Multi-omics reveals age-related differences in the diaphragm response to mechanical ventilation: a pilot study.

IF 5.3 2区 医学 Q2 CELL BIOLOGY
Qiong Lyu, Ya Wen, Xiang Zhang, Alex B Addinsall, Nicola Cacciani, Lars Larsson
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引用次数: 0

Abstract

Background: Old age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient.

Methods: Young (7-8 months) and old (28-32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition.

Results: According to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as "IL-17 signaling pathway", along with a higher level of inflammatory factors and cytokine/chemokine in plasma.

Conclusions: The dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.

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多组学揭示了膈肌对机械通气反应的年龄相关性差异:一项试点研究。
背景:在接受长期控制性机械通气(CMV)的 COVID-19 患者中,高龄与死亡率的显著增加有关,并被认为是与病毒感染相关的高炎症反应所致。然而,在没有病毒感染的情况下,我们对与年龄相关的 CMV 反应差异的了解仍然不足:方法:将年轻(7-8 个月)和年老(28-32 个月)的 F344 BN 杂交大鼠置于重症监护室条件下 5 天,即完全固定、机械通气和广泛监测。对膈肌进行转录组学(RNA-Seq)和蛋白质组学(邻近延伸分析)分析,并对血浆进行蛋白质组学分析,以研究暴露于重症监护室条件下的年轻大鼠和老年大鼠之间的分子差异:根据多组学分析,观察到年轻大鼠和年老大鼠的膈肌对 5 天 CMV 和固定的反应存在显著差异。在年轻大鼠中,代谢通路主要因固定而下调(神经肌肉传导的突触后阻断)。另一方面,在老龄大鼠中观察到了剧烈的免疫和炎症反应,即特定相关通路(如 "IL-17 信号通路")的上调,以及血浆中炎症因子和细胞因子/趋化因子水平的升高:结论:COVID-19 导致的高炎症和细胞因子风暴不仅反映了病毒感染,还可能与呼吸机诱发的膈肌功能障碍(VIDD)和长期 CMV 引起的高炎症反应有关。虽然机械通气是 COVID-19 ICU 患者的救生措施,但应谨慎使用 CMV,尤其是在老年患者中,并可考虑使用负压通气等其他呼吸支持手段。
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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