COPD affects approximately 10% of the global population, with three million annual deaths. About half of COPD cases are linked to smoking, but fewer than 50% of heavy smokers develop the disease. The pharmacoloical treatment of stable COPD relies on inhaled bronchodilators and corticosteroids (ICS). The ICS use benefit in terms of lung function and exacerbation rates to both current and ex-smokers with COPD although the magnitude of the effect is lower in heavy or current smokers compared to light or ex-smokers. Cigarette smoke (CS), rich in free radicals, increases immune cells recruitment in the lungs, particularly alveolar macrophages (AM) [1Lugg S.T., Scott A., Parekh D., Naidu B., Thickett D.R. Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease Thorax 2022 ;  77 : 94-101

Cliquez ici pour aller à la section Références]. Studies show varied results on the production of pro-inflammatory cytokines by AMs in smokers vs. ex- or non-smokers. Moreover, there is also a large variation in the therapeutic response to ICS in COPD patients. The lack of clear data prevents an objective view of the impact of CS on AM activation and their sensitivity to corticosteroids. This study evaluates the inflammatory responses induced by cigarette smoke extracts (CSE) on human lung macrophages in vitro and compares the effect of budesonide (BUD) under conditions exposed to CSE or LPS.

Lung tissues were obtained from 51 patients undergoing surgical resection for lung cancer. Peripheral tissues distant from the tumor were carefully dissected. Lung macrophages (LM) were isolated through cell adhesion from the peripheral tissue supernatant [2Salvator H., Grassin-Delyle S., Brollo M., Couderc L.J., Abrial C., Victoni T., et al. Adiponectin inhibits the production of TNF-α, IL-6 and chemokines by Human Lung Macrophages Front Pharmacol 2021 ;  12 : 718929

Cliquez ici pour aller à la section Références], while parenchymal explants (PE) were prepared by dissecting 50mg fragments from the lung tissues. LM and PE were cultured separately in a warm medium containing cigarette smoke extract (CSE) at concentrations of 1%, 5%, and 7.5% for 24hours. In some experiments, LPS (10ng/mL for LM, 1μg/mL for PE) or TNF-α (10ng/mL) was added to the culture one hour after CSE stimulation. Additionally, in certain conditions, LM or PE stimulated with CSE were pre-incubated with BUD at concentrations of 10⁻¹⁰, 10⁻⁹, and 10⁻⁸M for 30minutes before LPS stimulation. After 24hours, supernatants were collected, and cytokine production (TNF-α, IL-6, CCL2, CCL4, CXCL1, CXCL5, and CXCL8) was measured in the LM and PE supernatants using ELISA.

Our results show that CSE, both with and without stimulation by LPS or TNF-α, modulates the production of pro-inflammatory cytokines such as TNF-α, IL-6, CCL2, CCL4, CXCL1, CXCL5, and CXCL8 in LM. In contrast, these treatments did not have significant effects on cytokine production in the PE model. Additionally, we observed that the maximum release of pro-inflammatory cytokines by LM was higher when treated with both CSE and BUD compared to treatment with LPS and BUD.

This study has enhanced our understanding of the effects of CSE on LM compared to PE. We demonstrated that CSE alters the inflammatory cytokine and chemokine production in LM, as well as their immune response to LPS and TNF-α in the presence of CSE. Moreover, CSE diminishes the anti-inflammatory effects of BUD on LM. In contrast, PE showed only a weak response to CSE at the doses studied and did not exhibit clear signs of corticosteroid resistance.