Leukotriene B4 promotes reactive oxidant generation and leukocyte adherence during acute hypoxia

2001 ◽  
Vol 91 (3) ◽  
pp. 1160-1167 ◽  
Author(s):  
Dawn R. S. Steiner ◽  
Norberto C. Gonzalez ◽  
John G. Wood
Keyword(s):  
Acute Hypoxia ◽  
Leukotriene B4 ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Systemic Hypoxia ◽  
Microvascular Alterations ◽  
Reactive Oxidant ◽  
Underlying Mechanisms ◽  
Mesenteric Microcirculation

Acute systemic hypoxia produces rapid leukocyte adherence in the rat mesenteric microcirculation, although the underlying mechanisms are not fully known. Hypoxia is known to increase reactive oxygen species (ROS) generation, which could result in formation of the lipid inflammatory mediator leukotriene B4 (LTB4). The goal of this study was to examine the role of LTB4 in hypoxia-induced microvascular alterations. Using intravital microscopy, we determined the effect of the LTB4 antagonist, LTB4-dimethyl amide (LTB4-DMA), on ROS generation and leukocyte adherence in mesenteric venules during hypoxia. Exogenous LTB4 increased ROS generation to 144 ± 8% compared with control values and also promoted leukocyte adherence. These responses to LTB4 were blocked by pretreating the mesentery with LTB4-DMA. Leukopenia did not significantly attenuate the LTB4-induced increase in ROS generation (142 ± 12.1%). LTB4-DMA substantially, though not completely, reduced hypoxia-induced ROS generation from 66 ± 18% to 11 ± 4% above control values. Hypoxia-induced leukocyte adherence was significantly attenuated by LTB4-DMA. Our results support a role for LTB4in the mechanism of hypoxia-induced ROS generation and leukocyte adherence in the rat mesenteric microcirculation.

Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation

1999 ◽  
Vol 87 (5) ◽  
pp. 1734-1740 ◽  
Author(s):  
John G. Wood ◽  
Jennifer S. Johnson ◽  
Leone F. Mattioli ◽  
Norberto C. Gonzalez
Keyword(s):  
Functional Relationship ◽  
Ros Generation ◽  
Oxygen Species ◽  
Leukocyte Adherence ◽  
Systemic Hypoxia ◽  
Signal Changes ◽  
Adhesive Interactions ◽  
Reactive Oxidant ◽  
Mesenteric Microcirculation

We recently demonstrated that systemic hypoxia during reduced inspired [Formula: see text] produces a rapid increase in leukocyte adherence to rat mesenteric venules. Evidence suggests that the mechanism of this response involves decreased nitric oxide (NO) levels. One possible pathway for NO depletion could involve increased reactive oxygen species (ROS) generation resulting in inactivation of NO. The overall goal of the present study was to examine the role of ROS in promoting leukocyte-endothelial adherence during systemic hypoxia. Experiments were designed to 1) evaluate changes in ROS generation in the mesenteric microcirculation during systemic hypoxia, 2) determine how the ROS signal changes when [Formula: see text] levels return to normal after a period of systemic hypoxia, 3) assess the effect of antioxidants on ROS generation during hypoxia, and 4) utilize antioxidants to examine the functional relationship between ROS generation and leukocyte adherence during hypoxia. The major findings from this study are that systemic hypoxia increases ROS generation within the mesenteric microcirculation and that antioxidants prevent the increase in leukocyte-endothelial adhesive interactions observed in hypoxia.

Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats

2000 ◽  
Vol 89 (4) ◽  
pp. 1561-1568 ◽  
Author(s):  
John G. Wood ◽  
Jennifer S. Johnson ◽  
Leone F. Mattioli ◽  
Norberto C. Gonzalez
Keyword(s):  
Vascular Function ◽  
Microvascular Permeability ◽  
Hypoxic Exposure ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Conscious Animal ◽  
Subsequent Decrease ◽  
Conflicting Evidence ◽  
Systemic Hypoxia

We recently observed that acute systemic hypoxia produces rapid increases in leukocyte adherence in the mesenteric microcirculation of the anesthetized rat Wood JG, Johnson JS, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 1734–1740, 1999; Wood JG, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 873–881, 1999. Hypoxia-induced leukocyte adherence is associated with an increase in reactive oxygen species (ROS) generation and is attenuated by antioxidants or interventions that increase tissue levels of nitric oxide (NO). These results suggest that the acute effects of hypoxia on leukocyte-endothelial interactions are caused by a change in the ROS-NO balance. The present experiments were designed to extend our observations of the initial microcirculatory response to hypoxia; specifically, we wanted to determine whether the response to systemic hypoxia involves increased microvascular permeability and leukocyte emigration and whether ROS generation and decreased NO levels contribute to these responses. At this time, there is conflicting evidence, from in vitro studies, regarding the effect of hypoxia on these indexes of vascular function. Our studies were carried out in the physiological setting of the conscious animal, in which a prolonged hypoxic exposure is possible without the adverse effects that may develop under anesthesia. The central observation of these studies is that conscious animals exposed for 4 h to environmental hypoxia show increased microvascular permeability and emigration of leukocytes into the extravascular space of the mesenteric circulation. Furthermore, these events are dependent on increased ROS generation and, possibly, a subsequent decrease in tissue NO levels during systemic hypoxia. Our results show that systemic hypoxia profoundly affects vascular endothelial function through changes in the ROS-NO balance in the conscious animal.

scholarly journals The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

2021 ◽  
Vol 2021 ◽  
pp. 1-25
Author(s):  
Ting Hong ◽  
Yiyan Chen ◽  
Xiaoying Li ◽  
Yan Lu
Keyword(s):  
Oxidative Stress ◽  
Nuclear Receptors ◽  
Metabolic Stress ◽  
Hepatic Metabolism ◽  
Ros Generation ◽  
Nonalcoholic Fatty Liver ◽  
Oxidation Damage ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

scholarly journals Hydrogen Sulfide and Cellular Redox Homeostasis

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Zhi-Zhong Xie ◽  
Yang Liu ◽  
Jin-Song Bian
Keyword(s):  
Hydrogen Sulfide ◽  
Antioxidant Defense ◽  
Redox Homeostasis ◽  
Antioxidant Defense System ◽  
Ros Generation ◽  
Cellular Redox ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
Antioxidant Effects

Intracellular redox imbalance is mainly caused by overproduction of reactive oxygen species (ROS) or weakness of the natural antioxidant defense system. It is involved in the pathophysiology of a wide array of human diseases. Hydrogen sulfide (H2S) is now recognized as the third “gasotransmitters” and proved to exert a wide range of physiological and cytoprotective functions in the biological systems. Among these functions, the role of H2S in oxidative stress has been one of the main focuses over years. However, the underlying mechanisms for the antioxidant effect of H2S are still poorly comprehended. This review presents an overview of the current understanding of H2S specially focusing on the new understanding and mechanisms of the antioxidant effects of H2S based on recent reports. Both inhibition of ROS generation and stimulation of antioxidants are discussed. H2S-induced S-sulfhydration of key proteins (e.g., p66Shc and Keap1) is also one of the focuses of this review.

Role of 5′-AMP-activated protein kinase in stimulation of glucose transport in response to inhibition of oxidative phosphorylation

2006 ◽  
Vol 290 (2) ◽  
pp. C484-C491 ◽  
Author(s):  
Ming Jing ◽  
Faramarz Ismail-Beigi
Keyword(s):  
Protein Kinase ◽  
Oxidative Phosphorylation ◽  
Glucose Transport ◽  
Ros Generation ◽  
Transport Response ◽  
Resultant Increase ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

Glucose transport is stimulated in a variety of cells and tissues in response to inhibition of oxidative phosphorylation. However, the underlying mechanisms and mediating steps remain largely unknown. In the present study we first tested whether a decrease in the redox state of the cell per se and the resultant increase in generation of reactive oxygen species (ROS) lead to stimulation of glucose transport. Clone 9 cells (expressing the Glut1 isoform of facilitative glucose transporters) were exposed to azide, lactate, and ethanol for 1 h. Although all three agents stimulated glucose transport and increased cell NADH-to-NAD+ ratio and phospho-ERK1/2, signifying increased ROS generation, the response to the stimuli was not blocked by N-acetyl-l-cysteine (an agent that counteracts ROS); moreover, the response to azide was not blocked by diamide (an intracellular sulfhydryl oxidizing agent). We then found that cell AMP-to-ATP and ADP-to-ATP ratios were increased and 5′-AMP-activated protein kinase (AMPK) was stimulated by all three agents, as evidenced by increased phosphorylation of AMPK and acetyl-CoA carboxylase. We conclude that although azide, lactate, and ethanol increase NADH-to-NAD+ ratios and ROS production, their stimulatory effect on glucose transport is not mediated by increased ROS generation. However, all three agents increased cell AMP-to-ATP ratio and stimulated AMPK, making it likely that the latter pathway plays an important role in the glucose transport response.

Hypoxia causes leukocyte adherence to mesenteric venules in nonacclimatized, but not in acclimatized, rats

1999 ◽  
Vol 87 (3) ◽  
pp. 873-881 ◽  
Author(s):  
John G. Wood ◽  
Leone F. Mattioli ◽  
Norberto C. Gonzalez
Keyword(s):  
Nitric Oxide ◽  
Ischemia Reperfusion ◽  
Acute Hypoxia ◽  
Oxide Formation ◽  
Nitric Oxide Formation ◽  
Systemic Hypoxia ◽  
Adhesive Interactions ◽  
Acclimatization Period ◽  
Oxide Synthase

Although the effects of ischemia-reperfusion have received considerable attention, few studies have directly evaluated the microcirculatory response to systemic hypoxia. The overall objective of this study was to assess the effect of environmental hypoxia on adhesive interactions of circulating leukocytes with rat mesenteric venules by using intravital microscopy. Experiments were designed to 1) characterize the adhesive interactions of circulating leukocytes to venules during acute hypoxia produced by a reduction in inspired[Formula: see text], 2) evaluate the role of nitric oxide in these adhesive interactions, 3) determine whether the effect of hypoxia on leukocyte adhesive interactions differs between acclimatized and nonacclimatized rats, and 4) assess whether compensatory changes in nitric oxide formation contribute to this difference. The results showed that acute hypoxia promotes leukocyte-endothelial adherence in mesenteric venules of nonacclimatized rats. The mechanism of this response is consistent with depletion of nitric oxide within the microcirculation. In contrast, no leukocyte-endothelial adherence occurred during hypoxia in rats acclimatized to hypobaric hypoxia. The results are consistent with increased nitric oxide formation due to expression of inducible nitric oxide synthase during the acclimatization period. Further studies are needed to establish the cause of nitric oxide depletion during acute hypoxia as well as to define the compensatory responses that attenuate hypoxia-induced leukocyte-endothelial adherence in the microvasculature of acclimatized rats.

scholarly journals Neonatal lamb mortality: major risk factors and the potential ameliorative role of melatonin

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tom Flinn ◽  
David O. Kleemann ◽  
Alyce M. Swinbourne ◽  
Jennifer M. Kelly ◽  
Alice C. Weaver ◽  
...  
Keyword(s):  
Risk Factors ◽  
Production Systems ◽  
Acute Hypoxia ◽  
Melatonin Treatment ◽  
Ovine Placenta ◽  
Sheep Production ◽  
Underlying Mechanisms ◽  
Fetal Oxygenation ◽  
In Utero Development

Abstract High incidences of pre-weaning mortality continue to limit global sheep production, constituting a major economic and welfare concern. Despite significant advances in genetics, nutrition, and management, the proportion of lamb deaths has remained stable at 15–20% over the past four decades. There is mounting evidence that melatonin can improve outcomes in compromised ovine pregnancies via enhanced uterine bloodflow and neonatal neuroprotection. This review provides an overview of the major risk factors and underlying mechanisms involved in perinatal lamb mortality and discusses the potential of melatonin treatment as a remedial strategy. Supplementing pregnant ewes with melatonin enhances uterine bloodflow and fetal oxygenation, and potentially birthweight and neonatal thermogenic capacity. Melatonin freely crosses the ovine placenta and blood-brain barrier and provides neuroprotection to the fetal lamb during periods of chronic and acute hypoxia throughout gestation, with improved behavioural outcomes in hypoxic neonates. The current literature provides strong evidence that maternal melatonin treatment improves outcomes for lambs which experience compromised in utero development or prolonged parturition, though to date this has not been investigated in livestock production systems. As such there is a clear basis for continued research into the effects of maternal melatonin supplementation during gestation on pre-weaning survival under extensive production conditions.

scholarly journals UHRF1 mediates cell migration and invasion of gastric cancer

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Haixia Zhang ◽  
Yanli Song ◽  
Changqing Yang ◽  
Xianzheng Wu
Keyword(s):  
Gastric Cancer ◽  
Ring Finger ◽  
Migration And Invasion ◽  
Ros Generation ◽  
Ring Finger Protein ◽  
Caspase 9 ◽  
Sgc7901 Cell ◽  
Finger Protein ◽  
Underlying Mechanisms

Gastric cancer (GC) is a common highly aggressive malignant tumor in worldwide. Ubiquitin-like with PHD and ring-finger protein 1 (UHRF1) has a key role in several kinds of cancers development. However, the biology effect of UHRF1 on the tumorigenesis of GC remains unclear. In this research, the role of UHRF1 in the growth, migration, invasion and apoptosis and the underlying mechanisms were investigated in MGC803 and SGC7901 cells. The UHRF1 knockdown MGC803 and SGC7901 cell lines were used to investigate the roles of UHRF1 on GC cell growth, migration, invasion and apoptosis. The growth, migration and invasion rate of UHRF1 knockdown cells was lower than that of the control. Moreover, ROS generation and caspase-3/caspase-9 activities increased in UHRF1 knockdown cells. And mitochondrial membrane potential decreased in UHRF1 knockdown cells. These findings indicated that UHRF1 promoted the growth, migration and invasion of MGC803 and SGC7901 cells and inhibited apoptosis via a ROS-associated pathway.

Nitric oxide prevents leukocyte adherence: role of superoxide

1993 ◽  
Vol 265 (3) ◽  
pp. H862-H867 ◽  
Author(s):  
J. Gaboury ◽  
R. C. Woodman ◽  
D. N. Granger ◽  
P. Reinhardt ◽  
P. Kubes
Keyword(s):  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Leukocyte Adherence ◽  
No Donor ◽  
Rolling Leukocytes ◽  
Adherent Leukocytes ◽  
Generating System

The objective of this study was to determine whether the antiadhesive effects of NO for leukocytes are related to its ability to scavenge superoxide in vivo. Intravital microscopy was used to monitor leukocyte adherence and flux as well as velocity and number of rolling leukocytes in 25- to 40-microns venules. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX-XO), was infused into the mesenteric circulation in untreated animals and in animals pretreated with either superoxide dismutase (SOD) or the NO donor, SIN 1. In another series of studies, the mesenteric preparation was superfused with either platelet-activating factor (PAF) or leukotriene B4 (LTB4) followed by the administration of either SIN 1 or SOD. HX-XO infusion caused a significant increase in the number of rolling and adherent leukocytes (responses that were entirely inhibited by SOD or SIN 1). SOD and SIN 1 both attenuated the PAF-induced but not the LTB4-induced leukocyte adherence. The observation that both SOD and SIN 1 inhibit leukocyte adhesion only under conditions associated with superoxide formation (HX-XO and PAF, but not LTB4) strongly suggests that the antiadhesion properties of NO are related to its ability to inactivate the superoxide anion.

Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4

2003 ◽  
Vol 94 (6) ◽  
pp. 2313-2322 ◽  
Author(s):  
Alfred J. Casillan ◽  
Norberto C. Gonzalez ◽  
Jennifer S. Johnson ◽  
Dawn R. S. Steiner ◽  
John G. Wood
Keyword(s):  
Inflammatory Response ◽  
Vascular Permeability ◽  
Inflammatory Responses ◽  
Platelet Activating Factor ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Anesthetized Rats ◽  
Systemic Hypoxia ◽  
Paf Receptor ◽  
Web 2086

Systemic hypoxia produces a rapid microvascular inflammatory response characterized by increased reactive oxygen species (ROS) levels, leukocyte-endothelial adherence and emigration, and increased vascular permeability. The lipid inflammatory mediator leukotriene B4 (LTB4) is involved in the early hypoxia-induced responses (ROS generation and leukocyte adherence). Whether other lipid inflammatory mediators participate in this phenomenon is not known. The objective of these experiments was to study the role of platelet-activating factor (PAF) in the microvascular inflammatory response to hypoxia and its potential interactions with LTB4 in this response. Intravital microscopy was used to examine mesenteric venules of anesthetized rats. We found that WEB-2086, a PAF receptor antagonist, completely prevented the increase in ROS levels and leukocyte adherence during a brief reduction in inspired Po 2 to anesthetized rats; administration of either WEB-2086 or the LTB4 antagonist LTB4-DMA attenuated leukocyte emigration and the increase in vascular permeability to the same extent during prolonged systemic hypoxia in conscious rats. Furthermore, no additive effect was observed in either response when both antagonists were administered simultaneously. This study demonstrates a role for PAF in the rapid microvascular inflammatory response to hypoxia, as well as contributions of PAF and LTB4 to the slowly developing responses observed during sustained hypoxia. The incomplete blockade of the hypoxia-induced increases in vascular permeability and leukocyte emigration by combined administration of both antagonists indicates that factors in addition to LTB4 and PAF participate in these phenomena.

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