Expression of vascular endothelial growth factor and hypoxiainducible factor in the airway of asthmatic patients

Lee, Sook Young; Kwon, Soon Seog; Kim, Kwan Hyoung; Moon, Hwa Sik; Song, Jae-Young; Park, Sung Hak; Kim, Young Kyoon

doi:10.1016/s1081-1206(10)60971-4

Cited by 39 publications

(43 citation statements)

References 21 publications

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“…A recently recognized feature of chronic inflammatory airway diseases is the activation of the heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) within the airway or alveolar epithelium (36,45,56). Although HIF-1 is traditionally known as a master regulator of O 2 homeostasis, and a key mediator of adaptive responses to tissue hypoxia (53), HIF-1 has more recently emerged as an important mediator in immune and inflammatory responses (18,40).…”

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confidence: 99%

Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction

Olson¹,

Hristova²,

Heintz³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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The respiratory epithelium forms an important barrier against inhaled pollutants and microorganisms, and its barrier function is often compromised during inflammatory airway diseases. Epithelial activation of hypoxia-inducible factor-1 (HIF-1) represents one feature of airway inflammation, but the functional importance of HIF-1 within the respiratory epithelium is largely unknown. Using primary mouse tracheal epithelial (MTE) cells or immortalized human bronchial epithelial cells (16HBE14o-), we evaluated the impact of HIF-1 activation on loss of epithelial barrier function during oxidative stress. Exposure of either 16HBE14o- or MTE cells to H(2)O(2) resulted in significant loss of transepithelial electrical resistance and increased permeability to fluorescein isothiocyanate-dextran (4 kDa), and this was attenuated significantly after prior activation of HIF-1 by preexposure to hypoxia (2% O(2); 6 h) or the hypoxia mimics CoCl(2) or dimethyloxalylglycine (DMOG). Oxidative barrier loss was associated with reduced levels of the tight junction protein occludin and with hyperoxidation of the antioxidant enzyme peroxiredoxin (Prx-SO(2)H), events that were also attenuated by prior activation of HIF-1. Involvement of HIF-1 in these protective effects was confirmed using the pharmacological inhibitor YC-1 and by short-hairpin RNA knockdown of HIF-1α. The protective effects of HIF-1 were associated with induction of sestrin-2, a hypoxia-inducible enzyme known to reduce oxidative stress and minimize Prx hyperoxidation. Together, our results suggest that loss of epithelial barrier integrity by oxidative stress is minimized by activation of HIF-1, in part by induction of sestrin-2.

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confidence: 99%

Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction

Olson¹,

Hristova²,

Heintz³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The present studies were designed to explore whether administration of GSNO could be employed to suppress NFkB activation, markers of allergic inflammation, and mucus metaplasia in an ovalbumin (OVA) model of allergic airway disease in mice. In addition, in light of recent studies demonstrating a potential role for the transcription factor, hypoxiainducible factor (HIF)-1, in allergic airway inflammation (16), and its known regulation by NO and S-nitrosothiols (17), we also explored the impact of GSNO on activation of HIF-1 during allergic inflammation. Finally, we determined the contribution of NOS2, a presumed major source of endogenous NO and S-nitrosothiols during inflammation, in regulating these transcription factors in this model of allergic asthma.…”

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confidence: 99%

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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“…Other potential HIF-1 ␣ targets in asthma include vascular endothelial growth factor (VEGF), which is increased in the airway in asthmatics and causes angiogenesis [6] , and MUC5AC [7] . The expression of HIF-1 ␣ is increased in airway biopsies from asthmatics [8] and also in activated mast cells [9] . Furthermore, a novel thiol compound was recently shown to attenuate allergic lung inflammation in mice, in association with reduced HIF-1 ␣ expression [10] .…”

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confidence: 99%

Enhanced Interferon-γ Gene Expression in T Cells and Reduced Ovalbumin-Dependent Lung Eosinophilia in Hypoxia-Inducible Factor-1-α-Deficient Mice

Guo

Shimoda

et al. 2009

Int Arch Allergy Immunol

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Expression of vascular endothelial growth factor and hypoxiainducible factor in the airway of asthmatic patients

Cited by 39 publications

References 21 publications

Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction

Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction

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

Enhanced Interferon-γ Gene Expression in T Cells and Reduced Ovalbumin-Dependent Lung Eosinophilia in Hypoxia-Inducible Factor-1-α-Deficient Mice

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