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

Abstract

RationalePulmonary 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.ObjectivesWe investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights about potential disease mechanisms.MethodsBronchoalveolar 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.ResultsTotal phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and surfactant protein (SP)-B, SP-A and SP-D concentrations were lower, COPDversuscontrols, 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, COPDversuscontrols, log2FC of 0.40 (adj. p-value=0.0390) and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPDversusHV-ES, and predicted COPD status, AUC=0.85.ConclusionsUsing 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.

Evaluation of common protein biomarkers involved in the pathogenesis of respiratory diseases with proteomic methods: A systematic review

“…Finally, 119 studies were selected in this systematic review. Details and related findings of selected papers (age, sex, sample type, type of technique used, statistical analysis, number of increased or decreased proteins, model characteristics, validation test) are shown in supplementary files 20–123 . It listed for COPD, IPF, Asthma, BO, and mustard gas‐exposed victims, respectively.…”

Pulmonary Surfactant: A Mighty Thin Film

“…99−102 Surfactant abnormalities have also been noted with Chronic Obstructive Pulmonary Disease (COPD), a condition involving restricted air flow due to bronchitis (persistent bronchiolar inflammation) and/or to emphysema. 103 Surfactant dysfunction has also been associated with asthma. 104−106 Additionally, environmental factors as well as genetic mutations can impact pulmonary function, for example by inducing endoplasmic reticulum stress.…”

“…It was soon discovered that the large complex hydrophilic surfactant proteins, SP-A and SP-D, were intimately involved with the innate host defense systems responsible for maintaining clean alveolar surfaces by limiting microbial invasion. These collectins are also inherently involved with intra-alveolar surfactant metabolism. ,− Furthermore, while surfactant deficiency is important in RDS and ARDS, the presence of too much surfactant can lead to respiratory dysfunction with pulmonary alveolar proteinosis (PAP), which results from aberrant surfactant metabolism. − Surfactant abnormalities have also been noted with Chronic Obstructive Pulmonary Disease (COPD), a condition involving restricted air flow due to bronchitis (persistent bronchiolar inflammation) and/or to emphysema . Surfactant dysfunction has also been associated with asthma. − Additionally, environmental factors as well as genetic mutations can impact pulmonary function, for example by inducing endoplasmic reticulum stress. − …”

Peptide set test: a peptide-centric strategy to infer differentially expressed proteins

“…Liquid chromatography-mass spectrometry (LC-MS/MS)-based proteomics has proven to be a sensitive and unbiased tool for accelerating the understanding of various diseases, including cancer( Suh et al 2015 , Shu et al 2020 , Chaerkady et al 2021 , Ding et al 2022 , Hristova et al 2023 ). It enables the unraveling of disease mechanisms by revealing alterations in protein expression.…”

“…Technical variability in sample preparation, protein digestion, and instrumental stability can all contribute to the challenges faced by the LC-MS/MS platform, thereby affecting the statistical power of the study ( Piehowski et al 2013 ). Moreover, large inter-subject heterogeneity or subtle yet significant changes within compared cohorts pose additional complications, particularly in clinical settings ( Suh et al 2015 , Chakrabarti et al 2022 , Hristova et al 2023 ). These inherent statistical challenges drive the need for novel computational methods capable of extracting maximum insights from each dataset ( Chandramouli and Qian 2009 , Zhou et al 2012 ).…”