Abstract
BackgroundLung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models.MethodsMUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models.ResultsMUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone.ConclusionsThese results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.
Highlights
Lung inflammation in Chronic obstructive pulmonary disease (COPD) is poorly controlled by inhaled corticosteroids (ICS)
Triple therapy based on ICS in combination with Long-acting beta agonists (LABA) and Long-acting muscarinic antagonist (LAMA) is indicated in severe COPD at risk of exacerbations [3], the use of ICS is under debate and needs more evidence to adequately select the COPD phenotype that takes advantage of this combination
Mucin 1 cytoplasmic tail (MUC1-cytoplasmic tail (CT)) protein expression was down-regulated in lung tissue from smokers and COPD patients to a 65 and 30% of control respectively (Fig. 1d)
Summary
Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory, progressive and debilitating lung disease. It is a major cause of chronic morbidity, the fourth leading cause of death worldwide and is projected to be the third leading cause of death by 2020 [1]. Milara et al Respiratory Research (2018) 19:226 shown good activity in asthma, they are much less effective in improving lung function and have little or no effect on controlling the underlying chronic inflammation in COPD patients [2]. The loss of corticosteroid anti-inflammatory efficacy is a characteristic feature in COPD patients. The understanding of corticosteroid resistant mechanisms, as biomarkers of therapeutic response, could be of potential value to individualize COPD therapy
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