Oxidative stress is required for mechanical ventilation-induced protease activation in the diaphragm

Prolonged mechanical ventilation (MV) results in diaphragmatic weakness due to fiber atrophy and contractile dysfunction. Recent work reveals that activation of the proteases calpain and caspase-3 is required for MV-induced diaphragmatic atrophy and contractile dysfunction. However, the mechanism(s) responsible for activation of these proteases remains unknown. To address this issue, we tested the hypothesis that oxidative stress is essential for the activation of calpain and caspase-3 in the diaphragm during MV. Cause-and-effect was established by prevention of MV-induced diaphragmatic oxidative stress using the antioxidant Trolox. Treatment of animals with Trolox prevented MV-induced protein oxidation and lipid peroxidation in the diaphragm. Importantly, the Trolox-mediated protection from MV-induced oxidative stress prevented the activation of calpain and caspase-3 in the diaphragm during MV. Furthermore, the avoidance of MV-induced oxidative stress not only averted the activation of these proteases but also rescued the diaphragm from MV-induced diaphragmatic myofiber atrophy and contractile dysfunction. Collectively, these findings support the prediction that oxidative stress is required for MV-induced activation of calpain and caspase-3 in the diaphragm and are consistent with the concept that antioxidant therapy can retard MV-induced diaphragmatic weakness.

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Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction

Journal of Applied Physiology ◽

10.1152/japplphysiol.91106.2008 ◽

2009 ◽

Vol 106 (2) ◽

pp. 385-394 ◽

Cited By ~ 67

Author(s):

Melissa A. Whidden ◽

Joseph M. McClung ◽

Darin J. Falk ◽

Matthew B. Hudson ◽

Ashley J. Smuder ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Xanthine Oxidase ◽

Prolonged Mechanical Ventilation ◽

Oxidative Injury ◽

Contractile Dysfunction ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Oxidant Production ◽

Diaphragmatic Weakness

Respiratory muscle weakness resulting from both diaphragmatic contractile dysfunction and atrophy has been hypothesized to contribute to the weaning difficulties associated with prolonged mechanical ventilation (MV). While it is clear that oxidative injury contributes to MV-induced diaphragmatic weakness, the source(s) of oxidants in the diaphragm during MV remain unknown. These experiments tested the hypothesis that xanthine oxidase (XO) contributes to MV-induced oxidant production in the rat diaphragm and that oxypurinol, a XO inhibitor, would attenuate MV-induced diaphragmatic oxidative stress, contractile dysfunction, and atrophy. Adult female Sprague-Dawley rats were randomly assigned to one of six experimental groups: 1) control, 2) control with oxypurinol, 3) 12 h of MV, 4) 12 h of MV with oxypurinol, 5) 18 h of MV, or 6) 18 h of MV with oxypurinol. XO activity was significantly elevated in the diaphragm after MV, and oxypurinol administration inhibited this activity and provided protection against MV-induced oxidative stress and contractile dysfunction. Specifically, oxypurinol treatment partially attenuated both protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition retarded MV-induced diaphragmatic contractile dysfunction at stimulation frequencies >60 Hz. Collectively, these results suggest that oxidant production by XO contributes to MV-induced oxidative injury and contractile dysfunction in the diaphragm. Nonetheless, the failure of XO inhibition to completely prevent MV-induced diaphragmatic oxidative damage suggests that other sources of oxidant production are active in the diaphragm during prolonged MV.

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Apocynin attenuates diaphragm oxidative stress and protease activation during prolonged mechanical ventilation

Critical Care Medicine ◽

10.1097/ccm.0b013e31819cef63 ◽

2009 ◽

Vol 37 (4) ◽

pp. 1373-1379 ◽

Cited By ~ 61

Author(s):

Joseph M. McClung ◽

Darin Van Gammeren ◽

Melissa A. Whidden ◽

Darin J. Falk ◽

Andreas N. Kavazis ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Prolonged Mechanical Ventilation ◽

Protease Activation

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Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats

Anesthesiology ◽

10.1097/aln.0000000000002837 ◽

2019 ◽

Vol 131 (3) ◽

pp. 605-618 ◽

Cited By ~ 2

Author(s):

Nikolay Moroz ◽

Karen Maes ◽

Jean-Philippe Leduc-Gaudet ◽

Peter Goldberg ◽

Basil J. Petrof ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Quantitative Polymerase Chain Reaction ◽

Male Rats ◽

Contractile Dysfunction ◽

E3 Ligases ◽

Protein Ubiquitination ◽

Pathway Activation ◽

Controlled Mechanical Ventilation ◽

Fiber Atrophy

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Diaphragm dysfunction and atrophy develop during prolonged controlled mechanical ventilation. Fiber atrophy has been attributed to activation of the proteasome and autophagy proteolytic pathways. Oxidative stress activates the proteasome during controlled mechanical ventilation, but it is unclear whether it also activates autophagy. This study investigated whether pretreatment with the antioxidant N-acetylcysteine affects controlled mechanical ventilation–induced diaphragm contractile dysfunction, fiber atrophy, and proteasomal and autophagic pathway activation. The study also explored whether proteolytic pathway activity during controlled mechanical ventilation is mediated by microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes. Methods Three groups of adult male rats were studied (n = 10 per group). The animals in the first group were anesthetized and allowed to spontaneously breathe. Animals in the second group were pretreated with saline before undergoing controlled mechanical ventilation for 24 h. The animals in the third group were pretreated with N-acetylcysteine (150 mg/kg) before undergoing controlled mechanical ventilation for 24 h. Diaphragm contractility and activation of the proteasome and autophagy pathways were measured. Expressions of microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes were measured with quantitative polymerase chain reaction. Results Controlled mechanical ventilation decreased diaphragm twitch force from 428 ± 104 g/cm2 (mean ± SD) to 313 ± 50 g/cm2 and tetanic force from 2,491 ± 411 g/cm2 to 1,618 ± 177 g/cm2. Controlled mechanical ventilation also decreased diaphragm fiber size, increased expression of several autophagy genes, and augmented Atrogin-1, MuRF1, and Nedd4 expressions by 36-, 41-, and 8-fold, respectively. Controlled mechanical ventilation decreased the expressions of six microRNAs (miR-20a, miR-106b, miR-376, miR-101a, miR-204, and miR-93) that regulate autophagy genes. Pretreatment with N-acetylcysteine prevented diaphragm contractile dysfunction, attenuated protein ubiquitination, and downregulated E3 ligase and autophagy gene expression. It also reversed controlled mechanical ventilation–induced microRNA expression decreases. N-Acetylcysteine pretreatment had no affect on fiber atrophy. Conclusions Prolonged controlled mechanical ventilation activates the proteasome and autophagy pathways in the diaphragm through oxidative stress. Pathway activation is accomplished, in part, through inhibition of microRNAs that negatively regulate autophagy-related genes.

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Strawberry Intake Ameliorates Oxidative Stress and Decreases GABA Levels Induced by High-Fat Diet in Frontal Cortex of Rats

Antioxidants ◽

10.3390/antiox8030070 ◽

2019 ◽

Vol 8 (3) ◽

pp. 70 ◽

Cited By ~ 1

Author(s):

Cuauhtémoc Sandoval-Salazar ◽

Cecilia Oviedo-Solís ◽

Edmundo Lozoya-Gloria ◽

Herlinda Aguilar-Zavala ◽

Martha Solís-Ortiz ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Frontal Cortex ◽

Protein Oxidation ◽

High Fat Diet ◽

High Fat ◽

Gaba Concentration ◽

Obese Rats ◽

Lipid And Protein Oxidation

It has been proposed that there is a correlation between high-fat diet (HFD), oxidative stress and decreased γ-aminobutyric acid (GABA) levels, but this has not been thoroughly demonstrated. In the present study, we determined the effects of strawberry extract intake on the oxidative stress and GABA levels in the frontal cortex (FC) of obese rats. We observed that an HFD increased lipid and protein oxidation, and decreased GABA levels. Moreover, UV-irradiated strawberry extract (UViSE) decreased lipid peroxidation but not protein oxidation, whereas non-irradiated strawberry extract (NSE) reduced protein oxidation but not lipid peroxidation. Interestingly, NSE increased GABA concentration, whereas UViSE was not as effective. In conclusion, our results suggest that an HFD increases oxidative damage in the FC, whereas strawberry extract intake may ameliorate the disturbances associated with HFD-induced oxidative damage.

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The Mechanisms of Glutamine- and Fish Oil-Supplemented Resuscitation Fluids on Alleviating Oxidative Stress of the Lung and Liver in Rats with Trauma-Hemorrhagic Shock

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_062 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 429-429

Author(s):

Bing-Xiang Liu ◽

Hui-Chen Lo ◽

Chien-Hsing Lee

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Fish Oil ◽

Hemorrhagic Shock ◽

Catalase Activity ◽

Caspase 3 ◽

Neutrophil Infiltration ◽

Midline Laparotomy ◽

Shed Blood ◽

Main Factor

Abstract Objectives Oxidative stress has been demonstrated to be the cause of cellular and organ damage in patients with trauma hemorrhagic shock and reperfusion (THR). Our previous study showed that resuscitation fluids supplemented with glutamine and fish oil, the antioxidants with anti-inflammatory activities, may alleviate systemic inflammatory response and oxidative stress in the THR rats. The aim of this study was to further investigate the mechanisms of these supplements on alleviating THR-induced damage in the lung and liver, i.e., the 2 vulnerable organs in THR. Methods Male Wistar rats were suffered with 5 cm midline laparotomy and 2 catheterizations in the left carotid artery and right jugular vein individually for blood drawn to a mean arterial pressure 30 to 35 mmHg for 60 minutes and for resuscitation of shed blood and lactate Ringer's solution with or without L-alanyl-L-glutamine (13.5 mmole/kg/day) and/or fish oil (0.5 g/kg/day) within 10 minutes. The different resuscitation fluids were continuous infused (∼1.4 ml/h) for 42 hr. Normal healthy rats and intubation sham-operated rats were included as controls. Results In the lung, the THR-increased lipid peroxidation and toll-like receptor 4 (TLR4) were significantly decreased by glutamine with or without fish oil (one-way ANOVA, P < 0.05). Fish oil was the main factor to decrease myeloperoxidase and activated caspase 3 in the lung of the THR rats (two-way ANOVA, P < 0.05). In the liver, the THR-increased lipid peroxidation and TLR4 and the THR-decreased catalase activity were improved by glutamine and/or fish oil. In addition, fish oil was the main factor to decrease inducible and endothelial nitric oxide synthase (NOS) and to increase IkB and phosphorylated NF-kB and glutamine was the main factor to decrease activated caspase 3 in the liver of the THR rats. Conclusions These results suggest that fish oil may alleviate neutrophil infiltration and NOS activation and fish oil and glutamine may elevate catalase activity and alleviate apoptosis to attenuate the THR-induced damage in the lung and liver. Funding Sources MOST 102-2320-B-030-005-MY3.

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Hydroxychloroquine-Induced Toxic Myopathy Causing Diaphragmatic Weakness and Lung Collapse Requiring Prolonged Mechanical Ventilation

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709620950113 ◽

2020 ◽

Vol 8 ◽

pp. 232470962095011

Author(s):

Julie Pillittere ◽

Sundus Mian ◽

Timothy E. Richardson ◽

Andras Perl

Keyword(s):

Prolonged Mechanical Ventilation ◽

Ventilatory Support ◽

Antigen Expression ◽

Type Ii ◽

Prolonged Intubation ◽

Acute Hypercapnic Respiratory Failure ◽

Fiber Atrophy ◽

Diaphragmatic Weakness ◽

Toxic Myopathy ◽

Curvilinear Bodies

A 42-year-old woman with juvenile idiopathic arthritis was treated with anakinra, corticosteroids, and hydroxychloroquine when she developed chronic hypoxic respiratory myopathy. She was admitted to the intensive care unit for acute hypercapnic respiratory failure and required prolonged intubation, subsequent tracheostomy, and long-term ventilatory support due to multiple failed spontaneous breathing trials after discontinuation of anakinra and steroids. Muscle biopsy revealed type II fiber atrophy with the accumulation of autophagosomes and vacuoles presenting as curvilinear bodies, elevated MHC class I antigen expression, and infiltration by CD68+ macrophages and CD8+ T cells. Type II fiber atrophy was attributed to corticosteroid use and curvilinear bodies due to blockade of autophagy by hydroxychloroquine. After hydroxychloroquine was discontinued, the patient recovered to her prehospitalization baseline.

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Oxidative Stress Induction by Lead in Leaves of Radish (Raphanus sativus) Seedlings

Notulae Scientia Biologicae ◽

10.15835/nsb346360 ◽

2011 ◽

Vol 3 (4) ◽

pp. 93-99 ◽

Cited By ~ 3

Author(s):

Nadjet BITEUR ◽

Abdelkader AOUES ◽

Omar KHAROUBI ◽

Miloud SLIMANI

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Protein Oxidation ◽

Raphanus Sativus ◽

Lead Concentration ◽

Control Treatment ◽

Enzymatic Antioxidants ◽

Carotenoid Concentration ◽

Hydroponic System ◽

Physiological Processes

Oxidative stress was induced by lead acetate (Pb) in Raphanus sativus seedlings grown in a hydroponic system using sand as substrate. Thirty day old acclimated seeds were treated for 7 days with five Pb levels (0 as control, 100, 200, 500 and 1000 mg l-1). Parameters such as growth, oxidative damage markers (lipid peroxidation, protein oxidation and hydrogen peroxide contents) and enzymatic activities of catalase (CAT) and peroxidase (POD) were investigated. Lead concentration in plant tissues increased with increasing of Pb levels. Shoot fresh weight, chlorophyll and carotenoid concentration were significantly decreased at 100 mg l-1 Pb. Lipid peroxidation, protein oxidation and H2O2 levels were increased at 500 and 1000 mg l-1 Pb compared to control treatment, in shoots. Peroxidase activity showed a straight correlation with H2O2 concentration, whereas CAT activity decreased only in shoots. These changes in enzymatic and non-enzymatic antioxidants showed that the Pb exposition had a significant disturbance on Raphanus sativus plantlets and affect the biochemical and physiological processes.

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Lipid Peroxidation, Protein Oxidation, Gelatinases, and Their Inhibitors in a Group of Adults with Obesity

Hormone and Metabolic Research ◽

10.1055/a-0887-2770 ◽

2019 ◽

Vol 51 (06) ◽

pp. 389-395 ◽

Cited By ~ 1

Author(s):

Gregorio Caimi ◽

Baldassare Canino ◽

Maria Montana ◽

Caterina Urso ◽

Vincenzo Calandrino ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Protein Oxidation ◽

Thiobarbituric Acid ◽

Protein Carbonyl ◽

The Body ◽

Control Group ◽

The Matrix ◽

Markers Of Oxidative Stress ◽

Obese Subjects

AbstractThe association between obesity and cardiovascular diseases has a multifactorial pathogenesis, including the synthesis of inflammatory molecules, the increase in oxidative stress and the dysregulation of the matrix metalloprotease (MMP) concentration and activity. In a group of adults with obesity, divided in 2 subgroups according to the body mass index (BMI), we examined lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), protein oxidation, expressed as protein carbonyl groups (PCs), plasma gelatinases (MMP-2 and MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2). In the whole group, as well as in the 2 subgroups (with BMI 30–35 or BMI>35) of obese subjects, we observed an increase in TBARS, PCs, MMP-2, and MMP-9, and also TIMP-1 and TIMP-2 in comparison with the control group. A positive correlation between TBARS and PCs emerged in obese subjects and persisted after dividing obese subjects according to BMI. The correlation between MMP-2 and TIMP-2 was not statistically significant, while a significant correlation was present between MMP-9 and TIMP-1. The correlations between the markers of oxidative stress (TBARS and PCs) and those of the MMP/TIMP profile indicated a more marked influence of protein oxidation on MMPs and TIMPs in comparison with TBARS. The innovative aspect of our study was the simultaneous evaluation of oxidative stress markers and MMP/TIMP profile in adult obese subjects. We observed significant alterations and correlations that may negatively influence the clinical course of the disease.

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