A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong‐Suk; Atlas, Daphné; Lee, Yong Chul

doi:10.1038/emm.2007.82

Cited by 72 publications

(52 citation statements)

References 62 publications

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“…In addition, HIF-1 activation may also contribute to mucin gene expression (46). Based on these various considerations, the ability of GSNO to inhibit HIF-1 activation during allergic inflammation might suggest an anti-inflammatory role, similar to that of other anti-inflammatory compounds that were shown to suppress both NF-kB and HIF-1 (30,47). However, direct activation of HIF-1 by GSNO (as seen in naive mice) might also promote inflammation, remodeling, and/or mucus metaplasia.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Cytosolic or nuclear extractions from harvested lung tissues were performed as described previously (12). For western blot analysis, samples were processed by the procedure mentioned above.…”

Section: Cytosolic and Nuclear Protein Extractions For Analysis Of Nf-kbmentioning

confidence: 99%

Salidroside Attenuates Allergic Airway Inflammation Through Negative Regulation of Nuclear Factor-Kappa B and p38 Mitogen–Activated Protein Kinase

Yan

Choi

2014

J Pharmacol Sci

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Abstract. Salidroside is a biologically active ingredient of Rhodiola rosea, which has several interesting biological properties, including anti-oxidant and anti-inflammatory; however, its anti-allergic effects are poorly understood. The objective of this study is to determine whether salidroside attenuates the inflammatory response in an ovalbumin (OVA)-induced asthma model. OVA-sensitized/challenged mice show airway hyperresponsiveness (AHR) to inhaled methacholine and have an increased amount of T-helper2 type cytokines [interleukin (IL)-4, IL-5, and IL-13] and eosinophils in their bronchoalveolar lavage fluids and lung tissues. However, three successive intraperitoneal administrations of salidroside before the last OVA challenge result in significant inhibition of these asthmatic reactions. Moreover, OVA significantly increases the activation of nuclear factor-kappa B (NF-kB) and p38 mitogen-activated protein kinase (MAPK) in lung tissues, whereas salidroside markedly suppresses NF-kB translocation and reduces phosphorylation of p38 MAPK. Furthermore, salidroside attenuates the expression of intercellular adhesion molecule 1 and IL-6 through modulating the activities of p38 MAPK and NF-kB in the BEAS-2B cells stimulated by proinflammatory cytokines. These findings indicate that salidroside protects against OVA-induced airway inflammation and AHR, at least in part via downregulation of NF-kB and p38 MAPK activities. Our data support the utility of salidroside as a potential medicine for the treatment of asthma.

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“…Increased ROS generation, which results in an imbalance between oxidative forces and the antioxidant defense systems, has been implicated in the pathogenesis of asthma (Rahman et al, 1999;Dworski et al, 2000;Rahman et al, 2000;Lee et al, 2006Lee et al, , 2007Kirkham et al, 2006). ROS are capable of eliciting a variety of pathological changes, including the peroxidation of lipids, proteins, and DNA and the generation of chemoattractants, as well as enhancements of AHR, airway secretion, and vascular permeability in asthmatic airways (Barnes et al, 1990;Henricks et al, 2001;Andreadis et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

Kim

Moon

et al. 2008

Exp Mol Med

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Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-α, IL-1β, and LPS resulted in significant ROS production and NF-κB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-α levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b + macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.

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A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Cited by 72 publications

References 62 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

Salidroside Attenuates Allergic Airway Inflammation Through Negative Regulation of Nuclear Factor-Kappa B and p38 Mitogen–Activated Protein Kinase

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

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