scholarly journals Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats

2019 ◽  
Vol 131 (3) ◽  
pp. 605-618 ◽  
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.

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

2010 ◽  
Vol 108 (5) ◽  
pp. 1376-1382 ◽  
Author(s):  
Melissa A. Whidden ◽  
Ashley J. Smuder ◽  
Min Wu ◽  
Matthew B. Hudson ◽  
W. Bradley Nelson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Mechanical Ventilation ◽  
Protein Oxidation ◽  
Caspase 3 ◽  
Prolonged Mechanical Ventilation ◽  
Contractile Dysfunction ◽  
Protease Activation ◽  
Fiber Atrophy ◽  
Diaphragmatic Weakness

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.

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

2009 ◽  
Vol 106 (2) ◽  
pp. 385-394 ◽  
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.

scholarly journals Ethanolic Extract of Moringa oleifera Leaves Influences NF-κB Signaling Pathway to Restore Kidney Tissue from Cobalt-Mediated Oxidative Injury and Inflammation in Rats

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1031 ◽  
Author(s):  
Mohamed M. Abdel-Daim ◽  
Samah R. Khalil ◽  
Ashraf Awad ◽  
Ehsan H. Abu Zeid ◽  
Reda Abd El-Aziz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Moringa Oleifera ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Kidney Tissue ◽  
Ethanolic Extract ◽  
Male Rats ◽  
Control Group ◽  
The Impact

This study aimed to describe the protective efficacy of Moringa oleifera ethanolic extract (MOEE) against the impact of cobalt chloride (CoCl2) exposure on the rat’s kidney. Fifty male rats were assigned to five equal groups: a control group, a MOEE-administered group (400 mg/kg body weight (bw), daily via gastric tube), a CoCl2-intoxicated group (300 mg/L, daily in drinking water), a protective group, and a therapeutic co-administered group that received MOEE prior to or following and concurrently with CoCl2, respectively. The antioxidant status indices (superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)), oxidative stress markers (hydrogen peroxide (H2O2), 8-hydroxy-2-deoxyguanosine (8-OHdG), and malondialdehyde (MDA)), and inflammatory response markers (nitric oxide (NO), tumor necrosis factor (TNF-α), myeloperoxidase (MPO), and C-reactive protein (CRP)) were evaluated. The expression profiles of pro-inflammatory cytokines (nuclear factor-kappa B (NF-kB) and interleukin-6 (IL-6)) were also measured by real-time quantitative polymerase chain reaction (qRT-PCR). The results showed that CoCl2 exposure was associated with significant elevations of oxidative stress and inflammatory indices with reductions in the endogenous tissue antioxidants’ concentrations. Moreover, CoCl2 enhanced the activity of the NF-κB inflammatory-signaling pathway that plays a role in the associated inflammation of the kidney. MOEE ameliorated CoCl2-induced renal oxidative damage and inflammatory injury with the suppression of the mRNA expression pattern of pro-inflammatory cytokine-encoding genes. MOEE is more effective when it is administered with CoCl2 exposure as a prophylactic regimen. In conclusion, MOEE administration exhibited protective effects in counteracting CoCl2-induced renal injury in rats.

scholarly journals Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm

Thorax ◽  
2016 ◽  
Vol 71 (5) ◽  
pp. 436-445 ◽  
Author(s):  
Sabah N A Hussain ◽  
Anabelle S Cornachione ◽  
Céline Guichon ◽  
Auday Al Khunaizi ◽  
Felipe de Souza Leite ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Contractile Dysfunction ◽  
Protein Loss ◽  
Controlled Mechanical Ventilation

scholarly journals Oxypurinol attenuates mechanical ventilation‐induced diaphragmatic oxidative stress and contractile dysfunction

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Melissa A Whidden ◽  
Darin J Falk ◽  
Ashley J Smuder ◽  
Joseph M McClung ◽  
Scott K Powers
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Contractile Dysfunction

scholarly journals Apocynin attenuates mechanical ventilation‐induced diaphragmatic oxidative stress and contractile dysfunction

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Darin L Van Gammeren ◽  
Darin J Falk ◽  
Melissa A Deering ◽  
Keith C DeRuisseau ◽  
Joel P French ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Contractile Dysfunction

Mechanical ventilation results in progressive contractile dysfunction in the diaphragm

2002 ◽  
Vol 92 (5) ◽  
pp. 1851-1858 ◽  
Author(s):  
Scott K. Powers ◽  
R. Andrew Shanely ◽  
Jeff S. Coombes ◽  
Thomas J. Koesterer ◽  
Michael McKenzie ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Spontaneous Breathing ◽  
Contractile Function ◽  
Control Group ◽  
Contractile Dysfunction ◽  
Sprague Dawley ◽  
Short Term ◽  
Mechanically Ventilated ◽  
Sprague Dawley Rats ◽  
Controlled Mechanical Ventilation

These experiments tested the hypothesis that a relatively short duration of controlled mechanical ventilation (MV) will impair diaphragmatic maximal specific force generation (specific Po) and that this force deficit will be exacerbated with increased time on the ventilator. To test this postulate, adult Sprague-Dawley rats were randomly divided into one of six experimental groups: 1) control ( n = 12); 2) 12 h of MV ( n = 4); 3) 18 h of MV ( n = 4); 4) 18 h of anesthesia and spontaneous breathing ( n = 4); 5) 24 h of MV ( n = 7); and 6) 24 h of anesthesia and spontaneous breathing ( n = 4). MV animals were anesthetized, tracheostomized, and ventilated with room air. Animals in the control group were acutely anesthetized but were not exposed to MV. Animals in two spontaneous breathing groups were anesthetized and breathed spontaneously for either 18 or 24 h. No differences ( P > 0.05) existed in diaphragmatic specific Po between control and the two spontaneous breathing groups. In contrast, compared with control, all durations of MV resulted in a reduction ( P < 0.05) in diaphragmatic specific tension at stimulation frequencies ranging from 15 to 160 Hz. Furthermore, the MV-induced decrease in diaphragmatic specific Po was time dependent, with specific Po being ∼18 and ∼46% lower ( P < 0.05) in animals mechanically ventilated for 12 and 24 h, respectively. These data support the hypothesis that relatively short-term MV impairs diaphragmatic contractile function and that the magnitude of MV-induced force deficit increases with time on the ventilator.

scholarly journals Inhibition of the Ubiquitin–Proteasome Pathway Does Not Protect against Ventilator-induced Accelerated Proteolysis or Atrophy in the Diaphragm

2014 ◽  
Vol 121 (1) ◽  
pp. 115-126 ◽  
Author(s):  
Ashley J. Smuder ◽  
W. Bradley Nelson ◽  
Matthew B. Hudson ◽  
Andreas N. Kavazis ◽  
Scott K. Powers
Keyword(s):  
Caspase 3 ◽  
Ring Finger ◽  
Diaphragm Muscle ◽  
Contractile Dysfunction ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Life Saving ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Fiber Atrophy

Abstract Background: Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin–proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. Methods: The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). Results: The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. Conclusion: Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.

Effect of Turmeric and Ginger on Lipid Profile in Male Rats Exposed to Oxidative Stress

2019 ◽  
Vol 10 (01) ◽  
Author(s):  
Eman A. Al-Rekabi ◽  
Dheyaa K. Alomer ◽  
Rana Talib Al-Muswie ◽  
Khalid G. Al-Fartosi
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Drinking Water ◽  
Lipid Profile ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Male Rats ◽  
Control Group ◽  
Very Low Density Lipoprotein ◽  
Low Density

The present study aimed to investigate the effect of turmeric and ginger on lipid profile of male rats exposed to oxidative stress induced by hydrogen peroxide H2O2 at a concentration of 1% given with consumed drinking water to male rats. Methods: 200 mg/kg from turmeric and ginger were used, and the animals were treatment for 30 days. Results: the results showed a significant increase in cholesterol, triglycerides, low density lipoprotein (LDL), very low density lipoprotein (VLDL), whereas it explained a significant decrease in high density lipoprotein (HDL) of male rats exposed to oxidative stress when compared with control group. the results showed a significant decrease in cholesterol, triglycerides, (LDL), (VLDL), whereas it explained a significant increase in (HDL) of rats treated with turmeric and ginger at dose 200 mg/kg when compared with male rats exposed to oxidative stress.

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