Hristova Ventzislava A, Watson Alastair, Chaerkady Raghothama, Glover Matthew S, Ackland Jodie, Angerman Bastian, Belfield Graham, Belvisi Maria G, Burke Hannah, Cellura Doriana, Clark Howard W, Etal Damla, Freeman Anna, Heinson Ashley I, Hess Sonja, Hühn Michael, Hall Emily, Mackay Alex, Madsen Jens, McCrae Christopher, Muthas Daniel, Novick Steven, Ostridge Kristoffer, Öberg Lisa, Platt Adam, Postle Anthony D, Spalluto C Mirella, Vaarala Outi, Wang Junmin, Staples Karl J, Wilkinson Tom M A
Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
These authors contributed equally.
ERJ Open Res. 2022 May 15;9(3). doi: 10.1183/23120541.00378-2022. eCollection 2023 May.
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.
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.
Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD controls (log fold change (logFC) -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 controls (logFC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85).
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.
肺表面活性物质对肺的稳态至关重要，因为它可降低表面张力以防止肺泡塌陷，并提供重要的免疫调节和抗病原功能。先前的研究表明慢性阻塞性肺疾病（COPD）中某些个体表面活性物质成分存在失调。我们研究了COPD疾病指标与表面活性物质成分失调之间的关系，以深入了解潜在的疾病机制。
采用质谱法对已戒烟的轻度/中度COPD受试者（n = 26）、已戒烟的健康受试者（n = 20）和从不吸烟的健康受试者（n = 16）的支气管肺泡灌洗蛋白质组和脂质组进行表征。进行血清表面活性蛋白分析。
COPD患者中总磷脂酰胆碱、磷脂酰甘油、磷脂酰肌醇、表面活性蛋白（SP）-B、SP-A和SP-D浓度较低（对数倍变化（logFC）分别为-2.0、-2.2、-1.5、-0.5、-0.7和-0.5（校正p<0.02）），且与肺功能相关。总磷脂酰胆碱、磷脂酰甘油、磷脂酰肌醇、SP-A、SP-B、SP-D、天冬氨酸蛋白酶A和CD44与计算机断层扫描小气道疾病指标（呼气与吸气平均肺密度）呈负相关（r = -0.56、r = -0.58、r = -0.45、r = -0.36、r = -0.44、r = -0.37、r = -0.40和r = -0.39（校正p<0.05））。总磷脂酰胆碱、磷脂酰甘油、磷脂酰肌醇、SP-A、SP-B、SP-D和天冬氨酸蛋白酶A与肺气肿（低衰减区百分比）呈负相关：r分别为-0.55、-0.61、-0.48、-0.51、-0.41、-0.31和-0.34（校正p<0.05）。已知可降解SP-A和SP-D的中性粒细胞弹性蛋白酶在COPD患者中升高（logFC 0.40，校正p = 0.0390），且与SP-A和SP-D呈负相关。COPD患者血清SP-D高于已戒烟的健康志愿者，并可预测COPD状态（曲线下面积为0.85）。
通过多组学方法，我们首次证明COPD中存在整体表面活性物质失调，这与肺气肿相关，为疾病病因或后果的潜在机制提供了新的见解。
