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

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.

Metabolomic Profiling of Respiratory Muscles and Lung in Response to Long-Term Controlled Mechanical Ventilation

“…Long-term CMV has detrimental effects on lung, referred to as the ventilator-induced lung injury (VILI). Based on clinical and experimental studies, we have hypothesized that VILI and the subsequent release of cytokines and chemokines may induce systematic inflammation affecting peripheral organs including respiratory and limb muscles ( Lyu et al, 2021 ; Cacciani et al, 2022 ). This is further supported by current metabolomic alterations related to inflammatory responses in diaphragm, intercostals, and lung tissue.…”

“…According to transcriptomic analyses of the diaphragm in rats exposed to 5-day immobilization and CMV, genes related to energy production like glycolysis, TCA cycle and oxidative phosphorylation were downregulated ( Lyu et al, 2021 ). In the current study, many metabolite alterations confirmed attenuated energy metabolism in respiratory muscles after 5-day immobilization and CMV.…”

“…Identified DMs in each tissue were subject to metabolic pathway enrichment analysis. Enriched pathway with DMs number ≥5 was evaluated by several methods including zscore ( Lyu et al, 2021 ), enrichment value, and metabolite set enrichment analysis (MSEA). Zscore was used to indicate the down-/up-regulated status of the enriched pathway.…”

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study

“…Forty-six (81%) patients underwent a trial of non-invasive ventilation (NIV) before intubation (duration: 15 h; IQR 3-36). Median length of invasive ventilation was 14 days (IQR [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Median DTF at weaning start (or at SBT start) was 28.0 (IQR 21.7-38.9).…”

“…Fever due to viral infection can determine diaphragmatic dysfunction [ 21 ] through a “cytokine storm”, which in turn may contribute to muscle catabolism [ 22 ]. In a cluster analysis of 55 patients undergoing mechanical ventilation, Vivier et al detected a linear correlation between PaCO 2 and DTF [ 23 ].…”