American journal of respiratory and critical care medicine最新文献

Rationale: Ground-glass opacities (GGOs) in the absence of interstitial lung disease are understudied. Objectives: To assess the association of GGOs with white blood cells (WBCs) and progression of quantified chest computed tomography emphysema. Methods: We analyzed data of participants in the SPIROMICS study (Subpopulations and Intermediate Outcome Measures in COPD Study). Chest radiologists and pulmonologists labeled regions of the lung as GGOs, and the adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGOs (%GGO_AMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGO_AMFM with WBCs, changes in percentage emphysema, and clinical outcomes. Measurements and Main Results: Among 2,714 participants, 1,680 had chronic obstructive pulmonary disease (COPD) and 1,034 had normal spirometry. Among participants with COPD, on the basis of multivariable analysis, current smoking and chronic productive cough were associated with higher %GGO_AMFM. Higher %GGO_AMFM was cross-sectionally associated with higher WBC and neutrophil concentrations. Higher %GGO_AMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at 1-year follow-up visit by 11.7% (relative increase; 95% confidence interval, 7.5-16.1%; P < 0.001). We found no association between %GGO_AMFM and 1-year FEV₁ decline, but %GGO_AMFM was associated with exacerbations and all-cause mortality during a median follow-up of 1,544 days (interquartile interval, 1,118-2,059). Among normal spirometry participants, we found similar results, except that %GGO_AMFM was associated with progression to COPD at 1-year follow-up. Conclusions: Our findings suggest that GGO_AMFM is associated with increased systemic inflammation and emphysema progression.

Rationale: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. Objectives: To study IL-13-induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Rα antibody, dupilumab, in vitro. Methods: Quantitative computed tomography of the lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 with severe asthma, 11 with nonsevere asthma, and 18 healthy participants) in SARPIII (Severe Asthma Research Program III) and measured for mucin and cilia-related proteins. Epithelial cells were differentiated at air-liquid interface (ALI) with IL-13 with or without dupilumab and assessed for mucin, cilia, cilia beat frequency (CBF), and epithelial integrity (transepithelial electrical resistance [TEER]). Measurements and Main Results: Increased Muc5AC (mucin 5AC) (Δ + 263.2 ± 92.7 luminosity/epithelial area) and decreased ciliated cells (Δ - 0.07 ± 0.03 Foxj1⁺ cells/epithelial area) were observed in biopsies from patients with severe asthma when compared with healthy control subjects (P < 0.01 and P = 0.047, respectively). RNA sequencing of endobronchial cell brushings confirmed a Muc5AC increase with a decrease in a five-gene cilia-related mean in patients with severe asthma compared with healthy subjects (all P < 0.05). IL-13 (5 ng/ml)-differentiated ALI cultures of healthy and asthmatic samples (from participants with severe and nonsevere asthma) increased Muc5AC, decreased cilia (α-aceytl-tubulin) in samples from healthy participants (Δ + 6.5% ± 1.5%, Δ - 14.1% ± 2.7%; all P < 0.001 respectively) and participants with asthma (Δ + 4.4% ± 2.5%, Δ - 13.1% ± 2.7%; P = 0.084, P < 0.001 respectively), and decreased epithelial integrity (TEER) in samples from healthy participants (-140.9 ± 21.3 [ohms], P < 0.001), while decreasing CBF in samples from participants with asthma (Δ - 4.4 ± 1.7 [Hz], P < 0.01). When dupilumab was added to ALI with IL-13, there was no significant decrease in Mu5AC, but there was restoration of cilia in healthy participants and participants with asthma (absolute increase of 67.5% and 32.5% cilia, all P < 0.05, respectively), whereas CBF increased (Δ + 3.6 ± 1.1 [Hz], P < 0.001) and TEER decreased (only in asthma, Δ - 37.8 ± 16.2 [ohms], P < 0.05). Conclusions: IL-13 drives features of airway remodeling in severe asthma, which are partially reversed by inhibiting the IL-4Rα receptor in vitro.