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Comparative Study
. 2018 Apr 19:13:1279-1288.
doi: 10.2147/COPD.S159936. eCollection 2018.

Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells

Andrew Higham  1   2 , Pradeep Karur  1   2 , Natalie Jackson  2 , Danen M Cunoosamy  3 , Paul Jansson  3 , Dave Singh  1   2
Affiliations
Comparative Study

Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells

Andrew Higham et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Background: The effects of anti-inflammatory drugs in COPD patients may vary between different cell types. The aim of the current study was to assess the anti-inflammatory effects of the corticosteroid budesonide and a p38 MAPK inhibitor (AZD7624) on different cell types obtained from COPD patients and healthy controls.

Methods: Eight healthy smokers, 16 COPD infrequent exacerbators, and 16 frequent COPD exacerbators (≥2 exacerbations in the last year) were recruited for bronchoscopy and blood sampling. The anti-inflammatory effects of budesonide and AZD7624 were assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages and peripheral blood mononuclear cells and polyinosinic:polycytidylic acid-stimulated bronchial epithelial cells.

Results: The anti-inflammatory effects of budesonide varied greatly within a patient according to the cell type studied. Bronchial epithelial cells showed the lowest sensitivity to budesonide, while peripheral blood mononuclear cells showed the greatest sensitivity. AZD7624 had a greater effect than budesonide on cytokine production from bronchial epithelial cells. Exacerbation frequency did not influence corticosteroid sensitivity.

Conclusion: We observed variable corticosteroid and p38 MAPK inhibitor anti-inflammatory responses within the same individual depending on the cell type studied. These findings support the use of multiple anti-inflammatory strategies in COPD patients due to differences between cell types.

Keywords: PBMC; corticosteroid; epithelial cell; exacerbation; inflammation; macrophage.

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Conflict of interest statement

Disclosure DMC and PJ are employees of AstraZeneca, which funded the study. DS has received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards, and research grants from various pharmaceutical companies including Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skypharma, Takeda, Teva, Therevance, and Verona. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Group mean budesonide and AZD7624 concentration curves in PBMCs. Notes: The group mean data for inhibition of TNF-α (A and D), IL-6 (B and E), and IL-10 (C and F) by budesonide (A–C) and AZD7624 (D–F) are shown for HS (orange plot), COPD IFE (green plot), and COPD FE (blue plot). Data shown are mean ± SEM. Abbreviations: COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; HS, healthy smokers; IL, interleukin; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; SEM, standard error of the mean; TNF-α, tumor necrosis factor-α.
Figure 2
Figure 2
Group mean budesonide and AZD7624 concentration curves in alveolar macrophages. Notes: The group mean data for inhibition of TNF-α (A and D), IL-6 (B and E), and IL-10 (C and F) by budesonide (A–C) and AZD7624 (D–F) are shown for HS (orange plot), COPD IFE (green plot), and COPD FE (blue plot). Data shown are mean ± SEM. *, ** = significant difference between HS and COPD FE where p<0.05 and p<0.01 respectively. ^ = significant difference between HS and COPD IFE where p<0.05. ¶¶, ¶¶¶ = significant difference between COPD IFE and COPD FE where p<0.01 and p<0.001, respectively. Abbreviations: COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; HS, healthy smokers; IL, interleukin; LPS, lipopolysaccharide; SEM, standard error of the mean; TNF-α, tumor necrosis factor-α.
Figure 3
Figure 3
Individual budesonide concentration curves in alveolar macrophages. Notes: The individual concentration curves for budesonide inhibition of TNF-α (A–C), IL-6 (D–F), and IL-10 (G–I) by budesonide are shown for HS (A, D, and G), COPD IFE (B, E, and H), and COPD FE (C, F and I). Abbreviations: COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; HS, healthy smokers; IL, interleukin; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α.
Figure 4
Figure 4
Correlations of budesonide cytokine inhibition. Notes: Correlations were made between budesonide inhibition of TNF-α (A), IL-6 (B), and IL-10 (C) release from PBMCs and alveolar macrophages. Data shown are individual data points where R2 represents the coefficient of determination. Abbreviations: IL, interleukin; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α.
Figure 5
Figure 5
Group mean budesonide and AZD7624 concentration curves in BECs. Notes: The group mean data for inhibition of IL-6 (A and C) and CXCL10 (B and D) by budesonide (A–B) and AZD7624 (C–D) are shown for COPD IFE (green plot) and COPD FE (blue plot). Data shown are mean ± SEM. Abbreviations: BEC, bronchial epithelial cell; COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; CXCL10, C-X-C motif ligand 10; IL, interleukin; SEM, standard error of the mean.
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