Endogenous heme oxygenase induction is a critical mechanism attenuating apoptosis and restoring microvascular perfusion following limb ischemia/reperfusion

McCarter, Sarah D.; Akyea, Thelma; Lu, Xiangru; Bihari, Aurelia; Scott, Jeffrey R.; Badhwar, Amit; Dungey, Alison A.; Harris, Kenneth A.; Feng, Qingping; Potter, Richard F.

doi:10.1016/j.surg.2003.11.002

Cited by 29 publications

(21 citation statements)

References 40 publications

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“…It has been demonstrated that acute ischemia of the lower extremities in rats results in significant lung injury [32]. The present results were also supported by other investigators who stated that hepatocellular injury and hepatocyte death (necrotic and apoptotic) occurred following limb I/R [33]. Limb I/R injury can lead to permeability changes that may be closely related to the production of excessive OFRs and inflammatory cytokines.…”

Section: Discussionsupporting

confidence: 88%

The possible protective effect of exercise on liver damage following hind-limb ischemia–reperfusion injury in the adult male albino rat

Mohamed¹

2014

The Egyptian Journal of Histology

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BackgroundHind-limb ischemia-reperfusion (I/R) injury is not limited to the lower extremities; it also causes damage to remote organs. Aim of the work This study was undertaken to investigate the role of exercise in attenuating remote hepatic damage following hind-limb I/R injury. Materials and methodsForty-five adult male rats were divided into three groups: the control group, the I/R group, and the exercise+I/R group. The rats were left to swim for 1 h, five times a week, for 4 weeks before I/R. Bilateral hind-limb ischemia was induced by application of rubber bands above the greater trochanter for 3 h. Blood samples were taken after 3 h of reperfusion for determination of malondialdehyde, superoxide dismutase, tumor necrosis factor-α, and interleukin-6. Liver specimens were processed for light and electron microscopic study. ResultsIn the I/R group, the superoxide dismutase level decreased and plasma levels of malondialdehyde, tumor necrosis factor-α, and interleukin-6 significantly increased when compared with the control group. Light microscopic examination showed hepatocytes with vacuolated cytoplasm, dilated blood sinusoids, and portal vessels. An extensive amount of collagen fibers around portal tracts and intense immune reaction for caspase-3 were observed. The ultrastructure showed hepatocytes with swollen mitochondria and disrupted cristae and others with an electron-dense matrix. Kupffer cells showed apoptotic bodies. Ito cells appeared surrounded by wide areas of collagen fibers. The exercise+I/R group showed significant attenuation of the biochemical and histological alterations of I/R-induced liver injury. ConclusionExercise could attenuate remote liver damage following hind-limb I/R injury.

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Section: Discussionsupporting

confidence: 88%

The possible protective effect of exercise on liver damage following hind-limb ischemia–reperfusion injury in the adult male albino rat

Mohamed¹

2014

The Egyptian Journal of Histology

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“…See "Discussion" for details. ischemia/reperfusion liver damage (34,47,48). Moreover, our results may have therapeutic applications for other disease conditions, such as secondary organ injury after ischemia/ reperfusion, due to the excessive production of inflammatory cytokines and subsequent neutrophil involvement (49).…”

Section: Discussionmentioning

confidence: 81%

Nuclear Import of Proinflammatory Transcription Factors Is Required for Massive Liver Apoptosis Induced by Bacterial Lipopolysaccharide

Liu¹,

Li²,

Chen³

et al. 2004

Journal of Biological Chemistry

103

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Stimulation of macrophages with lipopolysaccharide (LPS) leads to the production of cytokines that elicit massive liver apoptosis. We investigated the in vivo role of stress-responsive transcription factors (SRTFs) in this process focusing on the precipitating events that are sensitive to a cell-permeant peptide inhibitor of SRTF nuclear import (cSN50). In the absence of cSN50, mice challenged with LPS displayed very early bursts of inflammatory cytokines/chemokines, tumor necrosis factor ␣ (1 h), interleukin 6 (2 h), interleukin 1 ␤ (2 h), and monocyte chemoattractant protein 1 (2 h). Activation of both initiator caspases 8 and 9 and effector caspase 3 was noted 4 h later when full-blown DNA fragmentation and chromatin condensation were first observed (6 h). At this time an increase of pro-apoptotic Bax gene expression was observed. It was preceded by a decrease of anti-apoptotic Bcl2 and BclX L gene transcripts. Massive apoptosis was accompanied by microvascular injury manifested by hemorrhagic necrosis and a precipitous drop in blood platelets observed at 6 h. An increase in fibrinogen/fibrin degradation products and a rise in plasminogen activator inhibitor 1 occurred between 4 and 6 h. Inhibition of SRTFs nuclear import with the cSN50 peptide abrogated all these changes and increased survival from 7 to 71%. Thus, the nuclear import of SRTFs induced by LPS is a prerequisite for activation of the genetic program that governs cytokines/ chemokines production, liver apoptosis, microvascular injury, and death. These results should facilitate the rational design of drugs that protect the liver from inflammation-driven apoptosis.Programmed cell death (apoptosis) is the major mechanism of embryonic development and remodeling of tissues and organs, homeostatic control of immune cells that recognize self and non-self antigens, and removal of virally infected cells (1). Apoptosis of hepatocytes may occur in fulminant hepatitis, an inflammatory process that is caused by viral and non-viral agents (2). For example, recent gene therapy approaches to correct an inborn error of metabolism led to fulminant liver failure (3). This inflammation-related complication of gene therapy impedes broader application of viral vectors (4, 5). The sequence of intracellular signaling events that underlie inflammation-driven development of ultimately fatal liver apoptosis remains incompletely understood.Fulminant liver apoptosis has been studied in several animal models. These studies indicate that activation of T cells with concanavalin A (6) or with agonists that interact with T cell receptor such as staphylococcal enterotoxin B can lead to massive apoptosis (7,8). Staphylococcal enterotoxin B-induced apoptosis occurs under conditions of metabolic stress imposed by 2-amino-2-deoxy-D-galactosamine (D-Gal).1 Similarly, activation of macrophages with their Toll-like receptors (TLR) agonists, such as lipopolysaccharide (LPS, endotoxin), induces massive liver apoptosis when animals are treated with ethanol or D-Gal (9, 10). By reversibly dep...

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“…However, the pathogenesis, morbid state and pathological process of LPS/D-GalN-induced acute liver damage in sublethal dose have remained elusive. An experimental animal challenged with a nonlethal amount of LPS/D-GalN may be of clinical importance as a number of inflammatory liver diseases in humans, including viral hepatitis, alcoholic liver disease, immune-or drug-induced liver injury and ischemia/reperfusion liver failure, have been shown to be dependent on TNF-a production [14][15][16][17][18][19]. Therefore, the rat model may provide a valuable approach to study acute liver injury mediated by inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

A Role of Cell Apoptosis in Lipopolysaccharide (LPS)-induced Nonlethal Liver Injury in d-galactosamine (d-GalN)-sensitized Rats

et al. 2007

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Lipopolysaccharide (LPS) is implicated in the pathology of acute liver injury and can induce lethal liver failure when simultaneously administered with D-galactosamine (D-GalN). At the present time, nonlethal liver failure, the liver injury of clinical implication, is incompletely understood following challenge by low-dose LPS/D-GalN. We report here our investigation of the effects of liver injury following a nonlethal dose LPS/D-GalN and the role of apoptosis in this disorder. Blood biochemistry indexes, including those of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), had risen by 6 h post-LPS/D-GalN injection, reached a peak at 24 h and sustained high levels at 48 h. An abnormal liver appearance was found at 24 and 48 h post-injection. Histopathological changes of hepatic injuries accompanied by hepatocellular death, inflammatory infiltration and hemorrhage began to appear at 6 h and were markedly aggravated at 24 and 48 h. Cell apoptosis was significantly induced by the nonlethal dose LPS/D-GalN challenge, and the apoptotic indexes (AIs) in 24 h- and 48 h-treated rats were approximately 70%, as estimated by the terminal transferase dUTP nick end labeling (TUNEL) assay. The mRNA levels of the inflammatory cytokine IL-1beta rose markedly at 6 h and maintained high levels at 24 and 48 h; however, TNF-alpha levels were normal in the liver tissues of 6-, 24- and 48-h-treated rats. mRNA expression of the damage gene nitric oxide synthase (NOS) was also induced early by the LPS/D-GalN challenge, reaching a peak at 6 h, then gradually decreasing in a stepwise manner; conversely, high expression levels of the apoptosis-inducing gene p53 mRNA were not found in the early post-injection period (6 h) but emerged in the crest-time of liver apoptosis (24 h) and were maintained at this level until the late stage (48 h). We also observed that in 24 h-treated rats, caspase-3, -8, -9 and -12 were markedly activated by LPS/D-GalN challenge. These results suggest that a challenge with low-dose LPS in conjunction with D-GalN can induce nonlethal but marked liver failure, the main morphological feature of which is hepatic apoptosis, which may be associated with a high expression of inducible (i)NOS (early post-injection period) and p53 genes (in the mid and late stages) and at least three apoptosis pathways participate in the pathogenesis.

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Endogenous heme oxygenase induction is a critical mechanism attenuating apoptosis and restoring microvascular perfusion following limb ischemia/reperfusion

Cited by 29 publications

References 40 publications

The possible protective effect of exercise on liver damage following hind-limb ischemia–reperfusion injury in the adult male albino rat

The possible protective effect of exercise on liver damage following hind-limb ischemia–reperfusion injury in the adult male albino rat

Nuclear Import of Proinflammatory Transcription Factors Is Required for Massive Liver Apoptosis Induced by Bacterial Lipopolysaccharide

A Role of Cell Apoptosis in Lipopolysaccharide (LPS)-induced Nonlethal Liver Injury in d-galactosamine (d-GalN)-sensitized Rats

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