2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model

Huerta-Yépez, Sara; Baay-Guzmán, Guillermina; Garcia-Zepeda, R.; Hernández-Pando, Rogelio; Vega, Mario I.; González-Bonilla, Cesar R.; Bonavida, Benjamin

doi:10.1016/j.clim.2008.07.023

Cited by 37 publications

(32 citation statements)

References 36 publications

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“…To determine HIF-1 activation during allergic airway inflammation, lung nuclear extracts were analyzed using an HIF-1 activity assay ( Figure 5A), and HIF-1a stabilization was determined in wholelung protein lysates by Western blot ( Figure 5B). As shown, HIF-1 was markedly activated in OVA/OVA animals compared with Alum/OVA control animals, in agreement with recent reports (30,31). The changes in overall lung HIF-1a protein levels and HIF-1 DNA binding activity in OVA/OVA mice were not associated with significant changes in HIF-1a mRNA, as determined by real-time PCR (Figure 5C), suggesting HIF-1 activation by a post-transcriptional mechanism.…”

Section: Activation Of Hif-1 During Allergic Airway Inflammation: Modsupporting

confidence: 91%

“…For example, the inhibitory effects of GSNO on matrix metalloproteinase27, an epithelial protease involved in regulating epithelial repair and transepithelial leukocyte trafficking (41), might promote epithelial injury and inflammation. Activation of HIF-1, by localized tissue hypoxia, or by various inflammatory mediators, including NO, is emerging as an important feature of inflammation and innate immunity, and may also contribute to allergic airway inflammation (30,31,42). Indeed, our studies confirm that overall lung HIF-1 activity is increased in response to allergen challenge of OVA-sensitized mice, and this is significantly affected by instillation of GSNO.…”

Section: Discussionsupporting

confidence: 69%

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Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

Olson

Kasahara²,

Hristova³

et al. 2011

Am J Respir Cell Mol Biol

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Induction of nitric oxide synthase (NOS)-2 and production of nitric oxide (NO) are common features of allergic airway disease. Conditions of severe asthma are associated with deficiency of airway S-nitrosothiols, a biological product of NO that can suppress inflammation by S-nitrosylation of the proinflammatory transcription factor, NF-kB. Therefore, restoration of airway S-nitrosothiols might have therapeutic benefit, and this was tested in a mouse model of ovalbumin (OVA)-induced allergic inflammation. Naive or OVAsensitized animals were administered S-nitrosoglutathione (GSNO; 50 ml, 10 mM) intratracheally before OVA challenge and analyzed 48 hours later. GSNO administration enhanced lung tissue S-nitrosothiol levels and reduced NF-kB activity in OVA-challenged animals compared with control animals, but did not lead to significant changes in total bronchoalveolar lavage cell counts, differentials, or mucus metaplasia markers. Administration of GSNO also altered the activation of hypoxia-inducible factor (HIF)-1, leading to HIF-1 activation in naive mice, but suppressed HIF-1 activation in OVA-challenged mice. We assessed the contribution of endogenous NOS2 in regulating NF-kB and/or HIF-1 activation and allergic airway inflammation using NOS2 2/2 mice. Although OVA-induced NF-kB activation was slightly increased in NOS2 2/2 mice, associated with small increases in bronchoalveolar lavage neutrophils, other markers of allergic inflammation and HIF-1 activation were similar in NOS2 2/2 and wildtype mice. Collectively, our studies indicate that instillation of GSNO can suppress NF-kB activation during allergic airway inflammation, but does not significantly affect overall markers of inflammation or mucus metaplasia, thus potentially limiting its therapeutic potential due to effects on additional signaling pathways, such as HIF-1.Keywords: nitric oxide; asthma; S-nitrosothiols; nuclear factor-kB; hypoxia inducible factor21Nitric oxide (NO) is a ubiquitous signaling molecule that is continuously produced within the airways of healthy individuals, primarily originating from constitutive expression of the inducible NO synthase (NOS)-2 (iNOS) within the respiratory epithelium (1, 2). Airway NO production is increased under conditions of infection or inflammation due to induction of NOS2. Indeed, induction of airway NOS2 and increased airway production of NO are common symptoms of allergic asthma, an inflammatory disease of the airways characterized by airway hyperreactivity, smooth muscle thickening, and mucus hypersecretion. Analysis of exhaled human breath has demonstrated higher levels of NO in patients with asthma compared with healthy control subjects, with increases in epithelial NOS2 being the primary site of its production (1, 2). Induction of NOS2 is critical in innate antimicrobial or antiviral host defense, but its contribution in conditions of airway inflammation, including allergic asthma, is still controversial, and includes both pro-and anti-inflammatory properties, based on studies with NOS2 inhibitors...

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Section: Activation Of Hif-1 During Allergic Airway Inflammation: Modsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 69%

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

Olson

Kasahara²,

Hristova³

et al. 2011

Am J Respir Cell Mol Biol

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“…It has been reported that 2ME 2 ameliorates Smad2/3 activation (21). Similarly, several studies from our laboratory and others have demonstrated that 2ME 2 can attenuate both PI3K/Akt/mTOR (22)(23)(24)(25) and extracellular signal-regulated protein kinase (ERK) (26,27), and accordingly 2ME 2 demonstrates strong antifibrotic effects (21,(28)(29)(30). This polypharmacologic profile could impart on 2ME 2 the merit of being a multipotent TGF-b3 inhibitor in uterine fibroid cells.…”

mentioning

confidence: 77%

“…Previous studies from our laboratory and others have demonstrated that 2ME 2 is a microtubule-targeting drug that demonstrates antifibrotic effects (21,(27)(28)(29). Therefore, we tested the hypothesis that 2ME 2 , by its effect on microtubule dynamics, ameliorates the TGF-b3 profibrotic response in huLM.…”

Section: Me 2 Ameliorates the Tgf-b3 Profibrotic Response In Hulm Cellsmentioning

confidence: 93%

2-Methoxyestradiol causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells

Salama

Diaz-Arrastia

Kılıç

et al. 2012

Fertility and Sterility

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“…In addition to anti-tumor actions, 2MEO displays antiinflammatory activity in animal models of rheumatoid arthritis (Josefsson and Tarkowski, 1997;Issekutz and Sapru, 2008;Plum et al, 2009), chronic airway inflammation (Huerta-Yepez et al, 2008), and pulmonary fibrosis (Langenbach et al, 2007;Tofovic et al, 2009). In many of these chronic models, the effects of 2MEO are attributed to antiangiogenic activity.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Evidence for Anti-Inflammatory Properties of 2-Methoxyestradiol

Shand

Langenbach²,

Keenan³

et al. 2010

J Pharmacol Exp Ther

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2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17␤-estradiol that interacts with estrogen receptors and microtubules. It has acute anti-inflammatory activity in animal models that is not attributable to known antiproliferative or antiangiogenic actions. Because macrophages are central to the innate inflammatory response, we examined whether suppression of macrophage activation by 2MEO could account for some of its anti-inflammatory effects. Inflammatory mediator production stimulated by lipopolysaccharide (LPS) and interferon-␥ in the J774 murine macrophage cell line or human monocytes was measured after treatment with 2MEO or the anti-inflammatory agent dexamethasone. The effect of these agents on LPSinduced acute lung inflammation in mice was also examined. 2MEO suppressed J774 macrophage interleukin-6 and prostaglandin E 2 production (by 30 and 47%, respectively, at 10 M) and human monocyte tumor necrosis factor-␣ production (by 60% at 3 M). Estradiol had no effect on J774 macrophage activation, nor did the estrogen receptor antagonist 7␣-[9- [(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17␤-diol (ICI 182,780) prevent the effects of 2MEO. The actions of 2MEO were not mimicked by the microtubuleinterfering agents colchicine or paclitaxel. In mice exposed to LPS, bronchoalveolar lavage protein content, a measure of vascular leak and epithelial injury, was reduced to a comparable extent (ϳ54%) by treatment with 2MEO (150 mg ⅐ kg Ϫ1 ) or dexamethasone (1 mg ⅐ kg Ϫ1 ). In addition, 2MEO reduced LPS-induced interleukin-6 gene expression. Thus, 2MEO modulates macrophage activation in vitro and has high-dose acute anti-inflammatory activity in vivo. These findings are consistent with the acute anti-inflammatory actions of 2MEO being mediated in part by the suppression of macrophage activation.

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2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model

Cited by 37 publications

References 36 publications

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

2-Methoxyestradiol causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells

In Vitro and In Vivo Evidence for Anti-Inflammatory Properties of 2-Methoxyestradiol

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