Arachidonic Acid Signaling in Pathogenesis of Allergy: Therapeutic Implications

Serrano-Mollar, Anna; Closa, Daniel

doi:10.2174/1568010053586354

Cited by 23 publications

(15 citation statements)

References 87 publications

(92 reference statements)

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“…Leukocytes and lymphocytes are known to express COX-1, COX-2, 5-LO, and 15-LO-1 (35–37), which are all capable of generating arachidonic acid-derived lipid hydroperoxides (1, 32, 38). Western blot analyses revealed that the lymphoblastoid CESS cell line did not express COX-2 or 15-LO-1.…”

Section: Discussionmentioning

confidence: 99%

5-Lipoxygenase-mediated Endogenous DNA Damage

Jian

Lee

Williams

et al. 2009

Journal of Biological Chemistry

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Lipoxygenases (LOs) convert polyunsaturated fatty acids into lipid hydroperoxides. Homolytic decomposition of lipid hydroperoxides gives rise to endogenous genotoxins such as 4-oxo-2(E)-nonenal, which cause the formation of mutagenic DNA adducts. Chiral lipidomics analysis was employed to show that a 5-LO-derived lipid hydroperoxide was responsible for endogenous DNA-adduct formation. The study employed human lymphoblastoid CESS cells, which expressed both 5-LO and the required 5-LO-activating protein (FLAP). The major lipid peroxidation product was 5(S)-hydroperoxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid, which was analyzed as its reduction product, 5(S)-hydroxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5(S)-HETE)). Concentrations of 5(S)-HETE increased from 0.07 ± 0.01 to 45.50 ± 4.05 pmol/107 cells upon stimulation of the CESS cells with calcium ionophore A23187. There was a concomitant increase in the 4-oxo-2(E)-nonenal-derived DNA-adduct, heptanone-etheno-2′-deoxyguanosine (HϵdGuo) from 2.41 ± 0.35 to 6.31 ± 0.73 adducts/107 normal bases. Biosynthesis of prostaglandins, 11(R)-hydroxy-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid, and 15(R,S)-hydroxy-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid revealed that there was cyclooxygenase (COX) activity in the CESS cells. Western blot analysis revealed that COX-1 was expressed by the cells, but there was no COX-2 or 15-LO-1. FLAP inhibitor reduced HϵdGuo-adducts and 5(S)-HETE to basal levels. In contrast, aspirin, which had no effect on 5(S)-HETE, blocked the formation of prostaglandins, 15-HETE, and 11-HETE but did not inhibit HϵdGuo-adduct formation. These data showed that 5-LO was the enzyme responsible for the generation of the HϵdGuo DNA-adduct in CESS cells.

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Section: Discussionmentioning

confidence: 99%

5-Lipoxygenase-mediated Endogenous DNA Damage

Jian

Lee

Williams

et al. 2009

Journal of Biological Chemistry

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“…Petroselinic acid was induced but 2-oxoarginine was reduced by both artesunate and dexamethasone. Elevation in petroselinic acid can suppress arachidonic acid which is a key lipid mediator that promotes airway inflammation (Weber et al 1995;Serrano-Mollar and Closa 2005). Reduction of 2-oxoarginine may help lessen certain lung toxicity (Marescau et al 1990).…”

Section: Antiinflammatorymentioning

confidence: 99%

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

et al. 2014

Metabolomics

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The anti-malarial drug artesunate possesses anti-inflammatory and anti-oxidative actions in experimental asthma, comparable to corticosteroid. We hypothesized that artesunate may modulate disease-relevant metabolic alterations in allergic asthma. To explore metabolic profile changes induced by artesunate in allergic airway inflammation, we analysed bronchoalveolar lavage fluid (BALF) and serum from naïve and ovalbumininduced asthma mice treated with artesunate, using both gas and liquid chromatography-mass spectrometry metabolomics. Pharmacokinetics analyses of serum and lung tissues revealed that artesunate is rapidly converted into the active metabolite dihydroartemisinin. Artesunate effectively suppressed BALF total and differential counts, and repressed BALF Th2 cytokines, IL-17, IL-12(p40), MCP-1 and G-CSF levels. Artesunate had no effects on both BALF and serum metabolome in naïve mice. Artesunate promoted restoration of BALF sterols (cholesterol, cholic acid and cortol), phosphatidylcholines and carbohydrates (arabinose, mannose and galactose) and of serum 18-oxocortisol, galactose, glucose and glucouronic acid in asthma. Artesunate prevented OVA-induced increases in pro-inflammatory metabolites from arginine-proline metabolic pathway, particularly BALF levels of urea and alanine and serum levels of urea, proline, valine and homoserine. Multiple statistical correlation analyses revealed association between altered BALF and serum metabolites and inflammatory cytokines. Dexamethasone failed to reduce Wanxing Eugene Ho and Yong-Jiang Xu have contributed equally to this work.Electronic supplementary material The online version of this article (doi:10.1007/s11306-014-0699-x) contains supplementary material, which is available to authorized users. Metabolomics (2015) 11:380-390 DOI 10.1007 urea level and caused widespread changes in metabolites irrelevant to asthma development. Here we report the first metabolome profile of artesunate treatment in experimental asthma. Artesunate restored specific metabolic perturbations in airway inflammation, which correlated well with its anti-inflammatory actions. Our metabolomics findings further strengthen the therapeutic value of using artesunate to treat allergic asthma.

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“…We have previously reported that IL-1␣ induces COX-2 expression in 18Co cells (20,21,50). Since eicosanoid production is known to increase during IBD (24,41,57) and since LOX products increase during AA metabolism (11,34,38,64) and are produced by neutrophils during inflammation (70,71), we tested the effect of HETEs and lipoxins on COX-2 protein expression in 18Co. Of the HETEs tested, only 15(S) alone increased COX-2 expression above that in control cells.…”

Section: Effect Of Lox Products On Il-1␣-induced Cox-2 Protein Levelsmentioning

confidence: 99%

HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts

Mari¹,

Saada²,

Mifflin³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E(2) secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1alpha-induced cyclooxygenase-2 (COX-2) expression is the result of NF-kappaB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1alpha-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 +/- 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-beta-d-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1alpha to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.

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Arachidonic Acid Signaling in Pathogenesis of Allergy: Therapeutic Implications

Cited by 23 publications

References 87 publications

5-Lipoxygenase-mediated Endogenous DNA Damage

5-Lipoxygenase-mediated Endogenous DNA Damage

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts

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