Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid

Saleh, Dina; Ernst, Pierre; Lim, Shuang Fang; Barnes, Peter J.; Giaid, Adel

doi:10.1096/fasebj.12.11.929

Cited by 395 publications

(352 citation statements)

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“…13,26,53 Here, evidence for reactive oxygen and nitrogen species involvement in airway epithelial cell apoptosis in asthma include the finding of increased nitrotyrosine in epithelial cells after inhibition of SOD in vitro, and in airway epithelial cells in vivo in asthma in other studies. 13,22,54 Other reports have shown that MnSOD is a target for tyrosine nitration and oxidation, 30,55 which leads to loss of enzyme function, subsequent oxidative damage of mitochondrial proteins, and ultimately cell death. 30,56 Here, we provide quantitative data on MnSOD oxidation and nitration in human asthmatic lungs.…”

Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

172

149

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Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

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Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

172

149

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“…By using a combinatorial library approach, it was anticipated that, through variations in X and Y functionality, specificity for individual redox factors could be achieved. We constructed a limited array (2 ϫ 6) where X was either NHCH 3 or NHBn and Y was methyl, phenyl, m-cyanophenyl, m-nitrophenyl, macetylaniline, or m-methylbenzoate. These analogs were evaluated for their ability to inhibit transcription in transiently transfected human lung epithelial A549 cells from either an AP-1 or NF-B reporter (22).…”

Section: Development Of Small-molecule Inhibitor Of Ap-1 Transcriptiomentioning

confidence: 99%

“…Specificity for individual redox factors was achieved through variations in X and Y functionality by using a combinatorial library approach. A limited array (2 ؋ 6) was constructed where X was either NHCH 3 …”

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confidence: 99%

“…The eosinophils and other leukocytes undergo respiratory burst activation with release of reactive oxygen species (ROS), including superoxide and its dismutation product, hydrogen peroxide (H 2 O 2 ) (2). Increased airway levels of ROS (3,4), coupled with decreased levels of antioxidants such as glutathione (5), may lead to an oxidant͞ antioxidant imbalance in the lungs of patients with asthma and activation of redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor B (NF-B). These transcription factors, in collaboration with Th2-specific transcription factors (i.e., c-maf, GATA-3, Stat6), control expression of Th2 cytokines (e.g., IL-4, IL-5, IL-13), the molecular hallmarks of asthma (6).…”

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confidence: 99%

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Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

Nguyen

Teo

Matsuda

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Asthma is characterized by an oxidant͞antioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors, nuclear factor B (NF-B), and activator protein-1 (AP-1). To develop therapeutic strategies for asthma, we used a chemogenomics approach to screen for small molecule inhibitor(s) of AP-1 transcription. We developed a ␤-strand mimetic template that acts as a reversible inhibitor (pseudosubstrate) of redox proteins. This template incorporates an enedione moiety to trap reactive cysteine nucleophiles in the active sites of redox proteins. Specificity for individual redox factors was achieved through variations in X and Y functionality by using a combinatorial library approach. A limited array (2 ؋ 6) was constructed where X was either NHCH 3

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“…As such, in asthmatics or other inflammatory lung diseases the exhaled NO appears to derive from NOS2 expressed within bronchial epithelial cells or immuno-inflammatory cells (Kharitonov et al 1994, Barnes 1995, Guo et al 2000, Van Der Vliet et al 2000, Yates 2001. Indeed, the level of NO concentration in exhaled air is considered to be a marker of airway inflammation and the exhaled NO observed in asthmatics has been associated with airway eosinophilia and AHR (Saleh et al 1998, Ricciardolo 2003.…”

mentioning

confidence: 99%