Isoflurane Attenuates Early Neutrophil-independent Hypoxia-Reoxygenation Injuries in the Reperfused Liver in Fasted Rats

1997 ◽  
Vol 86 (1) ◽  
pp. 128-136 ◽  
Author(s):  
Shinpei Kon ◽  
Mie Imai ◽  
Hideo Inaba
Keyword(s):  
Lactate Dehydrogenase ◽  
Kupffer Cells ◽  
Minimum Alveolar Concentration ◽  
Ischemia Reperfusion ◽  
Gas Mixture ◽  
Superoxide Generation ◽  
Lactate Dehydrogenase Release ◽  
Carbon Dioxide Gas ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

Background Ischemia-hypoxia followed by reperfusion and reoxygenation injures cells and organs. Previous studies have indicated that isoflurane may protect organs from ischemia-reperfusion or hypoxia-reoxygenation. This study investigated the ability of isoflurane to protect the liver from hypoxia-reoxygenation injury and the mechanisms of this phenomenon. Methods The isolated liver was perfused at a constant pressure of 12 cm H2O with a modified Krebs-Ringer-bicarbonate solution saturated with a 95% oxygen/5% carbon dioxide gas mixture. Hypoxic perfusion produced by decreasing the oxygen concentration in the gas mixture to 10% was followed by perfusion at 95% oxygen for 60 min. Viability of the liver was assessed by lactate dehydrogenase release from the liver. Isoflurane at 0.5, 1, and 2 minimum alveolar concentration was administered to assess the effect of isoflurane on hypoxia-reperfusion injury. To determine the effect of isoflurane on extracellular generation of superoxide in the liver, the reduction of ferricytochrome c with or without superoxide dismutase was measured. Results Lactate dehydrogenase release was transiently but dramatically increased by reoxygenation and significantly attenuated by 1 and 2 minimum alveolar concentration of isoflurane. Suppression of Kupffer cells with gadolinium chloride also attenuated the lactate dehydrogenase release. Isoflurane significantly reduced the superoxide generation on reperfusion. Conclusions The results show that isoflurane protected the liver from an early reoxygenation injury presumably mediated by Kupffer cells. The mechanisms of the inhibitory effects of isoflurane on the injury may involve suppression of extracellular superoxide generation during reoxygenation.

scholarly journals Two New Compounds From the Heartwood of Dalbergia melanoxylon and Their Protective Effect on Hypoxia/Reoxygenation Injury in H9c2

2021 ◽  
Vol 16 (1) ◽  
pp. 1934578X2098777
Author(s):  
Yang Liu ◽  
Ni Zhang ◽  
Jun-wei He ◽  
Lan-ying Chen ◽  
Li Yang ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Lactate Dehydrogenase ◽  
Protective Effect ◽  
Superoxide Dismutase Activity ◽  
Spectral Evidence ◽  
Reoxygenation Injury ◽  
Dalbergia Melanoxylon ◽  
New Compounds ◽  
Hypoxia Reoxygenation

A new neoflavonoid, named as (7 R)-(-)-3′,5-dihydroxy-4′,2,4-trimethoxy-dalbergiquinol (1) and a new phenanthrenedione, named as 3′,7-dihydroxy-3,6- dimethoxy-9-phenyl-1,4-phenanthrenedione (2), together with 4 known compounds, 5- O-methyldalbergiphenol (3), 3′,7-dihydroxy-4′,3,6-trimethoxy-9-phenyl-1,4-phenanthrenedione (4), (+)-obtusafuran (5), and melanoxin (6) were isolated from the heartwood of Dalbergia melanoxylon. Their structures were elucidated on the basis of chemical and spectral evidence, as well as by comparison with literature data. Moreover, compound 1 showed a protective effect on hypoxia/reoxygenation injury in H9c2 at 10.0 μM by decreasing lactate dehydrogenase and malondialdehyde activity and enhancing superoxide dismutase activity.

Abstract 172: Thrombopoietin Receptor Agonists Protect Human Cardiac Myocytes from Injury by Activation of Cell Survival Pathways

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
John E Baker ◽  
Jidong Su ◽  
Stacy Koprowski ◽  
Anuradha Dhanasekaran ◽  
Tom P Aufderheide ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Survival Pathways ◽  
Thrombopoietin Receptor ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart at a dose that does not increase platelet levels. Eltrombopag is a small molecule agonist of the thrombopoietin receptor; the physiological target of thrombopoietin. Administration of thrombopoietin and eltrombopag result in a dose- and time-dependent increase in platelet counts in patients with thrombocytopenia. However, the ability of eltrombopag and thrombopoietin to immediately protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (7500 cells, n=10/group) were treated with eltrombopag (0.1- 30.0 μM) or thrombopoietin ( 0.1 - 30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N 2 /5%CO 2 ) and 16 hours of reoxygenation to determine their ability to confer resistance to necrotic and apoptotic myocardial injury . The thrombopoietin receptor (c-Mpl) was detected in unstimulated human cardiac myocytes by western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner with an optimal concentration of 3 μM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred to cardiac myocytes with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple pro-survival pathways; inhibition of JAK-2 (AG-490, 10 μM), p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 10 μM), Akt/PI 3 kinase (Wortmannin, 100 nM), and src kinase (PP1, 20 μM) prior to and during hypoxia abolished cardiac myocyte protection by eltrombopag and thrombopoietin. These inhibitors had no effect on hypoxia/reoxygenation injury in myocytes when used alone. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer long-lasting benefit through activation of pro-survival pathways during ischemia.

O2-. release by activated Kupffer cells upon hypoxia-reoxygenation

1991 ◽  
Vol 261 (4) ◽  
pp. G602-G607 ◽  
Author(s):  
B. Rymsa ◽  
J. F. Wang ◽  
H. de Groot
Keyword(s):  
Nadph Oxidase ◽  
Kupffer Cells ◽  
Cell Injury ◽  
Cell Damage ◽  
Primary Cultures ◽  
Time Lag ◽  
Specific Inhibitor ◽  
Significant Difference ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

Primary cultures of rat liver Kupffer cells generated large amounts of superoxide anion radical (O2-.) when subjected to reoxygenation after a hypoxic period of at least 2 h. O2-. formation reached its maximum rate of approximately 25 nmol/10(6) cells within 1 h after reoxygenation. Two to four hours after reoxygenation, the number of injured cells began to increase and after 10 h approximately 60% of the cells were dead. During the period of O2-. release no significant difference in cell viability was observed between reoxygenated and hypoxically incubated cells, indicating a distinct time lag between O2-. release and onset of cell damage. Addition of diphenyliodonium, a specific inhibitor of the neutrophilic NADPH oxidase, to the Kupffer cells just before reoxygenation diminished both O2-. formation and cell injury up to 70%. Reoxygenation injury was completely prevented when superoxide dismutase and catalase were added immediately before reoxygenation. The results indicate that Kupffer cells subjected to hypoxia-reoxygenation generate a burst of reactive oxygen species and that this kind of "activation," probably by activating the NADPH oxidase, contributes to the self-destruction of the cells.

scholarly journals Polypeptide Globular Adiponectin Ameliorates Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury by Inhibiting Both Apoptosis and Necroptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Kaiyi Zhu ◽  
Jia Guo ◽  
Xiaoxue Yu ◽  
Que Wang ◽  
Chao Yan ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Endocrine System ◽  
Neonatal Rat ◽  
Protective Mechanisms ◽  
Lactate Dehydrogenase Release ◽  
P38mapk Signaling ◽  
Globular Adiponectin ◽  
Myocardial Ischemia Reperfusion ◽  
Hypoxia Reoxygenation

Adiponectin is a small peptide secreted and a key component of the endocrine system and immune system. Although globular adiponectin protects myocardial ischemia/reperfusion-induced cardiomyocyte injury, the protective mechanisms remain largely unresolved. Using a neonatal rat ventricular myocyte hypoxia/reoxygenation model, we investigated the role of its potential mechanisms of necroptosis in globular adiponectin-mediated protection in hypoxia/reoxygenation-induced cardiomyocyte injury as compared to apoptosis. We found that globular adiponectin treatment attenuated cardiomyocyte injury as indicated by increased cell viability and reduced lactate dehydrogenase release following hypoxia/reoxygenation. Immunofluorescence staining and Western blotting demonstrated that both necroptosis and apoptosis were triggered by hypoxia/reoxygenation and diminished by globular adiponectin. Necrostatin-1 (RIP1-specific inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) only mimicked the inhibition of necroptosis and apoptosis, respectively, by globular adiponectin in hypoxia/reoxygenation-treated cardiomyocytes. Globular adiponectin attenuated reactive oxygen species production, oxidative damage, and p38MAPK and NF-κB signaling, all important for necroptosis and apoptosis. Collectively, our study suggests that globular adiponectin inhibits hypoxia/reoxygenation-induced necroptosis and apoptosis in cardiomyocytes probably by reducing oxidative stress and interrupting p38MAPK signaling.

scholarly journals Evidence against increased hydroxyl radical production during oxygen deprivation-reoxygenation proximal tubular injury.

1992 ◽  
Vol 2 (11) ◽  
pp. 1627-1633
Author(s):  
R A Zager ◽  
D J Gmur ◽  
B A Schimpf ◽  
C R Bredl ◽  
C A Foerder
Keyword(s):  
Lactate Dehydrogenase ◽  
Hydroxyl Radical ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Second Phase ◽  
Renal Tubules ◽  
Tubular Injury ◽  
Lactate Dehydrogenase Release ◽  
Proximal Tubular

The purpose of this study was to assess whether proximal renal tubules generate excess hydroxyl radical (.OH) during hypoxia/reoxygenation or ischemia/reperfusion injury, thereby supporting the hypothesis that reactive oxygen species contribute to the pathogenesis of postischemic acute renal failure. In the first phase of the study, rat isolated proximal tubular segments (PTS) were subjected to hypoxia (95% N2- 5% CO2) for 15, 30, or 45 min, followed by 15 to 30 min of reoxygenation in the presence of sodium salicylate, a stable .OH trap. Cellular injury after hypoxia and reoxygenation was assessed by lactate dehydrogenase release; .OH production was gauged by hydroxylated salicylate by-product generation (2,3-, 2,5-dihydroxybenzoic acids (DHBA); quantified by HPLC/electrochemical detection). Continuously oxygenated PTS served as controls. Despite substantial lactate dehydrogenase release during hypoxia (8 to 46%) and reoxygenation (8 to 11%), DHBA production did not exceed that of the coincubated, continuously oxygenated control PTS. In the second phase of the study, salicylate-treated rats were subjected to 25 or 40 min of renal arterial occlusion +/- 15 min of reperfusion. No increase in renal DHBA concentrations occurred during ischemia or reperfusion, compared with that in sham-operated controls. To validate the salicylate trap method, PTS were incubated with a known .OH-generating system (Fe2+/Fe3+); in addition, rats were treated with antioxidant interventions (oxypurinol plus dimethylthiourea). Fe caused marked DHBA production, and the antioxidants halved in vivo DHBA generation. In conclusion, these results suggest that exaggerated .OH production is not a consequence of O2 deprivation/reoxygenation tubular injury.

MiR-421 inhibition protects H9c2 cells against hypoxia/reoxygenation-induced oxidative stress and apoptosis by targeting Sirt3

Perfusion ◽  
2019 ◽  
Vol 35 (3) ◽  
pp. 255-262 ◽  
Author(s):  
Yu Liu ◽  
Xi-Ming Qian ◽  
Qi-Cai He ◽  
Jia-Kan Weng
Keyword(s):  
Superoxide Dismutase ◽  
Lactate Dehydrogenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Activator Protein 1 ◽  
H9c2 Cells ◽  
Expression Levels ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Hypoxia Reoxygenation

Background: MicroRNAs (miRNAs) are involved in myocardial ischemia-reperfusion injury. miRNA-421 (miR-421) plays a significant role in the initiation of apoptosis and myocardial infarction. However, the molecular regulation of miR-421 in myocardial ischemia-reperfusion injury requires further elucidation. Methods: An in vitro hypoxia/reoxygenation model was established, and the expression levels of miR-421 and Sirtuin-3 (Sirt3) in H9c2 cells were quantified using quantitative real-time polymerase chain reaction. Flow cytometry was employed to measure the effects of miR-421 on myocardial apoptosis induced by hypoxia/reoxygenation. The activity of lactate dehydrogenase and superoxide dismutase and levels of malondialdehyde were measured. The binding sites of miR-421 on Sirt3 were predicted using TargetScan software. A luciferase reporter assay was used to validate the direct targeting of Sirt3 with miR-421. Protein expression levels of Sirt3 and its downstream proteins were evaluated using Western blot analysis. Results: Exposure of H9c2 cells to hypoxia/reoxygenation led to increased apoptosis, levels of malondialdehyde and lactate dehydrogenase, and decreased levels of superoxide dismutase. miR-421 knockdown resulted in decreased apoptosis, levels of lactate dehydrogenase and malondialdehyde, and increased superoxide dismutase levels in H9c2 cells. Hypoxia/reoxygenation significantly decreased the relative expression levels of Sirt3. Down-regulation of Sirt3 resulted from overexpression of miR-421, which directly targeted Sirt3. Knockdown of miR-421 up-regulated Sirt3 expression, inhibited activation of the Jun N-terminal kinase/activator protein 1 pathway and caspase 9/3-dependent cell death. Conclusion: The miR-421-Sirt3-Jun N-terminal kinase/activator protein 1 axis is a novel molecular mechanism that accommodates hypoxia/reoxygenation-induced oxidative stress and apoptosis and provides a new direction for the study and treatment of hypoxia/reoxygenation.

scholarly journals N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Yanmei Zhang ◽  
Gaoyong Chen ◽  
Shuping Zhong ◽  
Fuchun Zheng ◽  
Fenfei Gao ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Extracellular Calcium ◽  
Camp Content ◽  
Calcium Dependent ◽  
Reoxygenation Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Pka Pathway ◽  
Hypoxia Reoxygenation

N-n-butyl haloperidol iodide (F2) has been shown to antagonize myocardial ischemia/reperfusion injury by blocking calcium channels. This study explores the biological functions of ERK pathway in cardiomyocytes hypoxia/reoxygenation injury and clarifies the mechanisms by which F2ameliorates cardiomyocytes hypoxia/reoxygenation injury through the extracellular-calcium-dependent and -independent ERK1/2-related pathways. In extracellularcalcium-containing hypoxia/reoxygenation cardiomyocytes, PKCαand ERK1/2 were activated, Egr-1 protein level and cTnI leakage increased, and cell viability decreased. The ERK1/2 inhibitors suppressed extracellular-calcium-containing-hypoxia/reoxygenation-induced Egr-1 overexpression and cardiomyocytes injury. PKCαinhibitor downregulated extracellularcalcium-containing-hypoxia/reoxygenation-induced increase in p-ERK1/2 and Egr-1 expression. F2downregulated hypoxia/reoxygenation-induced elevation of p-PKCα, p-ERK1/2, and Egr-1 expression and inhibited cardiomyocytes damage. The ERK1/2 and PKCαactivators antagonized F2’s effects. In extracellular-calcium-free-hypoxia/reoxygenation cardiomyocytes, ERK1/2 was activated, LDH and cTnI leakage increased, and cell viability decreased. F2and ERK1/2 inhibitors antagonized extracellular-calcium-free-hypoxia/reoxygenation-induced ERK1/2 activation and suppressed cardiomyocytes damage. The ERK1/2 activator antagonized F2’s above effects. F2had no effect on cardiomyocyte cAMP content or PKA and Egr-1 expression. Altogether, ERK activation in extracellular-calcium-containing and extracellular-calcium-free hypoxia/reoxygenation leads to cardiomyocytes damage. F2may ameliorate cardiomyocytes hypoxia/reoxygenation injury by regulating the extracellular-calcium-dependent PKCα/ERK1/2/Egr-1 pathway and through the extracellular-calcium-independent ERK1/2 activation independently of the cAMP/PKA pathway or Egr-1 overexpression.

scholarly journals Minimal role of xanthine oxidase and oxygen free radicals in rat renal tubular reoxygenation injury.

1991 ◽  
Vol 1 (7) ◽  
pp. 959-969
Author(s):  
R B Doctor ◽  
L J Mandel
Keyword(s):  
Free Radicals ◽  
Lactate Dehydrogenase ◽  
Xanthine Oxidase ◽  
Oxygen Radicals ◽  
Oxygen Free Radicals ◽  
Proximal Tubules ◽  
Lactate Dehydrogenase Release ◽  
Reoxygenation Injury ◽  
Isolated Rat

The role of xanthine oxidase and oxygen free radicals in postischemic reperfusion injury in the rat kidney remains controversial. Proximal tubules, the focal segment affected by ischemic renal injury, were isolated in bulk, assayed for xanthine oxidase activity, and subjected to 60 min of anoxia or hypoxia and 60 min of reoxygenation to evaluate the participation of xanthine oxidase and oxygen radicals in proximal tubule reoxygenation injury. The total xanthine oxidase in isolated rat proximal tubules was 1.1 mU/mg of protein, approximately 30% to 40% of the activity found in rat intestine and liver. Lactate dehydrogenase release, an indicator of irreversible cell damage, increased substantially during anoxia (39.8 +/- 2.3 versus 9.8 +/- 1.8% in controls) with an additional 8 to 12% release during reoxygenation. Addition of 0.2 mM allopurinol, a potent xanthine oxidase inhibitor, and dimethylthiourea, a hydroxyl radical scavenger, failed to protect against the reoxygenation lactate dehydrogenase release. Analysis of xanthine oxidase substrate levels after anoxia and flux rates during reoxygenation indicates that hypoxanthine and xanthine concentrations are in a 15-fold excess over the enzyme Km and 0.3 mU/mg of protein of xanthine oxidase activity exists during reoxygenation. Hypoxic tubule suspensions had a minimal lactate dehydrogenase release during hypoxia and failed to demonstrate accelerated injury upon reoxygenation. In conclusion, although xanthine oxidase is present and active during reoxygenation in isolated rat proximal tubules, oxygen radicals did not mediate reoxygenation injury.

scholarly journals Scutellarin attenuates hypoxia/reoxygenation injury in hepatocytes by inhibiting apoptosis and oxidative stress through regulating Keap1/Nrf2/ARE signaling

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Haiyuan Wu ◽  
Lan Jia
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Protective Effects ◽  
Sod Activity ◽  
Reoxygenation Injury ◽  
Nrf2 Expression ◽  
And Oxidative Stress ◽  
Hypoxia Reoxygenation

Abstract Scutellarin is a natural flavonoid that has been found to exhibit anti-ischemic effect. However, the effect of scutellarin on hepatic hypoxia/reoxygenation (ischemia–reperfusion (I/R)) injury remains unknown. The aim of the present study was to explore the protective effect of scutellarin on I/R-induced injury in hepatocytes. Our results showed that scutellarin improved cell viability in hepatocytes exposed to hypoxia/reoxygenation (H/R). Scutellarin treatment resulted in decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased superoxide dismutase (SOD) activity in H/R-induced hepatocytes. In addition, scutellarin reduced cell apoptosis in H/R-stimulated hepatocytes, as proved by the decreased apoptotic rate. Moreover, scutellarin significantly up-regulated bcl-2 expression and down-regulated bax expression in hepatocytes exposed to H/R. Furthermore, scutellarin treatment caused significant decrease in Keap1 expression and increase in nuclear Nrf2 expression. Besides, scutellarin induced the mRNA expressions of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Inhibition of Nrf2 significantly reversed the protective effects of scutellarin on H/R-stimulated hepatocytes. In conclusion, these findings demonstrated that scutellarin protected hepatocytes from H/R-induced oxidative injury through regulating the Keap1/Nrf2/ARE signaling pathway, indicating a potential relevance of scutellarin in attenuating hepatic I/R injury.

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