Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant,<i>N</i>-acetyl-l-cysteine, and novel thiol antioxidant,<i>N,N′</i>-bis-2-mercaptoethyl isophthalamide

Patel, Rishi B.; Kotha, Sainath R.; Sauers, Lynn A.; Malireddy, Smitha; Gurney, Travis O.; Gupta, Niladri; Elton, Terry S.; Magalang, Ulysses J.; Marsh, Clay B.; Haley, Boyd E.; Parinandi, Narasimham L.

doi:10.3109/15376516.2012.673089

Cited by 22 publications

(14 citation statements)

References 56 publications

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“…1). These data are in agreement with other previous studies, which have reported an increase in the production of ROS upon treatment with BLM (2,19). Antioxidant enzymes are involved in the detoxification or scavenging of oxidative free radicals in A B C the cells.…”

Section: Discussionsupporting

confidence: 83%

“…Previous studies have suggested that alteration of oxidative stress and thiol-redox are initiating and propagating forces in the pathogenesis of bleomycin (BLM)-induced pulmonary fibrosis (1,2). BLM is an effective chemotherapeutic agent used primarily in the treatment of lymphoma, squamous cell carcinoma, testicular cancer and malignant pleural effusion (3).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Kruppel-like factor 9 in bleomycin-induced pulmonary toxicity

Wang

et al. 2015

Molecular Medicine Reports

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Abstract.Oxidative stress or the production of reactive oxygen species (ROS) has been implicated as an important factor in the development of bleomycin (BLM)-induced pulmonary toxicity; however, the mechanism behind the toxicity remains to be elucidated. The present study aimed to investigate the key factor involved in BLM-induced toxicity. The study was conducted in human pulmonary fibroblast (HPF) cells and in a mouse model. The ROS level, cell death assay, protein and gene expression levels of Kruppel-like factor 9 (Klf9) and other associated factors were assessed. A dose-dependent increase in ROS, lipid peroxidation, cell death, and protein and mRNA expression levels of NF-E2-related transcription factor 2 (Nrf2) and Klf9 were observed in BLM-treated cells. However, the expression levels of the other antioxidant proteins assessed, including catalase, super oxide dismutase, glutathione reductase and thioredoxin reductase 2, were decreased. The expression levels of Nrf2 were decreased in cells treated with a higher concentration (>200 µM) of BLM. These results suggested that in response to increased intracellular levels of ROS, above a critical threshold, Nrf2 stimulates the expression of Klf9, resulting in a further increase in Klf9-mediated ROS production and subsequent cell death. Furthermore, the data suggested that Klf9 may be considered as an adjunctive therapeutic target for BLM-induced pulmonary toxicity.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Involvement of Kruppel-like factor 9 in bleomycin-induced pulmonary toxicity

Wang

et al. 2015

Molecular Medicine Reports

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“…Changes in intracellular GSH levels altered epithelial barrier function, which was associated with alterations of tight junction protein expression. Oxidative stress induced by various reactive oxygen species disrupts barrier function by altering tight junctions (35), and treatment with triol-redox antioxidants protects barrier integrity in the lung and intestine (15,29,31). Baneriee et al (5) reported that the thiol antioxidant N-acetylcysteine amide could protect the blood-brain barrier from oxidative damage in HIV-1 Tg mice by increasing tight junction proteins and restoring blood-brain barrier function.…”

Section: Resultsmentioning

confidence: 97%

Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats

Fan

Staitieh

Jensen

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.

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“…Our results demonstrate that NAC pretreatment increases survival in cultured corneal endothelial cells exposed to oxidative and ER stress. Others have shown similar protective effects of NAC on oxidative stress induced by bleomycin in cultured lung vascular endothelial cells (Patel et al, 2012). To our knowledge, however, the present work is the first to report a protective effect of NAC on ER stress induced by thapsigargin.…”

mentioning

confidence: 67%

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy

Kim

Meng

Jun

2014

Experimental Eye Research

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The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo® luminescent reagent. Two-month-old homozygous knock-in Col8a2L450W/L450W mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (pitalic>0.01). Corneal endothelial cell density (CD) was higher (p=0.001) and percent polymegathism was lower (p=0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD.

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Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant,N-acetyl-l-cysteine, and novel thiol antioxidant,N,N′-bis-2-mercaptoethyl isophthalamide

Cited by 22 publications

References 56 publications

Involvement of Kruppel-like factor 9 in bleomycin-induced pulmonary toxicity

Involvement of Kruppel-like factor 9 in bleomycin-induced pulmonary toxicity

Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy

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