after LPS minus basal level) and shown as mean ± SEM.
Figure 5
Figure 5
Effect of LPS (Stim) and LPS plus dexamethasone (LPS/Dex) on the ratio of LTB4 to LXA4 from alveolar macrophages. In both asthmatic groups, the ratio of released LTB4 to released LXA4 is increased after LPS and this is not reversed in the presence of dexamethasone. *p < 0.05 compared to baseline (base) within each group; +p < 0.01 compared to LPS/Dex of normal subjects. Data shown as shown as mean ± SEM.
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