Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF‐κB‐independent mechanism

Birrell, Mark A.; McCluskie, Kerryn; Wong, Sing‐Wai; Donnelly, Louise E.; Barnes, Peter J.; Belvisi, Maria G.

doi:10.1096/fj.04-2691fje

Cited by 157 publications

(122 citation statements)

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“…The potency (EC 50 ) of GW3965 and T1317 in a LXR cell-based reporter gene assay has been published at 190 Ϯ 30 and 85 Ϯ 10 nM, respectively (22). Dexamethasone (10…”

Section: Collection Of Human Lung Tissue Macrophages (Hltms)-mentioning

confidence: 99%

“…A similar range of tissues were collected from 3 male naïve Wistar rats (180 -200 g of the same strain used in the LPS-challenged model below), and RNA was extracted as outlined above and in Birrell et al (22). LXR␣ and -␤ mRNA expression was established as outlined above in the human cells.…”

Section: Collection Of Human Lung Tissue Macrophages (Hltms)-mentioning

confidence: 99%

“…Vehicle or T1317 (1, 3, 10, and 30 mg/kg, twice a day for 4 days and 7 and 4 h before sampling) was orally dosed to Wistar rats, and 4 h after the last dose the animals were culled, and the lung was collected and stored at Ϫ80°C. ABCA-1 mRNA expression was assessed using real-time TaqMan reverse transcription-PCR as outlined above and in Birrell et al (22). The data were expressed as -fold difference from vehicle-treated samples.…”

Section: Establishing An Appropriate Dose Of Lxr Ligand To Use In Thementioning

confidence: 99%

“…Rats were challenged with an aerosol of endotoxin-free saline (for 30 min) or LPS (0.3 mg/ml) as previously described (22). Vehicle (0.5% methylcellulose and 0.2% Tween 80 in water, 2 ml/kg), GW3965 (30 mg/kg), or T1317 (30 mg/kg) were administered orally 1 h before and 2 h post-challenge.…”

Section: Determination Of the Effect Of Gw3965 And T1317 On Lps-inducmentioning

confidence: 99%

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Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Birrell

Catley

Hardaker

et al. 2007

Journal of Biological Chemistry

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The liver X receptors (LXR␣/␤) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis. It has also been suggested that LXR agonists possess anti-inflammatory properties. The aim of this work was to determine the effect of LXR agonists on the innate immune response in human primary lung macrophages and a pre-clinical rodent model of lung inflammation. Before profiling the impact of the agonist, we established that both the human macrophages and the rodent lungs expressed LXR␣/␤. We then used two structurally distinct LXR agonists to demonstrate that activation of this transcription factor reduces cytokine production in THP-1 cells and lung macrophages. Then, using the expression profile of ATP binding cassettes A1 (ABCA-1; a gene directly linked to LXR activation) as a biomarker for lung exposure of the compound, we demonstrated an LXR-dependent reduction in lung neutrophilia rodents in vivo. This inhibition was not associated with a suppression of c-Fos/c-Jun mRNA expression or NF-B/AP-1 DNA binding, suggesting that any anti-inflammatory activity of LXR agonists is not via inhibition of NF-B/AP-1 transcriptional activity. These data do not completely rule out an impact of these agonists on these two prominent transcription factors. In summary, this study is the first to demonstrate anti-inflammatory actions of LXRs in the lung. Chronic innate inflammatory responses observed in some airway diseases is thought to be central to disease pathogenesis. Therefore, data suggest that LXR ligands have utility in the treatment of lung diseases that involves chronic inflammation mediated by macrophages and neutrophils.The liver X receptors (LXR) 2 are part of the nuclear receptor super family and exist in two forms known as LXR␣ and LXR␤. These receptors are coded by two separate genes, Nr1h3 and Nr1h2, respectively (1). LXRs form obligate heterodimers with another orphan nuclear receptor, RXR, and regulate cholesterol and lipid homeostasis. Originally it was believed that LXRs were orphan receptors until the discovery of endogenous ligands; that is, the oxysterols (1-4). LXR directly controls the transcription of several genes involved in the cholesterol efflux pathway including ATP binding cassettes A1 (ABCA-1) and G1 (5-8). The nuclear receptors LXR␣ and LXR␤ have been implicated in the control of cholesterol and fatty acid metabolism, and in the intestine ligand activation of LXR/RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6). A dual LXR␣/␤ agonist has been shown to reduce the development of atherosclerosis (9), and in a similar murine model the same authors found that two LXR␣/␤ agonists reduced inflammatory mRNA expression. This data suggest that LXR agonists may reduce atherosclerosis not only by promoting cholesterol efflux but also by limiting the production of inflammatory mediators in the artery wall (10). This anti-inflammatory profile has also been shown in two murine models of contact dermati...

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“…The potency (EC 50 ) of GW3965 and T1317 in a LXR cell-based reporter gene assay has been published at 190 Ϯ 30 and 85 Ϯ 10 nM, respectively (22). Dexamethasone (10…”

Section: Collection Of Human Lung Tissue Macrophages (Hltms)-mentioning

confidence: 99%

Section: Collection Of Human Lung Tissue Macrophages (Hltms)-mentioning

confidence: 99%

Section: Establishing An Appropriate Dose Of Lxr Ligand To Use In Thementioning

confidence: 99%

Section: Determination Of the Effect Of Gw3965 And T1317 On Lps-inducmentioning

confidence: 99%

See 2 more Smart Citations

Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Birrell

Catley

Hardaker

et al. 2007

Journal of Biological Chemistry

Self Cite

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“…Resveratrol (trans-3,5,4Ј-trihydroxy-trans-stilbene) is a naturally occurring compound that has been shown to prevent some forms of cancer (12)(13)(14) and other inflammatory diseases (15,16); however, the mechanism of action remains to be elucidated. Notably, resveratrol has been shown to inhibit the peroxidase activity of MPO (17); however, no studies have been published regarding its ability to scavenge HOCl.…”

mentioning

confidence: 99%

Myeloperoxidase-induced Genomic DNA-centered Radicals

Gomez-Mejiba

Zhai

Giménez

et al. 2010

Journal of Biological Chemistry

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Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis.Activation of neutrophils can initiate chemical mutagenesis and carcinogenesis by producing oxidative damage to the genome in the inflammatory environment (1-3). Myeloperoxidase (MPO, 4 donor hydrogen peroxide, oxidoreductase, EC 1.11.1.7), is a hemeprotein found in the azurophilic granules of neutrophils (4 -6). MPO uses H 2 O 2 to oxidize chloride ions, converting them into the powerful oxidant hypochlorous acid (HOCl/OCl Ϫ , pK a ϭ 7.46) (5). Although other mammalian peroxidases can oxidize a number of halides and pseudohalides to hypohalous and pseudohypohalous acids, MPO is the only mammalian enzyme that produces HOCl under physiological conditions (5). In sites of inflammation, H 2 O 2 used in the MPOcatalyzed oxidation of chloride is produced by dismutation of superoxide radical anion (O 2 . ). It is noteworthy that DNA is negatively charged and MPO is a cationic protein (5), which suggests that they can bind each other by electrostatic interactions. MPO is known to be taken up by cells surrounding an inflammatory site (7). It might be anticipated that this would make them highly vulnerable to DNA damage induced by H 2 O 2 . DNA-chloramines, which are less reactive than HOCl, are produced when HOCl reacts with DNA at its heterocyclic (ring) amino groups of guanosine and thymine groups and with exocyclic amino groups of guanosine, adenosine, and cytidine (8). Once formed, DNA-chloramines appear to undergo both one-and two-electron decay to produce DNA nitrogen-centered radicals, a process that is catalyzed by reduced metals and is promoted by UV irradiation and high temperatures (8 -9). Importantly, nitrogen-and carboncentered radicals can be trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) to form radic...

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