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

Ventzislava A Hristova; Alastair Watson; Raghothama Chaerkady; Matthew S Glover; Jodie Ackland; Bastian Angerman; Graham Belfield; Maria G Belvisi; Hannah Burke; Doriana Cellura; Howard W Clark; Damla Etal; Anna Freeman; Ashley I Heinson; Sonja Hess; Michael Hühn; Emily Hall; Alex Mackay; Jens Madsen; Christopher McCrae; Daniel Muthas; Steven Novick; Kristoffer Ostridge; Lisa Öberg; Adam Platt; Anthony D Postle; C Mirella Spalluto; Outi Vaarala; Junmin Wang; Karl J Staples; Tom M A Wilkinson; MICA II Study group

doi:10.1183/23120541.00378-2022

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

ERJ Open Res. 2022 May 15;9(3):00378-2022. doi: 10.1183/23120541.00378-2022. eCollection 2023 May.

Authors

Ventzislava A Hristova^{1

2}, Alastair Watson^{3

4

2}, Raghothama Chaerkady¹, Matthew S Glover¹, Jodie Ackland³, Bastian Angerman⁵, Graham Belfield⁶, Maria G Belvisi^{7

8}, Hannah Burke^{3

9}, Doriana Cellura³, Howard W Clark^{10

11}, Damla Etal⁶, Anna Freeman^{3

9}, Ashley I Heinson³, Sonja Hess¹, Michael Hühn⁵, Emily Hall³, Alex Mackay^{5

8}, Jens Madsen³, Christopher McCrae¹², Daniel Muthas⁵, Steven Novick¹³, Kristoffer Ostridge^{3

5}, Lisa Öberg⁵, Adam Platt¹⁴, Anthony D Postle³, C Mirella Spalluto³, Outi Vaarala¹⁵, Junmin Wang¹, Karl J Staples^{3

9}, Tom M A Wilkinson^{3

9}; MICA II Study group

Affiliations

¹ Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
² These authors contributed equally.
³ Faculty of Medicine, University of Southampton, Southampton, UK.
⁴ School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁵ Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁶ Translational Genomics, Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁷ Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁸ NHLI, Imperial College, London, UK.
⁹ NIHR Southampton Biomedical Research Centre, University Hospital, Southampton, UK.
¹⁰ Neonatology, Faculty of Population Health Sciences, EGA Institute for Women's Health, University College London, London, UK.
¹¹ NIHR University College London Hospital Biomedical Research, University College London Hospital, London, UK.
¹² Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, USA.
¹³ Data Sciences and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
¹⁴ Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹⁵ Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Abstract

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.