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 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 Redox regulation of diaphragm proteolysis during mechanical ventilation

2008 ◽  
Vol 294 (5) ◽  
pp. R1608-R1617 ◽  
Author(s):  
J. M. McClung ◽  
M. A. Whidden ◽  
A. N. Kavazis ◽  
D. J. Falk ◽  
K. C. DeRuisseau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Protein Concentration ◽  
Redox Regulation ◽  
20S Proteasome ◽  
Substrate Availability ◽  
Sprague Dawley ◽  
Α Subunit ◽  
Sprague Dawley Rats ◽  
Critical Site

Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome α-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (μg/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.

Mechanical ventilation-induced oxidative stress in the diaphragm

2003 ◽  
Vol 95 (3) ◽  
pp. 1116-1124 ◽  
Author(s):  
Murat A. Zergeroglu ◽  
Michael J. McKenzie ◽  
R. Andrew Shanely ◽  
Darin Van Gammeren ◽  
Keith C. DeRuisseau ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Spontaneous Breathing ◽  
Prolonged Mechanical Ventilation ◽  
Oxidative Injury ◽  
Rapid Onset ◽  
Protein Carbonyl ◽  
Oxidative Modification ◽  
Lipid Hydroperoxides ◽  
Sprague Dawley ◽  
Carbonyl Derivatives

Prolonged mechanical ventilation (MV) results in oxidative damage in the diaphragm; however, it is unclear whether this MV-induced oxidative injury occurs rapidly or develops slowly over time. Furthermore, it is unknown whether both soluble (cytosolic) and insoluble (myofibrillar) proteins are equally susceptible to oxidation during MV. These experiments tested two hypotheses: 1) MV-induced oxidative injury in the diaphragm occurs within the first 6 h after the initiation of MV; and 2) MV is associated with oxidative modification of both soluble and insoluble proteins. Adult Sprague-Dawley rats were randomly divided into one of seven experimental groups: 1) control ( n = 8); 2) 3-h MV ( n = 8); 3) 6-h MV ( n = 6); 4) 18-h MV ( n = 8); 5) 3-h anesthesia-spontaneous breathing ( n = 8); 6) 6-h anesthesia-spontaneous breathing ( n = 6); and 7) 18-h anesthesia-spontaneous breathing ( n = 8). Markers of oxidative injury in the diaphragm included the measurement of reactive (protein) carbonyl derivatives (RCD) and total lipid hydroperoxides. Three hours of MV did not result in oxidative injury in the diaphragm. In contrast, both 6 and 18 h of MV promoted oxidative injury in the diaphragm, as indicated by increases in both protein RCD and lipid hydroperoxides. Electrophoretic separation of soluble and insoluble proteins indicated that the MV-induced accumulation of RCD was limited to insoluble proteins with molecular masses of ∼200, 120, 80, and 40 kDa. We conclude that MV results in a rapid onset of oxidative injury in the diaphragm and that insoluble proteins are primary targets of MV-induced protein oxidation.

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.

Effects of Dietary Supplements on Space Radiation-Induced Oxidative Stress in Sprague-Dawley Rats

2004 ◽  
Vol 162 (5) ◽  
pp. 572-579 ◽  
Author(s):  
Jun Guan ◽  
X. Steven Wan ◽  
Zhaozong Zhou ◽  
Jeffrey Ware ◽  
Jeremiah J. Donahue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dietary Supplements ◽  
Space Radiation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Radiation Induced

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

2007 ◽  
Vol 292 (2) ◽  
pp. F861-F867 ◽  
Author(s):  
Melvin R. Hayden ◽  
Nazif A. Chowdhury ◽  
Shawna A. Cooper ◽  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Proximal Tubule ◽  
Structural Damage ◽  
Kidney Tissue ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

scholarly journals Effect of liposome-encapsulated hemoglobin resuscitation on proteostasis in small intestinal epithelium after hemorrhagic shock

2016 ◽  
Vol 311 (1) ◽  
pp. G180-G191 ◽  
Author(s):  
Geeta Rao ◽  
Vivek R. Yadav ◽  
Shanjana Awasthi ◽  
Pamela R. Roberts ◽  
Vibhudutta Awasthi
Keyword(s):  
Oxidative Stress ◽  
Hemorrhagic Shock ◽  
Multiorgan Failure ◽  
Sprague Dawley ◽  
Barrier Dysfunction ◽  
Protective Mechanisms ◽  
Unfolded Protein ◽  
Sprague Dawley Rats ◽  
Markers Of Oxidative Stress ◽  
Protein Response

Gut barrier dysfunction is the major trigger for multiorgan failure associated with hemorrhagic shock (HS). Although the molecular mediators responsible for this dysfunction are unclear, oxidative stress-induced disruption of proteostasis contributes to the gut pathology in HS. The objective of this study was to investigate whether resuscitation with nanoparticulate liposome-encapsulated hemoglobin (LEH) is able to restore the gut proteostatic mechanisms. Sprague-Dawley rats were recruited in four groups: control, HS, HS+LEH, and HS+saline. HS was induced by withdrawing 45% blood, and isovolemic LEH or saline was administered after 15 min of shock. The rats were euthanized at 6 h to collect plasma and ileum for measurement of the markers of oxidative stress, unfolded protein response (UPR), proteasome function, and autophagy. HS significantly increased the protein and lipid oxidation, trypsin-like proteasome activity, and plasma levels of IFNγ. These effects were prevented by LEH resuscitation. However, saline was not able to reduce protein oxidation and plasma IFNγ in hemorrhaged rats. Saline resuscitation also suppressed the markers of UPR and autophagy below the basal levels; the HS or LEH groups showed no effect on the UPR and autophagy. Histological analysis showed that LEH resuscitation significantly increased the villus height and thickness of the submucosal and muscularis layers compared with the HS and saline groups. Overall, the results showed that LEH resuscitation was effective in normalizing the indicators of proteostasis stress in ileal tissue. On the other hand, saline-resuscitated animals showed a decoupling of oxidative stress and cellular protective mechanisms.

Dietary exposure to silver nanoparticles in Sprague–Dawley rats: Effects on oxidative stress and inflammation

2013 ◽  
Vol 60 ◽  
pp. 297-301 ◽  
Author(s):  
R. Ebabe Elle ◽  
S. Gaillet ◽  
J. Vidé ◽  
C. Romain ◽  
C. Lauret ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Silver Nanoparticles ◽  
Dietary Exposure ◽  
Sprague Dawley ◽  
Sprague Dawley Rats
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