Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis

Abstract

Background Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested. Methods In this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production. Results We demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air–liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk. Conclusions For the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease.

Cryptotanshinone Reverses Corticosteroid Insensitivity by Inhibition of Phosphoinositide-3-Kinase-δ in Chronic Obstructive Pulmonary Disease

“…Corticosteroid resistance is common in patients with COPD, and several studies have shown that both resident cells in lung (alveolar macrophages) and circulating cells (peripheral-blood mononuclear cells) in patients with COPD are not sensitive to corticosteroid. 25 , 26 In this study, we have explored the role of monocytes/macrophages in corticosteroid insensitivity using COPD PBMCs, CSE-exposed human U937 monocytic cells and confirmed the effectiveness of cryptotanshinone in regaining corticosteroid sensitivity in COPD accompanied by inhibiting PI3K/Akt activity and restoring HDAC2 levels in mononuclear cells. This is the first report to show corticosteroid re-sensitizing capability of cryptotanshinone in modulating PI3K/Akt activity and HDAC2 in the context of COPD.…”

Platycodon grandiflorus polysaccharides deeply participate in the anti-chronic bronchitis effects of platycodon grandiflorus decoction, a representative of “the lung and intestine are related”

“…Increased mucus secretion, mucin expression, and inflammatory response in the lungs are indicators of the severity of CB ( Andelid et al, 2021 ). Figure 1C shows that the acidic mucus (red arrow) in the lung tissues of the MC group increased significantly.…”

Salidroside restores glucocorticoid sensitivity in chronic obstructive pulmonary disease by activating Nrf2/HO-1 pathway

“…Second, we should determine whether our findings also exist in pulmonary macrophages and airway epithelial cells. Although PBMC and U937 cells are classical vitro models for studying corticosteroid resistance (41), pulmonary macrophages and airway epithelial cells have irreplaceable physiological characteristics (42,43).…”