机械通气和肺损伤反应中区域性转录组谱与肺容积的关系。
The association between regional transcriptome profiles and lung volumes in response to mechanical ventilation and lung injury.
机构信息
Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.
Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, VIC, Australia.
出版信息
Respir Res. 2022 Feb 19;23(1):35. doi: 10.1186/s12931-022-01958-2.
BACKGROUND
Lung inhomogeneity plays a pivotal role in the development of ventilator-induced lung injury (VILI), particularly in the context of pre-existing lung injury. The mechanisms that underlie this interaction are poorly understood. We aimed to elucidate the regional transcriptomic response to mechanical ventilation (MV), with or without pre-existing lung injury, and link this to the regional lung volume response to MV.
METHODS
Adult female BALB/c mice were randomly assigned into one of four groups: Saline, MV, lipopolysaccharide (LPS) or LPS/MV. Lung volumes (tidal volume, Vt; end-expiratory volume, EEV) were measured at baseline or after 2 h of ventilation using four-dimensional computed tomography (4DCT). Regional lung tissue samples corresponding to specific imaging regions were analysed for the transcriptome response by RNA-Seq. Bioinformatics analyses were conducted and the regional expression of dysregulated gene clusters was then correlated with the lung volume response.
RESULTS
MV in the absence of pre-existing lung injury was associated with regional variations in tidal stretch. The addition of LPS also caused regional increases in EEV. We identified 345, 141 and 184 region-specific differentially expressed genes in response to MV, LPS and LPS/MV, respectively. Amongst these candidate genes, up-regulation of genes related to immune responses were positively correlated with increased regional tidal stretch in the MV group, while dysregulation of genes associated with endothelial barrier related pathways were associated with increased regional EEV and Vt when MV was combined with LPS. Further protein-protein interaction analysis led to the identification of two protein clusters representing the PI3K/Akt and MEK/ERK signalling hubs which may explain the interaction between MV and LPS exposure.
CONCLUSION
The biological pathways associated with lung volume inhomogeneity during MV, and MV in the presence of pre-existing inflammation, differed. MV related tidal stretch induced up-regulation of immune response genes, while LPS combined with MV disrupted PI3K/Akt and MEK/ERK signalling.
背景
肺不均匀性在呼吸机诱导性肺损伤（VILI）的发展中起着关键作用，尤其是在预先存在的肺损伤的情况下。其潜在机制尚不清楚。我们旨在阐明机械通气（MV）时的区域性转录组反应，无论是否存在预先存在的肺损伤，并将其与 MV 时的区域性肺容积反应联系起来。
方法
成年雌性 BALB/c 小鼠被随机分为四组：盐水、MV、脂多糖（LPS）或 LPS/MV。使用四维计算机断层扫描（4DCT）在基线或通气 2 小时后测量潮气量（Vt）和呼气末容积（EEV）。通过 RNA-Seq 分析对应特定成像区域的区域性肺组织样本的转录组反应。进行生物信息学分析，然后将失调基因簇的区域性表达与肺容积反应相关联。
结果
在没有预先存在的肺损伤的情况下，MV 与潮气量拉伸的区域性变化有关。LPS 的加入也导致 EEV 的区域性增加。我们分别在 MV、LPS 和 LPS/MV 反应中鉴定出 345、141 和 184 个区域特异性差异表达基因。在这些候选基因中，与免疫反应相关的基因上调与 MV 组中区域性潮气量拉伸增加呈正相关，而与内皮屏障相关途径相关的基因失调与 LPS 与 MV 联合时的区域性 EEV 和 Vt 增加相关。进一步的蛋白质-蛋白质相互作用分析导致了两个蛋白质簇的鉴定，代表了 PI3K/Akt 和 MEK/ERK 信号枢纽，这可能解释了 MV 和 LPS 暴露之间的相互作用。
结论
MV 时肺容积不均匀的相关生物学途径，以及存在预先存在炎症时的 MV 不同。MV 相关的潮气量拉伸诱导免疫反应基因的上调，而 LPS 与 MV 联合破坏了 PI3K/Akt 和 MEK/ERK 信号。
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