Comparison of sulfur mustard induced mechanism of cell damage in dependency of time course and cell type

Bloch, Wilhelm; Elischer, A.; Schriek, M.; Böhm, Konrad J.; Moghbeli, Fatemeh; Kehe, Kai; Szinicz, L.; Steinritz, Dirk

doi:10.1016/j.tox.2006.04.005

Cited by 4 publications

(2 citation statements)

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“…iNOS is an inducible form of nitric oxide synthase which is expressed by epithelial cells as well as activated neutrophils and macrophages that infiltrate during inflammation (Bloch et al , 2007; Gao et al , 2007). CEES-induced infiltration of neutrophils and macrophages, which is linked to the activation of MAPK/Akt-NF-κB/AP-1 pathways, was observed in our earlier studies in SKH-1 hairless mice (Pal et al , 2009; Tewari-Singh et al , 2009), indicating that iNOS is another important inflammatory mediator in the skin injury response observed in the CEES-skin injury model.…”

Section: Discussionmentioning

confidence: 99%

Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin

Jain

Tewari‐Singh

et al. 2011

Toxicology Letters

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Bifunctional alkyalating agent, Sulfur mustard (SM)-caused cutaneous injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, skin samples from mice exposed to 2 or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in COX-2, iNOS, and MMP-9 levels, indicating the involvement of DNA damage and inflammation in CEES-caused skin injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-caused DNA damage and the induction of inflammatory molecules. Oral GSH (300mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced skin injuries involve DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing skin injuries in humans by SM.

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Section: Discussionmentioning

confidence: 99%

Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin

Jain

Tewari‐Singh

et al. 2011

Toxicology Letters

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“…36 In addition, some early molecular events of SM, including its analogue-mediated damage, such as p53 Ser15 phosphorylation, AKT signal pathway inhibition, nitric oxide synthase activation, and intracellular calcium level increase, have been proved to occur simultaneously with DNA repair or to be the direct results of sulfhydryl-containing macromolecule depletion (actin and Ca 2+ translocase injury) or oxidative stress. [37][38][39][40][41][42] These molecular changes ultimately caused cellular morphological deformities, loss of cellular integrity, cell cycle arrest, and cell apoptosis. Therefore, the molecules that are highly reactive with SM in a cell, together with their directly associated molecular pathways constitute the underlying mechanism of SMmediated tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis

Long

Chen

et al. 2016

Toxicol. Res.

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Sulfur mustard (SM) is a well known chemical warfare agent that poses a major threat to military personnel and also populace. It targets multiple macromolecules, and its toxic effects are mediated by complex mechanisms. However, the sequence and manner of SM-induced cellular and molecular events underpinning the pathological processes are not fully elucidated. Effective therapeutic agents against SM poisoning are also lacking. The present study aimed to determine the dynamic cytotoxic profiles of SM in primary cultured human epidermal keratinocytes-fetal (HEK-f) and human dermal fibroblasts-adult (HDF-a) by establishing a high content analysis (HCA)-based multiparametric toxicity assay panel. SM was found to produce multiple, concentration-dependent cellular responses, including abnormal cellular morphology, cycle arrest, apoptosis, necrosis, mitochondrial membrane potential imbalance, increased membrane permeability, oxidative stress, DNA damage, and lysosome impairment. Time-course analysis indicated that the cellular and molecular responses related to the highly reactive targets of SM, such as glutathione depletion, reactive oxygen species release, DNA and lysosomal damage, and actin microfilament architecture modification, were congenerous initial events for SM injury. Moreover, this study demonstrated a novel finding that SM induced autophagy, and it was closely related to lysosome alterations in both cell types. Higher susceptibility of HEK-f cells to SM was associated with early lysosomal damage and decreased autophagy activity. Multiparametric HCA also revealed the concentration-dependent cytoprotective effect of hydroxychloroquine in HDF-a cells. The above results provided overall and objective evidence for elucidating the cytotoxic mechanism of SM, and also a good scientific base for further research on countermeasures against SM injury.

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Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering

et al. 2009

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Comparison of sulfur mustard induced mechanism of cell damage in dependency of time course and cell type

Cited by 4 publications

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Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin

Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin

Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis

Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering

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