<i>N</i>-acetylcysteine administration alters the response to inspiratory loading in oxygen-supplemented rats

Supinski, Gerald S.; Stofan, D.; Ciufo, R.; DiMarco, Anthony F.

doi:10.1152/jappl.1997.82.4.1119

Cited by 51 publications

(53 citation statements)

References 22 publications

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“…In rats subjected to 60 -70% IRL, MAP fell to ϳ25 mmHg (post-IRL) and, after removal of the load, to Ͻ10 mmHg despite 15 min of mechanical ventilation (11), a result consistent with irreversible cardiac injury. In decerebrate rats subjected to IRL, MAP decreased from approximately 150 to 39 mmHg over the final few minutes before respiratory arrest (46); smaller falls were observed in two other studies (45,47). Borzone et al (12,13) noted that rats breathing air and subjected to IRL failed within 10 min because of hypoxemia and hypotension unless they were given supplementary O 2 .…”

Section: Discussionmentioning

confidence: 92%

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading

Simpson¹,

Iscoe²

2007

Journal of Applied Physiology

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Simpson JA, Iscoe S. Cardiorespiratory failure in rat induced by severe inspiratory resistive loading. J Appl Physiol 102: [1556][1557][1558][1559][1560][1561][1562][1563][1564] 2007. First published December 7, 2006; doi:10.1152/japplphysiol.00785.2006.-The mechanisms underlying acute respiratory failure induced by respiratory loads are unclear. We hypothesized that, in contrast to a moderate inspiratory resistive load, a severe one would elicit central respiratory failure (decreased respiratory drive) before diaphragmatic injury and fatigue. We also wished to elucidate the factors that predict endurance time and peak tracheal pressure generation. Anesthetized rats breathed air against a severe load (ϳ75% of the peak tracheal pressure generated during a 30-s occlusion) until pump failure (fall in tracheal pressure to half; mean 38 min). Hypercapnia and hypoxemia developed rapidly (ϳ4 min), coincident with diaphragmatic fatigue (decreased ratio of transdiaphragmatic pressure to peak integrated phrenic activity) and the detection in blood of the fast isoform of skeletal troponin I (muscle injury). At ϳ23 min, respiratory frequency and then blood pressure fell, followed immediately by secondary diaphragmatic fatigue. Blood taken after termination of loading contained cardiac troponin T (myocardial injury). Contrary to our hypothesis, diaphragmatic fatigue and injury occurred early in loading before central failure, evident only as a change in the timing but not the drive component of the central respiratory pattern generator.Stepwise multiple regression analysis selected changes in mean arterial pressure and arterial PCO 2 during loading as the principal contributing factors in load endurance time, and changes in mean arterial pressure as the principal contributing factor in peak tracheal pressure generation. In conclusion, the temporal development of respiratory failure is not stereotyped but depends on load magnitude; moreover respiratory loads induce cardiorespiratory, not just respiratory, failure. diaphragm; fatigue; heart; injury; troponin WHEN THE RESPIRATORY MUSCLES are subjected to contractile demands that exceed their energy supply, respiratory pump failure (inadequate pressure generation) eventually occurs (e.g., 35). Pump failure can result from central failure (inadequate output from the respiratory central pattern generator; sometimes referred to as central fatigue) (50), peripheral fatigue (35) (neurotransmission failure, decreased contractile function; 9), or some combination. Central failure is denoted by a decrease in central neural output despite adequate chemical drive, peripheral fatigue by a reduction in force-generating capacity that is reversible by rest (35), and neurotransmission failure by impaired transmission of the action potential across the neuromuscular junction. All have been implicated in respiratory pump failure, but there is no consensus about either their relative contributions or the sequence in which they occur. Even with similar protocols in healthy human subjects (27,33) o...

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Section: Discussionmentioning

confidence: 92%

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading

Simpson¹,

Iscoe²

2007

Journal of Applied Physiology

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“…Most studies in the literature have used a high inspiratory load, demonstrating a time-to-task failure that ranged from few minutes to 1 h maximum (2,47). However, recent studies have shown that IRB with a moderate load differs from that with a high load (21,42,43,51,55,56).…”

Section: Discussionmentioning

confidence: 99%

“…NAC is an antioxidant that acts both as a free radical scavenger and as a source of cysteine for glutathione synthesis. During IRB, NAC delays fatigue (52), increases the time to respiratory arrest (47), decreases the delayed diaphragmatic injury (at 3 days after severe IRB) (23), restores diaphragmatic glutathione levels (47), and decreases intradiaphragmatic protein carbonyl formation (5). In our model NAC administration blunted protein carbonyl formation in the diaphragm, decreased IRB-induced cytokine upregulation, and in parallel decreased P38, ERK1/2, and NF-B/p65 subunit phosphorylation, suggesting that ROS is a stimulus for MAPKs and NF-B activation and hence cytokine production in response to IRB.…”

Section: Role Of Oxidative Stressmentioning

confidence: 99%

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress

Sigala

Zacharatos²,

Toumpanakis

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11–7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.

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“…It has been well established that production of ROS and lipid peroxidation products is elevated in the ventilatory muscles during strenuous muscle contractions (36,37,39). Supinski et al (36) investigated the association between increased lipid peroxidation and the development of muscle fatigue in dogs.…”

Section: Discussionmentioning

confidence: 99%

Modifications of proteins by 4-hydroxy-2-nonenal in the ventilatory muscles of rats

Hussain¹,

Matar²,

Barreiro³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Although 4-hydroxy-2-nonenal (HNE, a product of lipid peroxidation) is a major cause of oxidative damage inside skeletal muscles, the exact proteins modified by HNE are unknown. We used two-dimensional electrophoresis, immunoblotting, and mass spectrometry to identify selective proteins targeted by HNE inside the diaphragm of rats under two conditions: severe sepsis [induced by E. coli lipopolysaccharides (LPS)] and during strenuous muscle contractions elicited by severe inspiratory resistive loading (IRL). Diaphragm HNE-protein adduct formation (detected with a polyclonal antibody) increased significantly after 1 and 3 h of LPS injection with a return to baseline values thereafter. Similarly, HNE-protein adduct formation inside the diaphragm rose significantly after 6 but not 3 h of IRL. Mass spectrometry analysis of HNE-modified proteins revealed enolase 3b, aldolase and triosephosphate isomerase 1, creatine kinase, carbonic anyhdrase III, aconitase 2, dihydrolipoamide dehydrogenase, and electron transfer flavoprotein-β. Measurements of in vitro enolase activity in the presence of pure HNE revealed that HNE significantly attenuated enolase activity in a dose-dependent fashion, suggesting that HNE-derived modifications have inhibitory effects on enzyme activity. We conclude that lipid peroxidation products may inhibit muscle contractile performance through selective targeting of enzymes involved in glycolysis, energy production as well as CO2 hydration.

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N-acetylcysteine administration alters the response to inspiratory loading in oxygen-supplemented rats

Cited by 51 publications

References 22 publications

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress

Modifications of proteins by 4-hydroxy-2-nonenal in the ventilatory muscles of rats

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