Abstract
Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by persistent respiratory symptoms and progressive airflow limitation as a consequence of a chronic inflammatory response. Corticosteroids are the main treatment for COPD patients with a history of exacerbation, in that they attenuate exacerbation and dyspnea, and improve the response to bronchodilators. Nevertheless, despite corticosteroid administration, COPD patients still undergo exacerbation phases. In this context, the aim of this study was to evaluate the activity of Absent in melanoma 2 (AIM2) inflammasome-dependent pathways under corticosteroid treatment during COPD exacerbation. Stable and exacerbated COPD-derived Peripheral Blood Mononuclear Cells (PBMCs) were treated with a well-known anti-inflammatory agent, Dexamethasone (DEX), in the presence or not of Poly (deoxyadenylic-deoxythymidylate) acid (Poly dA:dT), an AIM2 ligand. We found that IL-1α was highly increased when AIM2 was activated from Poly dA:dT in exacerbated, but not in stable, COPD-derived PBMCs. To note, the release of IL-1α after the stimulation of AIM2 in PBMCs obtained from stable (hospitalized) COPD patients was not higher from the basal conditions, though it was still as high as that observed for Poly dA:dT-stimulated PBMCs obtained from exacerbated patients. This effect was associated with a higher expression of AIM2 in pair-matched circulating CD14+ cells obtained from hospitalized patients who passed from the exacerbation to stable status. Because the difference between stable and exacerbated COPD patients relies on the treatment with corticosteroids, exacerbated and stable COPD-derived PBMCs were treated with DEX. Indeed, the release of IL-1α and TGF-β was not altered after DEX treatment. In conclusion, we found that the administration of DEX in vitro on exacerbated COPD-derived PBMCs was not able to revert the detrimental inflammatory mechanism associated with AIM2 activation responsible for the release of IL-1α and the ensuing TGF-β, contributing to the severity of disease.
Highlights
Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease affecting approximately 10% of individuals older than 45 years worldwide (Barnes, 2016)
We found that the administration of Dexamethasone in vitro on exacerbated Chronic obstructive pulmonary disease (COPD)-derived Peripheral Blood Mononuclear Cells (PBMCs) was not able to revert the detrimental inflammatory mechanism associated with Absent in melanoma 2 (AIM2) activation responsible for the release of IL1α and the ensuing TGF-β, contributing to the severity of the disease
During basal conditions the release of IL-1α from PBMCs obtained from stable COPD patients was significantly higher than that released from Poly (deoxyadenylic-deoxythymidylate) acid (Poly dA):dTstimulated exacerbated COPD-derived PBMCs (Figure 1A, red bars vs. black bars)
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease affecting approximately 10% of individuals older than 45 years worldwide (Barnes, 2016). The clinical picture of COPD patients is characterized by chronic bronchitis, emphysema, shortness of breath and increased cough, due to mucus hypersecretion, airway obstruction and tissue remodeling (De Nardo et al, 2014), all symptoms associated with pulmonary chronic inflammation that leads to a progressive and irreversible decline of lung function (Sugimoto et al, 2016). The infiltration of immune cells such as neutrophils, macrophages, CD4+ and CD8+ lymphocytes, B cells, and other inflammatory cells into the small airways contributes to the pathogenesis of COPD through the release of several factors (e.g., cytokines, proteases and growth factors), resulting in tissue injury and airspace enlargement, hallmarks of this pathology (Borchers et al, 2007; Huang et al, 2017; Wang Y. et al, 2018). The majority of patients are resistant to even high doses of inhaled or oral steroids (Barnes, 2013)
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