Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation.

Morrow, Jason D.; Awad, Joseph; Kato, Tatsuko; Takahashi, Kihito; Badr, Kamal F.; Roberts, L. Jackson; Burk, Raymond F.

doi:10.1172/jci116143

Cited by 315 publications

(179 citation statements)

References 15 publications

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“…acute intoxication (in which concentrations of over 4000 pg/ml have been found 18,19 ), were maintained elevated ( Figure 2) for the entire experimental period (with a sharp peak at 4 h and decrease at 48 h, Figure 2 inset, with respect to the usual time of measurement, that is, 24 h after the last injection). In particular, very high levels of F 2 -isoprostanes were found at 7 weeks (the end of the experiment, Figure 3a) and this was accompanied by a marked increase of hepatic collagen content (measured as hydroxyproline, Figure 3b).…”

Section: Isoprostanes and Liver Fibrosis M Comporti Et Almentioning

confidence: 92%

“…An elevated level of plasma F 2 -isoprostanes has been reported 18,19 to be associated with acute CCl 4 intoxication. We therefore investigated whether elevated isoprostane levels are maintained throughout the experimental period.…”

mentioning

confidence: 99%

“…Moreover, negligible amounts of F 2 -isoprostanes are released by cultured Kupffer cells when challenged with CCl 4 . 43 Also, it has been shown 18,19 that both free and total (sum of free plus esterified) isoprostanes are dramatically increased in the liver after CCl 4 intoxication.…”

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confidence: 99%

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F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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Carbon tetrachloride (CCl 4 )-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F 2 -isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F 2 -isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl 4 -induced hepatic fibrosis, plasma F 2 -isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F 2 -isoprostanes in the concentration range found in the in vivo studies (10 À9 -10 À8 M), a striking increase in DNA synthesis (reversed by the thromboxane A 2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F 2 -isoprostanes markedly increased the production of transforming growth factor-b1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F 2 -isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.

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Section: Isoprostanes and Liver Fibrosis M Comporti Et Almentioning

confidence: 92%

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confidence: 99%

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F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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“…Analysis of oxidative damage to lipids was quantified by measuring F 2 − isoprostanes in lipids using a highly precise and accurate assay employing gas chromatography/mass spectrometry (14).…”

Section: Oxidative Lipid Damagementioning

confidence: 99%

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

et al. 2001

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Oxidative stress has been implicated as a causal factor in the aging process of the heart and other tissues. To determine the extent of age-related myocardial oxidative stress, oxidant production, antioxidant status, and oxidative DNA damage were measured in hearts of young (2 months) and old (28 months) male Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly threefold increase in the rate of oxidant production compared to young rats, as measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. Determination of myocardial antioxidant status revealed a significant twofold decline in the levels of ascorbic acid (P = 0.03), but not α-tocopherol. A significant age-related increase (P = 0.05) in steady-state levels of oxidative DNA damage was observed, as monitored by 8-oxo-2′-deoxyguanosine levels. To investigate whether dietary supplementation with (R)-α-lipoic acid (LA) was effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LA-supplemented rats exhibited a markedly lower rate of oxidant production that was no longer significantly different from that in cells from unsupplemented, young rats. Lipoic acid supplementation also restored myocardial ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the aging rat heart is under increased mitochondrial-induced oxidative stress, which is significantly attenuated by lipoic acid supplementation. Keywordsaging; cardiac myocytes; oxidative stress; lipoic acid Aging is associated with an increased incidence of cardiac arrhythmias and diastolic and systolic dysfunction, which may ultimately lead to heart failure. Heart failure alone is the leading cause of hospitalization, permanent disability, and death in persons over the age of HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript 65 (1) in the U.S. Because of the enormous suffering and health care burden that cardiac dysfunction causes, much effort has gone into understanding the mechanisms leading to agerelated myocardial decline. It has been difficult, however, to separate the effects of aging per se from those of age-associated diseases (atherosclerosis, diabetes, hypertension) on cardiac performance. Thus, the relative contribution of 'aging' to myocardial dysfunction is not well defined.Even though the mechanisms leading to alterations in cardiac performance are not well understood, there is reason to suspect increased oxidative stress to significantly contribute to myocardial dysfunction with age. It is generally agreed that isolated mitochondrial preparations from old compared to young hearts produce more reactive oxygen species (ROS), reflecting an age-related decline in coupling of electron transport to ATP production. These changes in mitochondria may lead to the reported increase in superoxide and hydrogen peroxide production in mitochondria prepared from old vs. young rats (2-4). Thus, it is conceiv...

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“…Several cell types have been shown to release increased levels of the F 2 isoprostane, 8-iso PGF 2a , when stimulated with in¯ammatory mediators or subjected to oxidative stress in vitro (Patrignani et al, 1996;Vacchiano et al, 1998;Jourdan et al, 1999). Furthermore, 8-iso PGF 2a levels are elevated in rats in vivo when prooxidant conditions are induced experimentally (Morrow et al, 1992b;Dabbagh et al, 1994;Awad et al, 1994;Lynch et al, 1996). Similarly, elevated isoprostane production has been demonstrated in clinical conditions characterized by oxidant stress including diabetes (Davi et al, 1999), alcoholism (Alehnik et al, 1998), paraquat poisoning (Delanty et al, 1996), myocardial reperfusion (Reilly et al, 1997), critical illness (Carpenter et al, 1998), pre-eclampsia (Walsh et al, 2000) and smoking (Morrow et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the effects of isoprostanes on platelet aggregation in human whole blood

Cranshaw

Evans

Mitchell

2001

British J Pharmacology

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1 We tested the e ects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer.2 None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a subthreshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE 1 48-iso PGE 2 48-iso PGF 2a 48-iso PGF 3a 48-iso-13,14-dihydro-15-keto PGF 2a ). 3 Blood incubated with LPS to induce a gross in¯ammatory response exhibited a time dependent (2 ± 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. 4 L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. 5 Thus, in human whole blood the action of 8-iso PGE 1 , 8-iso PGE 2 , 8-iso PGF 2a , 8-iso PGF 3a , and 8-iso-13,14-dihydro-15-keto PGF 2a is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to in¯ammatory stimulation.

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Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation.

Cited by 315 publications

References 15 publications

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Oxidative stress in the aging rat heart is reversed by dietary supplementation with ( R )‐α‐lipoic acid

Characterization of the effects of isoprostanes on platelet aggregation in human whole blood

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