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. 2025 Jun;136(6):e70046.
doi: 10.1111/bcpt.70046.

Differences in the Inflammatory Response and Corticoid Responsiveness of Human Lung Macrophages and Parenchymal Explants Exposed to Cigarette Smoke Extracts

Marion Brollo  1 , Quentin Marquant  1 , Hélène Salvator  1   2   3 , Justine Cohen  4 , Matthieu Glorion  1   5 , Alexis Ferré  6 , Martin Dres  7   8 , Nicolas Roche  9 , Stanislas Grassin-Delyle  1   3   10 , Philippe Devillier  1   3
Affiliations

Differences in the Inflammatory Response and Corticoid Responsiveness of Human Lung Macrophages and Parenchymal Explants Exposed to Cigarette Smoke Extracts

Marion Brollo et al. Basic Clin Pharmacol Toxicol. 2025 Jun.

Abstract

Smoking is the main cause of chronic obstructive pulmonary disease (COPD) and is associated with corticosteroid resistance. Given the paucity of data on human lung preparations, macrophages (LMs), and parenchymal explants (LPEs) were exposed to cigarette smoke extracts (CSE) in the presence or absence of lipopolysaccharide (LPS). Moreover, LMs and LPEs were treated with budesonide prior exposure to CSE or LPS. The levels of cytokines (TNF-α, IL-6) and chemokines (CCL2, CCL4, CXCL1, CXCL5, and CXCL8) in the supernatants were measured using ELISAs. In LMs, exposure to CSE was not associated with significant difference in the production of cytokines and chemokines, with the notable exception of greater CXCL8 production. The results were generally the same for LPEs. CSE exposure did not potentiate the LPS-induced production of the cytokines and chemokines and even tended to reduce this production in LMs and LPEs. Lastly, CSE exposure inhibited budesonide's anti-inflammatory activity in LMs but not in LPEs. This study extends the data on the CSE inflammatory effects and its inhibition of corticosteroid efficacy in human lung preparations. Our findings question the relevance of these preparations with regard to the long-term toxicity of smoking and the corticosteroid resistance observed in smokers and in patients with COPD.

Keywords: chronic obstructive pulmonary disease; cigarette smoke extract; corticosteroid resistance; cytokine; glucocorticoid; lung explant; lung macrophage.

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Conflict of interest statement

Nicolas Roche has given paid lectures and/or done consulting for Boehringer Ingelheim, GlaxoSmithKline, Astra Zeneca, Sanofi, Chiesi, Pfizer, Novartis, Austral, Biosency, Zambon, MSD, and Menarini all unrelated to the present work; Nicolas Roche reports participation in research projects funded by Boehringer‐Ingelheim, Pfizer, and GlaxoSmihLine, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. Nicolas Roche is European Respiratory Society Science Council Chair. Martin Dres reports participation in research projects funded by GlaxoSmihKLine and Fisher & Paykel all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. Philippe Devillier has given paid lectures and/or done consulting for Boehringer Ingelheim, GlaxoSmithKline, Astra Zeneca, Chiesi, and Menarini all unrelated to the present work. The remaining authors report no potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Effects of CSE and CSC on the basal production and LPS‐stimulated production of cytokines by human LMs. The values are quoted as the mean ± SEM of 12–21 independent experiments (for CSE) or 7–11 independent experiments (for CSC).
FIGURE 2
FIGURE 2
Effects of CSE and CSC on the basal production and the LPS‐stimulated production of cytokines by human LPEs. The results are quoted as the mean ± SEM of 15 independent experiments (for CSE) and 7–10 independent experiments (for CSC).
FIGURE 3
FIGURE 3
Effects of budesonide on the production of cytokines by human LMs (left column) and by LPEs (right column) not exposed to LPS or CSE (basal, ⚫) or exposed to LPS (▲) or CSE (■). The results are shown as the mean ± SEM of 7–15 independent experiments. The curves were fitted using nonlinear regression (least‐squares fit).
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