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

Figures & data

Table 1 Demographics and clinical characteristics of the study population

	Healthy smokers	COPD patients
		Infrequent exacerbators	Frequent exacerbators
Male/female, n	4/4	14/2	10/6
Age	54	62	66
Current/ex-smoker, n	8/0	7/9	7/9
Pack-years	28.7	51.0	37.4
Exacerbations in last year	N/A	0	2.1
ICS (Y/N), n	0	11/5	15/1
BDP equivalent	N/A	1,372	1,514
FEV1 (L)	3.1	1.8	1.4
FEV1 (%)	77	52	48
FVC (L)	4.0	3.9	3.2
FEV1/FVC ratio (%)	78	46	45
Reversibility (%)	13	11	12
GOLD 1/2/3/4, n	N/A	0/13/3/0	0/10/6/0
GOLD A/B/C/D, n	N/A	5/7/0/4	0/2/5/9

Note: Data are presented as mean.

Abbreviations: BDP, beclomethasone dipropionate; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Imitative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; N/A, not applicable.

Table 2 IC₅₀, IC₃₀, and EC₅₀ values calculated from sigmoidal curve fitting of budesonide inhibition in PBMCs

	TNF-α			IL-6			IL-10
	HS	COPD IFE	COPD FE	HS	COPD IFE	COPD FE	HS	COPD IFE	COPD FE
IC50 budesonide (nM)	6.4	4.9	5.6	9.5	10	6.0	N/C	N/C	N/C
IC30 budesonide (nM)	0.2	0.2	0.2	0.6	0.4	0.4	7.6	12	6.3
EC50 budesonide (nM)	1.0	0.9	1.0	1.3	1.0	1.1	1.6	0.8	1.2

Abbreviations: COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; HS, healthy smokers; IL, interleukin; N/C, not calculated as inhibition did not reach 50%; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α.

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 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.

Table 3 IC₅₀, IC₃₀, and EC₅₀ values calculated from sigmoidal curve fitting of budesonide inhibition in alveolar macrophages

	TNF-α			IL-6			IL-10
	HS	COPD IFE	COPD FE	HS	COPD IFE	COPD FE	HS	COPD IFE	COPD FE
IC50 budesonide (nM)	2.4	65	N/C	47	N/C	N/C	0.5	19	17
IC30 budesonide (nM)	0.5	1.3	4.9	4.5	3.5	13	0.2	0.4	0.6
EC50 budesonide (nM)	1.0	1.2	1.0	4.1	1.1	1.7	0.5	0.9	0.8

Abbreviations: COPD FE, COPD frequent exacerbators; COPD IFE, COPD infrequent exacerbators; HS, healthy smokers; IL, interleukin; N/C, not calculated as inhibition did not reach 50%; TNF-α, tumor necrosis factor-α.

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 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 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.