RT Journal Article
SR Electronic
T1 Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD
JF ERJ Open Research
JO erjor
FD European Respiratory Society
SP 00378-2022
DO 10.1183/23120541.00378-2022
A1 Ventzislava A. Hristova
A1 Alastair Watson
A1 Raghothama Chaerkady
A1 Matthew S. Glover
A1 Jodie Ackland
A1 Bastian Angerman
A1 Graham Belfield
A1 Maria G. Belvisi
A1 Hannah Burke
A1 Doriana Cellura
A1 Howard W. Clark
A1 Damla Etal
A1 Anna Freeman
A1 Ashley I Heinson
A1 Sonja Hess
A1 Michael Hühn
A1 Emily Hall
A1 Alex Mackay
A1 Jens Madsen
A1 Christopher McCrae
A1 Daniel Muthas
A1 Steven Novick
A1 Kristoffer Ostridge
A1 Lisa Öberg
A1 Adam Platt
A1 Anthony D. Postle
A1 C. Mirella Spalluto
A1 Outi Vaarala
A1 Junmin Wang
A1 Karl J. Staples
A1 Tom M.A Wilkinson
A1 ,
YR 2022
UL http://openres.ersjournals.com/content/early/2022/10/13/23120541.00378-2022.abstract
AB 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 versus 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, 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 versus 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 versus 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflicts of interest: This project was funded by AstraZeneca. Ventzislava A. Hristova, Raghothama Chaerkady, Matthew S. Glover, Bastian Angermann, Graham Belfield, Maria G. Belvisi, Damla Etal, Sonja Hess, Michael Hühn, Christopher McCrae, Daniel Muthas, Steven Novick, Kristoffer Ostridge, Lisa Öberg, Adam Platt, Junmin Wang, report being employees of AstraZeneca and holding AstraZeneca employee stocks and/or stock options.Conflicts of interest: Alex Mackay reports being an employee of AstraZeneca during the conduct of the study and an employee of Novartis upon submission of this article.Conflicts of interest: Novartis played no role and made no contribution, financial or otherwise, to the work in this manuscript.Conflicts of interest: Outi Vaarala reports being an employee of AstraZeneca from 1.8.2014–3.6.2019 and an employee of OrionPharma from June 10, 2019; during the conduct of this study; and owning AstraZeneca stock.Conflicts of interest: Karl J. Staples reports receiving grants from AstraZeneca within the submitted work.Conflicts of interest: Tom M.A Wilkinson reports grants and personal fees from AstraZeneca, during the conduct of the study; personal fees and other from MMH, grants and personal fees from GSK, personal fees from BI, grants and personal fees from Synairgen, outside the submitted work.Conflicts of interest: Alastair Watson, Jodie Ackland, Hannah Burke, Doriana Cellura, Howard Clark, Anna Freeman, Emily Hall, Ashley I Heinson, Jens Madsen, Anthony D. Postle and C. Mirella Spalluto report having no conflicts of interest.