A biochemical hypothesis explaining the generation of pathology in human skin by mustard gas (HD) is presented which links the initiation of DNA damages to local alterations of metabolism and subsequent development of blisters. The proposed sequence involves HD alkylation of purines in DNA which are processed to form apurinic sites. Apurinic endonucleases act at these sites to produce backbone breaks in DNA which cause activation of the chromosomal enzyme poly(ADP-ribose)polymerase. This enzyme utilizes NAD+ as a substrate and, at vesicating doses of HD, would deplete the cells of their NAD+ content. The depletion in NAD+ would cause inhibition of glycolysis, and the resulting accumulation of common intermediates would stimulate the NADP+-dependent hexosemonophosphate shunt (HMS). Such stimulation of the HMS has been associated with DNA damage and enhancement of protease synthesis and release. These proteases could be responsible for development of subepidermal blisters which result from fluid accumulation in the cavity created by separation of the moribund basal cell layer from the basement membrane—a characteristic feature of HD-exposed human skin. Partial validation of this biochemical hypothesis has been achieved. DNA alkylated with either monofunctional or bifunctional sulfur mustards, followed by spontaneous or enzymatic depurination, was shown to be sensitized to degradation by apurinic endonuclease. Studies on the effect of HD on human skin grafted to athymic nude mice demonstrated dose- and time-related decreases in NAD+ levels. These decreases in NAD+ levels proceded and correlated to the predicted severity of pathology. The participation of poly(ADP-ribose)polymerase activity in the HD-induced NAD+ loss was substantiated by prevention of this loss in the presence of inhibitors of the enzyme. Additional supporting evidence for the proposed mechanism was obtained at the cellular level by studies which utilized human leukocytes. The subsequent involvement of the HMS and proteases in HD-induced vesication is discussed.
Last. Bruno Papirmeister(DA: United States Department of the Army)H-Index: 12
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Abstract O 6 -Ethylthioethyldeoxyguanosine has been synthesized from 6-chloro-3′,5′-di- O -acetyldeoxyguanosine and characterized by UV, fluorescence, and mass spectrometry. High-pressure liquid chromatography studies have shown that this modified nucleoside is formed when the one-armed sulfur mustard, chloroethyl ethyl sulfide, reacts with deoxyguanosine. This result supports the hypothesis that the mutagenic effects of the sulfur mustards are caused in part by substitution of the O 6 -position...
AbstractSulfur mustard (SM) is a powerful vesicant in humans whose pathogenic mechanism is not well understood and an agent for which no effective therapy exists. We selected human skin grafted to congenitally athymic nude mice to study SM-induced injury because the injury in various animal models differs from skin injury in humans. Grafts made from full-thickness human neonatal foreskin or from partial-thickness adult facial, mammary, and abdominal skin were exposed to SM in either the liquid o...
#1Bruno Papirmeister(DA: United States Department of the Army)H-Index: 12
#2Clark L. Gross(DA: United States Department of the Army)H-Index: 11
Last. Henry Louis Meier(DA: United States Department of the Army)H-Index: 11
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AbstractThe human skin graft/nude mouse model was used to study sulfur mustard (SM) -induced pathology of skin at the ultrastructural level. The electron microscope confirms and extends the histopathology previously noted under light microscopy. SM caused extensive injury to the basal keratinocytes, the severity of which was dependent on both time and dose. Ultrastructurally visible damage took several hours to develop. The following sequence of morphological changes was observed: (a) Extensive ...
This study was undertaken to determine whether plasminogen was present within the epidermis. Cryostat sections of normal human skin were incubated with either whole rabbit antihuman plasminogen serum, the IgG fraction thereof, or the immune-specific IgG fraction thereof, purified by affinity chromatography on plasminogen-Sepharose. Standard indirect immunofluorescent techniques using rhodamine-conjugated goat antirabbit IgG were subsequently employed. Fluorescence was localized to the basal laye...
Binding of anti-cell surface pemphigus autoantibodies to cultured human epidermal cells stimulates synthesis and secretion of plasminogen activator (PA). Increases in PA activity were detected within 6 h of the addition of IgG and stimulation was dependent upon IgG concentration. Stimulation of PA activity was inhibited by cycloheximide, which indicates that synthesis of protein was necessary. Pharmacological doses of dexamethasone also prevented IgG-induced stimulation of PA. Electrophoretic pr...
The effect of several classes of DNA-damaging chemicals and closely related compounds on cellular nicotinamide adenine dinucleotide (NAD) levels was studied in freshly isolated peripheral human lymphocytes. Of the 21 compounds examined, 7 were direct DNA-damaging agents and 14 were non-DNA-damaging compounds or required metabolic activation to cause DNA damage. Rapid lowering of cellular NAD levels was caused by each of the direct DNA-damaging chemicals examined in this study including N -methyl...
In a search for new inhibitors of the nuclear enzyme poly(ADP-ribose) synthetase, it was found that various benzamides substituted in the 3-position were the most inhibitory compounds found to date. Two of the benzamides, 3-aminobenzamide and 3-methoxybenzamide, were found to be competitive inhibitors, with Ki values or less than 2 microM.
Abstract We have studied plasminogen activator (PA) synthesis in fibroblast cultures exposed to ultraviolet light (UV) and to several agents that produce DNA damage. PA synthesis was induced by UV in chicken, hamster, rat, mouse and human fibroblasts. The rate of enzyme synthesis, like the inhibition of 3 H-thymidine incorporation, was a first-order function of UV fluence, and the UV sensitivity of these responses was very similar. The kinetics of PA induction after UV were much slower and the d...
Sulfur mustard, a chemical warfare agent known to be a vesicant of skin, readily diffuses in the blood stream and reaches internal organs. In the present study, we used the analog (2-chloroethyl)-ethyl-sulfide (CEES) to provide novel data on the systemic diffusion of vesicants and on their ability to induce brain damage, which result in neurological disorders. SKH-1 hairless mice were topically exposed to CEES and sacrificed at different time until 14 days after exposure. A plasma metabolomics s...
2-Chloroethyl ethyl sulfide (CEES) is a simulant for the chemical warfare agent, bis(2-chloroethyl) sulfide, also known as mustard gas. Here, we demonstrate a facile and rapid method to synthesize a functionalized metal–organic framework (MOF) material for the detection of CEES at trace level. During the synthesis of Zr-BTC, the in situ encapsulation of a fluorescent material (fluorescein) into Zr-BTC voids is performed by a simple solvothermal reaction. The produced F@Zr-BTC is used as a fluore...
Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in ord...
#1Thomas W. Sawyer(DRDC: Defence Research and Development Canada)H-Index: 16
Abstract In the long and intensive search for effective treatments to counteract the toxicity of the chemical warfare (CW) agent sulphur mustard (H; bis(2-chloroethyl) sulphide), the most auspicious and consistent results have been obtained with the drug N-acetylcysteine (NAC), particularly with respect to its therapeutic use against the effects of inhaled H. It is a synthetic cysteine derivative that has been used in a wide variety of clinical applications for decades and a wealth of informatio...
#1Somaye Sadeghi(Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 2
#2Mahtab Tapak(Shahid Beheshti University of Medical Sciences and Health Services)
Last. Nariman Mosaffa(Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 12
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Abstract Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as w...
Abstract Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for it...
Abstract Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the...
#1A. K. Soni(DRDE: Defence Research and Development Establishment)H-Index: 1
#2A.S.B. Bhaskar(DRDE: Defence Research and Development Establishment)H-Index: 13
Last. G. M. Kannan(DRDE: Defence Research and Development Establishment)H-Index: 22
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Abstract Our previous study showed that percutaneous sulfur mustard (SM) exposure induced pulmonary toxicity, which was attenuated by DRDE-07 (S-2[2-aminoethylamino] ethyl phenyl sulphide) pretreatment. The present study aimed to evaluate the protective efficacy of DRDE-07 and its analogues viz., DRDE-30 (S-2(2-aminoethyl amino)ethyl propyl sulphide) and DRDE-35 (S-2(2-aminoethyl amino)ethyl butyl sulphide) against SM. Thirty minutes before percutaneous SM (0.8 LD50) exposure, female Swiss mice ...
Last. Alireza Shahriary(BMSU: Baqiyatallah University of Medical Sciences)H-Index: 9
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AbstractDysregulation of matrix metalloproteinases (MMPs) is now considered as one of the main toxicity effects of sulfur mustard (SM). Numerous studies have found overexpression of MMPs, but the m...
Last. Tanja Popp(LMU: Ludwig Maximilian University of Munich)H-Index: 15
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Abstract Although its first military use in Ypres was 100 years ago, no causal therapy for sulfur mustard (SM) intoxications exists so far. To improve the therapeutic options for the treatment of SM intoxications, we developed a co-culture of keratinocytes (HaCaT cells) and immunocompetent cells (THP-1 cells) to identify potential substances for further research. Here, we report on the influence of necrosulfonamide (NSA) on the course of a SM intoxication in vitro. The cells were challenged with...
