Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

RATIONALE: Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and antipathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD. We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights into potential disease mechanisms. METHODS: Bronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed. RESULTS: Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD versus controls (log2 fold change (log2FC) -2.0, -2.2, -1.5, -0.5, -0.7 and -0.5 (adjusted p<0.02), respectively) and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D, napsin A and CD44 inversely correlated with computed tomography small airways disease measures (expiratory to inspiratory mean lung density) (r= -0.56, r= -0.58, r= -0.45, r= -0.36, r= -0.44, r= -0.37, r= -0.40 and r= -0.39 (adjusted p<0.05)). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (% low-attenuation areas): r= -0.55, r= -0.61, r= -0.48, r= -0.51, r= -0.41, r= -0.31 and r= -0.34, respectively (adjusted p<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated in COPD versus controls (log2FC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD versus healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85). CONCLUSIONS: Using a multiomics approach, we demonstrate, for the first time, global surfactant dysregulation in COPD that was associated with emphysema, giving new insights into potential mechanisms underlying the cause or consequence of disease

NTHi killing activity is reduced in COPD patients and is associated with a differential microbiome

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to NTHi killing activity. Mild-to-moderate COPD patients encompassing frequent and infrequent exacerbators and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). In addition, antigen-antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of COPD and HV subjects respectively. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects (OR = 5.64; 95% CI = 1.75-20.20; p = 0.001). Stratification of COPD patients by NTHi killing activity identified unique microbial and protein signatures wherein Firmicutes, Actinobacteria and haptoglobin were enriched in patients with killing activity. We report that differences in host immune responses and NTHi-killing activity are associated with microbiome changes in mild-to-moderate COPD. This is suggestive of a potential link between the respiratory microbiome and immune activity against NTHi in the context of COPD pathogenesis even at this disease stage.</p

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD.

RATIONALE: Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and antipathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD. We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights into potential disease mechanisms. METHODS: Bronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed. RESULTS: Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD versus controls (log2 fold change (log2FC) -2.0, -2.2, -1.5, -0.5, -0.7 and -0.5 (adjusted p<0.02), respectively) and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D, napsin A and CD44 inversely correlated with computed tomography small airways disease measures (expiratory to inspiratory mean lung density) (r= -0.56, r= -0.58, r= -0.45, r= -0.36, r= -0.44, r= -0.37, r= -0.40 and r= -0.39 (adjusted p<0.05)). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (% low-attenuation areas): r= -0.55, r= -0.61, r= -0.48, r= -0.51, r= -0.41, r= -0.31 and r= -0.34, respectively (adjusted p<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated in COPD versus controls (log2FC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD versus healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85). CONCLUSIONS: Using a multiomics approach, we demonstrate, for the first time, global surfactant dysregulation in COPD that was associated with emphysema, giving new insights into potential mechanisms underlying the cause or consequence of disease

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

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