Hristova, Ventzislava A., Watson, Alastair, Chaerkady, Raghothama, Glover, Matthew S., Ackland, Jodie, Angermann, Bastian, Belfield, Graham, Belvisi, Maria, Burke, Hannah, Cellura, Doriana, Clark, Howard W., Etal, Damla, Freeman, Anna, Heinson, Ashley, Hess, S., Hühn, Michael, Hall, Emily, Mackay, Alex, Madsen, Jens, McCrae, Christopher, Muthas, Daniel, Novick, Steven, Ostridge, Kristoffer, Oberg, Lisa, Platt, Adam, Postle, Anthony, Spalluto, Cosma Mirella, Vaarala, Outi, Wang, Junmin, Staples, Karl J. and Wilkinson, Tom MA , (2022) Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD. ERJ Open Research. (In Press)
Abstract
Rationale
Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and anti-pathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD.
Objectives
We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights about 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 and surfactant protein (SP)-B, SP-A and SP-D concentrations were lower, COPD vs. controls, log2 fold change (log2FC)=-2.0, -2.2, -1.5, -0.5, -0.7, -0.5 (adj. p-value<0.02), respectively, and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and SP-A, SP-B, SP-D, NAPSA and CD44 inversely correlated with CT small airways disease measures (E/I MLD), r=-0.56, r=-0.58, r=-0.45, r=-0.36, r=-0.44, r=-0.37, r=-0.40, r=-0.39 (adj. p- value<0.05). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (%LAA): r=-0.55, r=-0.61, r=-0.48,
135 r=-0.51, r=-0.41, r=-0.31, r=-0.34, respectively (adj. p-value<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated, COPD vs. controls, log2FC of 0.40 (adj. p-value=0.0390) and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD vs. HV-ES, and predicted COPD status, AUC=0.85.
Conclusions
Using a multiomics approach we, for the first time, demonstrate global surfactant dysregulation in COPD which was associated with emphysema giving new insights about potential mechanisms underlying the cause or consequence of disease.
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