N-acetylcysteine and endothelial cell injury by sulfur mustard

Atkins, Kevin B.; Lodhi, Irfan J.; Hurley, Lauren L.; Hinshaw, Daniel B.

doi:10.1002/1099-1263(200012)20:1+<::aid-jat671>3.0.co;2-u

Cited by 62 publications

(47 citation statements)

References 18 publications

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“…Another mechanism by which extracellular GSH could protect the cells from CEES-induced damage is its possible extracellular conjugation with CEES, preventing CEES from entering the cell and causing its toxic effects (Salmen et al, 2005). Although the protective effects of 10 and 50 mM NAC have been shown in lipopolysaccharide-stimulated macrophages and endothelial cells (Atkins et al, 2000;Paromov et al, 2008), respectively, we observed both the protective and therapeutic effects of NAC at a 50 mM concentration against CEES-caused decrease in cell viability. The efficacy of NAC in ameliorating CEES-caused toxicity was stronger than that of GSH in HaCaT cells, which could be due to better uptake of GSH in JB6 cells compared with HaCaT cells as observed in this study, even though the GSH levels in control JB6 cells were lower than those in HaCaT cells.…”

Section: Discussionmentioning

confidence: 54%

“…CEES-caused mitochondrial oxidative damage and altered mitochondrial membrane potential are also reported in lung, liver, and other tissues, further indicating a role of oxidative stress in CEES-caused toxicity (Jafari, 2007;Gould et al, 2009;Black et al, 2010). Therefore, supplementing GSH or its precursors, including NAC, could help minimize this oxidative stress and reduce HD/CEES-caused toxicity, although its associated mechanism and defined biological systems are not well known (Amir et al, 1998;Atkins et al, 2000;Han et al, 2004;Arfsten et al, 2007;Paromov et al, 2007Paromov et al, , 2008. The protective role of extracellular GSH is highlighted in a study using the macrophage monocyte cell line J774 as well as in the mitotically active SVK 14 keratinocyte cell line (Smith et al, 1997;Amir et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In Vivo

Tewari‐Singh¹,

Agarwal²,

Huang³

et al. 2010

J Pharmacol Exp Ther

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Exposure to chemical warfare agent sulfur mustard (HD) is reported to cause GSH depletion, which plays an important role in HD-linked oxidative stress and skin injury. Using the HD analog 2-chloroethyl ethyl sulfide (CEES), we evaluated the role of GSH and its efficacy in ameliorating CEES-caused skin injury. Using mouse JB6 and human HaCaT epidermal keratinocytes, we observed both protective and therapeutic effects of exogenous GSH (1 or 10 mM) in attenuating a CEES-caused decrease in cell viability and DNA synthesis, as well as S and G 2 M phase arrest in cell cycle progression. However, the protective effect of GSH was stronger than its ability to reverse CEES-induced cytotoxic effect. The observed effect of GSH could be associated with an increase in intracellular GSH levels after its treatment before or after CEES exposure, which strongly depleted cellular GSH levels. N-Acetyl cysteine, a GSH precursor, also showed both protective and therapeutic effects against CEES-caused cytotoxicity. Buthionine sulfoximine, which reduces cellular GSH levels, caused an increased CEES cytotoxicity in both JB6 and HaCaT cells. In further studies translating GSH effects in cell culture, pretreatment of mice with 300 mg/kg GSH via oral gavage 1 h before topical application of CEES resulted in significant protection against CEEScaused increase in skin bifold and epidermal thickness, apoptotic cell death, and myeloperoxidase activity, which could be associated with increased skin GSH levels. Together, these results highlight GSH efficacy in ameliorating CEES-caused skin injury and further support the need for effective antioxidant countermeasures against skin injury by HD exposure.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In Vivo

Tewari‐Singh¹,

Agarwal²,

Huang³

et al. 2010

J Pharmacol Exp Ther

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“…Their antioxidative potential and importance in skin pathophysiology had been tested previously in a large number of investigations [2,[11][12][13][14]. However, the delivery of antioxidants to skin remains problematic in some cases.…”

Section: Mechanism Of Cees/hd-induced Skin Damagementioning

confidence: 99%

Topical Application of Liposomal Antioxidants for Protection Against CEES Induced Skin Damage

Stone¹,

Paromov²

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS.

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“…In humans, NAC is an effective chemoprotectant against toxic side-effects associated with cancer chemotherapy (Gurtoo et al, 1983;Holoye et al, 1983;Unverferth et al, 1983) and provides clinical benefit to persons with chronic obstructive pulmonary disease, probably by helping to neutraUze airway H2O2 formation (Kasielski and Nowak, 2001). In vitro experiments have also demonstrated the effectiveness of NAC in reducing or eliminating toxicity in various cell types (Atkins et al, 2000;Babich and Zuckerbraun, 2001;Noh et al, 1999;Park et al, 2002;Rao and Shaha, 2002;Recchioni et al, 2002;Ryu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Impact of 30-Day Oral Dosing with N-acetyl-l-cysteine on Sprague-Dawley Rat Physiology

et al. 2004

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The public reportina burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instnjotlons. ^^.^/^^'"a existing data sou^^^^^ gathering and malnteining the data needed, and completing and reviewing the collection of lnfom,ation Serjd comments regarding this Ijurden estimate or any other asped of ^|^*='™ <>' infonnation including suggestions for reducing this burden to Washington Headquarteis Services. Directorate for infomiation , 1215 Jefferson Dav^s High™y;suite 12IH Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for falling to comply with a collection of Information if it does not display a currently valid 0MB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT TJ-PE Final REPORT DATE (DD-MM-YYYY) 07-13-2004 TITLE AND SUBTITLE Impact SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION/AVAILABILITY STATEMENTApproved for public release; distribution is unlimited. SUPPLEMENTARY NOTES 242 ABSTRACT (Maximum 200 words)A number of studies have demonstrated a protective effect associated with N-acetyl-L-cysteine (NAC) against toxic chemical exposure. However, the impact of long-term oral dosing on tissue pathology has not been detennlned. In this study, we assessed the impact of long-term oral NAC administration on organ histopathology and tissue glutathione (GSH) and total glutathione-Stransferase (GST) activity levels in Sprague-Dawley (SD) rats. Groups of 20 SD rats (10 male, 10 female), 8 weeks of age, were dosed daily by oral gavage with deionized H2O (negative controls) or NAC solution at a rate of 600 or 1,200 mg/kg/d for 30 days. Animals were euthanized 6 hours after treatment on study Day 30. There were no significant differences in final body weights or weekly average weight gain between treatment groups. Serum alanine aminotransferase (ALT) activities were significantly elevated (p^O.05) in NAC-treated animals compared to controls when measured on study Day 30. Histopathologic evaluation of the liver, stomach, small intestine, liver, kidneys, spleen, thymus, and lungs revealed no lesions associated with NAC administration. When measured on study Day 30, total GST activity for kidney and skin from NAC-treated animals were increased 39-131% as compared to controls. Tissue GSH concentrations from NAC-treated animals were increased 24-81% as compared with negative controls. -H=wthePsfadies-afe-Fieede€l-te-d6teFmiB6-i^4he-observed4ocreaseJn-tissue GSH concentration and GST activity provide a degree of chemoprotection against dernial and systemic chemical toxicants. SUBJECT TERMS Disclaimer:This work was supported by the U.S. Navy Office of Naval Research Work Unit #60263. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. This article is approved for pubhc release, di...

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N-acetylcysteine and endothelial cell injury by sulfur mustard

Cited by 62 publications

References 18 publications

Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In Vivo

Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In Vivo

Topical Application of Liposomal Antioxidants for Protection Against CEES Induced Skin Damage

Impact of 30-Day Oral Dosing with N-acetyl-l-cysteine on Sprague-Dawley Rat Physiology

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