Ventilator-induced diaphragm dysfunction in critical                     illness

Mechanical ventilation is an essential intervention for intensive care unit patients with acute lung injury. However, the use of controlled mechanical ventilation in both animal and human models causes ventilator-induced diaphragm dysfunction, wherein a substantial reduction in diaphragmatic force-generating capacity occurs, along with structural injury and atrophy of diaphragm muscle fibers. Although diaphragm dysfunction, noted in most mechanically ventilated patients, is correlated with poor clinical outcome, the specific pathophysiology underlying ventilator-induced diaphragm dysfunction requires further elucidation. Numerous factors may underlie this condition in humans as well as animals, such as increased oxidative stress, calcium-activated calpain and caspase-3, the ubiquitin–proteasome system, autophagy–lysosomal pathway, and proapoptotic proteins. All these alter protein synthesis and degradation, thus resulting in muscle atrophy and impaired contractility and compromising oxidative phosphorylation and upregulating glycolysis associated with impaired mitochondrial function. Furthermore, infection combined with mechanical stretch may induce multisystem organ failure and render the diaphragm more sensitive to ventilator-induced diaphragm dysfunction. Herein, several major cellular mechanisms associated with autophagy, apoptosis, and mitochondrial biogenesis—including toll-like receptor 4, nuclear factor-κB, Src, class O of forkhead box, signal transducer and activator of transcription 3, and Janus kinase—are reviewed. In addition, we discuss the potential therapeutic strategies used to ameliorate ventilator-induced diaphragm dysfunction and thus prevent delay in the management of patients under prolonged duration of mechanical ventilation. Impact statement Mechanical ventilation (MV) is life-saving for patients with acute respiratory failure but also causes difficult liberation of patients from ventilator due to rapid decrease of diaphragm muscle endurance and strength, which is termed ventilator-induced diaphragmatic damage (VIDD). Numerous studies have revealed that VIDD could increase extubation failure, ICU stay, ICU mortality, and healthcare expenditures. However, the mechanisms of VIDD, potentially involving a multistep process including muscle atrophy, oxidative loads, structural damage, and muscle fiber remodeling, are not fully elucidated. Further research is necessary to unravel mechanistic framework for understanding the molecular mechanisms underlying VIDD, especially mitochondrial dysfunction and increased mitochondrial oxidative stress, and develop better MV strategies, rehabilitative programs, and pharmacologic agents to translate this knowledge into clinical benefits.

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Diaphragm muscle atrophy in the mouse after long-term mechanical ventilation

Muscle & Nerve ◽

10.1002/mus.23748 ◽

2013 ◽

Vol 48 (2) ◽

pp. 272-278 ◽

Cited By ~ 20

Author(s):

Huibin Tang ◽

Myung Lee ◽

Amanda Khuong ◽

Erika Wright ◽

Joseph B. Shrager

Keyword(s):

Mechanical Ventilation ◽

Muscle Atrophy ◽

Diaphragm Muscle

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Sedation Using Propofol Induces Similar Diaphragm Dysfunction and Atrophy during Spontaneous Breathing and Mechanical Ventilation in Rats

Anesthesiology ◽

10.1097/aln.0000000000000125 ◽

2014 ◽

Vol 120 (3) ◽

pp. 665-672 ◽

Cited By ~ 17

Author(s):

Christian S. Bruells ◽

Karen Maes ◽

Rolf Rossaint ◽

Debby Thomas ◽

Nele Cielen ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Internal Control ◽

Spontaneous Breathing ◽

Antioxidant Properties ◽

Diaphragmatic Dysfunction ◽

Cross Sectional ◽

Diaphragm Dysfunction ◽

Propofol Sedation ◽

Diaphragm Atrophy

Abstract Background: Mechanical ventilation is crucial for patients with respiratory failure. The mechanical takeover of diaphragm function leads to diaphragm dysfunction and atrophy (ventilator-induced diaphragmatic dysfunction), with an increase in oxidative stress as a major contributor. In most patients, a sedative regimen has to be initiated to allow tube tolerance and ventilator synchrony. Clinical data imply a correlation between cumulative propofol dosage and diaphragm dysfunction, whereas laboratory investigations have revealed that propofol has some antioxidant properties. The authors hypothesized that propofol reduces markers of oxidative stress, atrophy, and contractile dysfunction in the diaphragm. Methods: Male Wistar rats (n = 8 per group) were subjected to either 24 h of mechanical ventilation or were undergone breathing spontaneously for 24 h under propofol sedation to test for drug effects. Another acutely sacrificed group served as controls. After sacrifice, diaphragm tissue was removed, and contractile properties, cross-sectional areas, oxidative stress, and proteolysis were examined. The gastrocnemius served as internal control. Results: Propofol did not protect against diaphragm atrophy, oxidative stress, and protease activation. The decrease in tetanic force compared with controls was similar in the spontaneous breathing group (31%) and in the ventilated group (34%), and both groups showed the same amount of muscle atrophy. The gastrocnemius muscle fibers did not show atrophy. Conclusions: Propofol does not protect against ventilator-induced diaphragmatic dysfunction or oxidative injury. Notably, spontaneous breathing under propofol sedation resulted in the same amount of diaphragm atrophy and dysfunction although diaphragm activation per se protects against ventilator-induced diaphragmatic dysfunction. This makes a drug effect of propofol likely.

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Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4805493 ◽

2018 ◽

Vol 2018 ◽

pp. 1-19 ◽

Cited By ~ 4

Author(s):

Andrew J. O’Leary ◽

Sarah E. Drummond ◽

Deirdre Edge ◽

Ken D. O’Halloran

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Muscle Weakness ◽

Contractile Function ◽

Acute Hypoxia ◽

Oxygen Deficit ◽

Diaphragm Muscle ◽

Hypoxic Stress ◽

Diaphragm Dysfunction ◽

Acetyl Cysteine

Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2 = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1α protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy.

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Knockdown of metallothionein 1 and 2 does not affect atrophy or oxidant activity in a novel in vitro model

Journal of Applied Physiology ◽

10.1152/japplphysiol.00588.2010 ◽

2010 ◽

Vol 109 (5) ◽

pp. 1515-1523 ◽

Cited By ~ 4

Author(s):

Robert D. Hyldahl ◽

Kevin S. O'Fallon ◽

Lawrence M. Schwartz ◽

Priscilla M. Clarkson

Keyword(s):

Oxidative Stress ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Antioxidant Properties ◽

Muscle Size ◽

Skeletal Muscle Atrophy ◽

Vitro Model ◽

Serum Reduction ◽

And Function

Skeletal muscle atrophy is a significant health problem that results in decreased muscle size and function and has been associated with increases in oxidative stress. The molecular mechanisms that regulate muscle atrophy, however, are largely unknown. The metallothioneins (MT), a family of genes with antioxidant properties, have been found to be consistently upregulated during muscle atrophy, although their function during muscle atrophy is unknown. Therefore, we hypothesized that MT knockdown would result in greater oxidative stress and an enhanced atrophy response in C2C12 myotubes subjected to serum reduction (SR), a novel atrophy-inducing stimulus. Forty-eight hours before SR, myotubes were transfected with small interfering RNA (siRNA) sequences designed to decrease MT expression. Muscle atrophy and oxidative stress were then measured at baseline and for 72 h following SR. Muscle atrophy was quantified by immunocytochemistry and myotube diameter measurements. Oxidative stress was measured using the fluorescent probe 5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein. SR resulted in a significant increase in oxidative stress and a decrease in myotube size and protein content. However, there were no differences observed in the extent of muscle atrophy or oxidant activity following MT knockdown. We therefore conclude that the novel SR model results in a strong atrophy response and an increase in oxidant activity in cultured myotubes and that knockdown of MT does not affect that response.

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The Extract of Sonneratia apetala Leaves and Branches Ameliorates Hyperuricemia in Mice by Regulating Renal Uric Acid Transporters and Suppressing the Activation of the JAK/STAT Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.698219 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu-Lin Wu ◽

Jin-Fen Chen ◽

Lin-Yun Jiang ◽

Xiao-Li Wu ◽

Yu-Hong Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Uric Acid ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Organic Anion ◽

Janus Kinase ◽

Vehicle Group ◽

Cytokine Signaling ◽

Sonneratia Apetala ◽

Stat Signaling

Sonneratia apetala Buch-Ham., an exotic mangrove species with antidiabetic, antibacterial, and antioxidant capacities, mainly distributes in the southeast coastal areas in China. The present work investigated the protective effects of Sonneratia apetala leaves and branches extraction (SAL) on hyperuricemia (HUA) in mice. Potassium oxonate (PO) and hypoxanthine (HX) were used to establish the HUA model by challenge for consecutive 7 days. Results revealed that SAL inhibited the increases in kidney weight and index compared to the vehicle group. Meanwhile, SAL significantly decreased the levels of uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) in serum. Additionally, SAL inhibited the activity of xanthine oxidase (XOD) in the liver. SAL ameliorated PO- and HX-induced histopathological changes. Moreover, it regulated oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content. Also, SAL inhibited the increases in renal levels of interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), and transforming growth factor-β (TGF-β). SAL remarkably reduced suppressor of cytokine signaling 3 (SOCS3), Janus kinase 2 (JAK2), and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) expression. In addition, SAL inhibited the activation of nuclear factor kappa-B (NF-κB) in the kidney. Furthermore, SAL protected against HUA by regulating renal UA transporters of organic anion transporter (OAT1), urate reabsorption transporter 1 (URAT1), and glucose transporter 9 (GLUT9). These findings suggested that SAL ameliorated HUA by inhibiting the production of uric acid and enhancing renal urate excretion, which are related to oxidative stress and inflammation, and the possible molecular mechanisms include its ability to inhibit the JAK/STAT signaling pathway. Thus, SAL might be developed into a promising agent for HUA treatments.

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AT1 receptor blocker attenuates mechanical ventilation‐induced atrophy and oxidative stress in the diaphragm muscle (1102.39)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.1102.39 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Oh‐Sung Kwon ◽

Ashley Smuder ◽

Kurt Sollanek ◽

Michael Wiggs ◽

Erin Talbert ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

At1 Receptor ◽

Diaphragm Muscle ◽

Receptor Blocker ◽

At1 Receptor Blocker ◽

And Oxidative Stress

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Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation‐induced diaphragm dysfunction

The FASEB Journal ◽

10.1096/fj.13-244210 ◽

2014 ◽

Vol 28 (7) ◽

pp. 2790-2803 ◽

Cited By ~ 29

Author(s):

Ira J. Smith ◽

Guillermo L. Godinez ◽

Baljit K. Singh ◽

Kelly M. McCaughey ◽

Raniel R. Alcantara ◽

...

Keyword(s):

Mechanical Ventilation ◽

Janus Kinase ◽

Kinase Signaling ◽

Diaphragm Dysfunction ◽

Controlled Mechanical Ventilation

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Elevated Levels of Apelin-36 in Heart Failure Due to Chronic Systemic Hypoxia

International Journal of Angiology ◽

10.1055/s-0038-1676340 ◽

2018 ◽

Vol 28 (03) ◽

pp. 194-199

Author(s):

Frans Ferdinal ◽

David Limanan ◽

Retno Dwi Rini ◽

Rio Alexsandro ◽

Rizal Helmi

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Structural Damage ◽

Molecular Mechanisms ◽

Ventricular Remodeling ◽

Biological Effects ◽

Orphan Receptor ◽

Control Group ◽

Sprague Dawley ◽

Systemic Hypoxia

AbstractApelin is a novel adipokine identified as an endogenous ligand of the specific orphan receptor APJ. Among the various isoforms of apelin, an increase in the apelin-36 plasma level has been associated with oxidative stress, and this isoform has various biological effects, such as positive inotropic, vasodilatory, and antiatherosclerotic effects. Therefore, apelin-36 may be used as a biomarker of heart failure (HF). Advances in the understanding of the molecular mechanisms underlying HF cannot be achieved without the use of animal models. However, it is unclear whether chronic systemic hypoxia can cause HF in rats. The present study aimed to determine whether chronic systemic hypoxia can cause HF in rats and whether apelin-36 can be used as a biomarker of HF. The study included Sprague–Dawley rats. The rats were randomly divided into seven groups (n = 4). One of the groups was a control group, and the six other groups were exposed to hypoxia (8% O2) for different durations (6 hours, 1 day, 3 days, 5 days, 7 days, and 14 days). The exposure groups showed ventricular hypertrophy accompanied by myocardial structural damage, which indicated ventricular remodeling. In addition, the exposure groups showed elevated apelin-36 plasma levels and signs of oxidative stress. Moreover, gel electrophoresis of heart tissue showed five bands that corresponded to apelin isotypes, including apelin-36. In an experimental rat HF model with chronic systemic hypoxia, apelin-36 was elevated along with oxidative stress. Apelin-36 along with oxidative stress may serve as a biomarker of HF in this model.

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