Sulfur Mustard Induces Apoptosis and Necrosis in Endothelial Cells

Dąbrowska, Milena; Becks, Lauren L.; Lelli, Joseph L.; Levee, Minette G.; Hinshaw, Daniel B.

doi:10.1006/taap.1996.0324

Cited by 94 publications

(50 citation statements)

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“…In addition, the percentage of apoptotic BC increased significantly from 18% at 6 hours postexposure to 59% at 12 hours postexposure. These observations are in strong agreement with the results reported by Dabrowska et al (4). They exposed cultured endothelial cells with 100 µM SM and found a significant increase in the number of apoptotic endothelial cells with increasing postexposure times.…”

Section: Discussionsupporting

confidence: 93%

Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

Kan¹,

Pleva²,

Hamilton³

et al. 2003

Toxicol Pathol

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The present study was aimed to examine whether apoptosis is involved in the pathogenesis of sulfur mustard (SM)-induced basal cell death. Skin sites of the hairless guinea pig exposed to SM vapor for 8 minutes were harvested at 3, 6, 12, 24, and 48 hours postexposure. Immunohistochemical detection of basal cell apoptosis was performed using the ApopTag in situ apoptosis labeling kit. Only occasional apoptotic basal cells (BC) were observed in nonexposed and perilesional control sites. At lesional sites, apoptosis of BC was not detected at 3 hours postexposure. However, at 6 hours and 12 hours postexposure, 18% and 59% of BC were apoptotic, respectively. At 24 and 48 hours postexposure, individual apoptotic basal cells were not clearly recognizable due to necrosis. At the ultrastructural level, degenerating BC exhibited typical apoptotic morphology including nuclear condensation and chromatin margination. The results suggest that apoptotic cell death is a cytotoxic mechanism with the number of BC undergoing apoptosis significantly increasing from 6 to 12 hours postexposure. In addition, because necrosis is preferential at 24 hours postexposure, we believe that SM-induced cell death involves early apoptosis and late necrosis, which temporally overlap to produce a single cell death pathway along an apoptotic-necrotic continuum.

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Section: Discussionsupporting

confidence: 93%

Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

Kan¹,

Pleva²,

Hamilton³

et al. 2003

Toxicol Pathol

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“…If the cells were exposed to a concentration above 100 µM for a longer time, the number of apoptotic cells declined again. Similar results were obtained in endothelial cells exposed to SM (Dabrowska et al, 1996). This suggests that apoptosis is an early event induced at low concentrations and that necrosis takes over later, particularly at higher concentrations.…”

Section: Discussionsupporting

confidence: 90%

“…It is a well-established fact that high-dose exposure of alkylating agents causes severe damage leading to apoptosis and necrosis of many cell types, including keratinocytes (Kehe et al, 2000), endothelial cells (Dabrowska et al, 1996) and lung epithelial cells (Calvet et al, 1999). In the present study we have demonstrated that lower doses of the nitrogen mustard melphalan activate intracellular signal transduction pathways in bronchial and alveolar epithelial cells leading to a proinflammatory response.…”

Section: Discussionmentioning

confidence: 72%

The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-κB and inflammatory response in lung epithelial cells

et al. 2005

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To investigate how respiratory epithelial cells react to an alkylating agent, we exposed human bronchial (BEAS-2B) and alveolar (A549) cells to the nitrogen mustard derivative melphalan. The BEAS-2B cells were highly sensitive to melphalan, as shown by a reduced viability after a 10-min incubation with 300 microM melphalan. The A549 cells were less sensitive and required several hours of exposure to reduce significantly in viability. However, exposure to melphalan also induces activation of intracellular signal transduction pathways, as indicated by phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38 (proteins belonging to the family of stress-induced mitogen-activated phosphorylated kinases, MAPK) within 5 min, as well as translocation of the transcription factor nuclear factor (NF)-kappaB to the nucleus within 45 min. This early activation was followed by elevated levels of tumor necrosis factor (TNF)-alpha mRNA within 2 h. We also observed increased expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of both cell lines 18 h after exposure to 25 microM melphalan and an increased adhesion of monocytes to the epithelial cells in vitro.In conclusion, we have demonstrated that alkylating compounds not only cause cell death of lung epithelial cells but also activate stress-associated MAPK signal transduction pathways and induce expression of mediators known to participate in the recruitment of inflammatory cells.

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“…Caspase-3 appears to be a converging point for distinct apoptotic pathways (Nicholson et al, 1995) and, in an number of analysed systems, caspase-3 cleaves key proteins involved in the structure and integrity of the cell, including PARP. We treated transduced keratinocytes with sulfur mustard in order to induce a higher rate of apoptosis in these cells (Dabrowska et al, 1996;Rosenthal et al, 1998) and thereby allow us to determine whether the caspase pathway was activated during E7-augmented apoptosis. Preliminary studies showed that the treatment of the cells with 50 mM sulfur mustard was sucient to induce apoptosis (by bisbenzimide staining) in 40% of the E7-transduced cells (data not shown).…”

Section: A Cell Death Elisa Con®rms the Sensitization Of E7-transducementioning

confidence: 99%

The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis

Stöppler

Johnson

et al. 1998

Oncogene

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The`high risk' human papillomaviruses are associated with the development of anogenital carcinomas and their E6 and E7 genes possess immortalizing and transforming functions in several in vitro culture systems. Recently the E6 gene has also been shown to enhance the apoptosis of human mammary epithelial cells. To determine the apoptotic activity of these oncogenes in the natural host cell, we infected genital keratinocytes with retroviruses expressing either HPV-16 E6, E7, or both the E6 and E7 (E6/7) genes. Apoptosis was quantitated under normal growth conditions or when induced by tumor necrosis factor a/cycloheximide or sulfur mustard. In contrast to previous ®ndings with mammary epithelial cells, the E6 gene did not signi®cantly augment either spontaneous or induced apoptosis. E6 also did not suppress apoptosis in normal keratinocytes (despite dramatically reducing their p53 levels), suggesting that p53-independent events mediated this eect. In contrast, E7 increased both spontaneous and induced apoptosis as well as the cellular levels of p53 and p21 protein. Interestingly, coexpression of E6 abrogated E7-facilitated apoptosis by tumor necrosis factor a nearly completely, but had only a minor protective eect on sulfur mustard induced apoptosis in these cells, demonstrating at least in part the p53-dependence and -independence of these two apoptotic pathways. Finally, our results indicate that the apoptosis of normal and E7-expressing keratinocytes is dierentially aected by E6 expression and that E7, when unaccompanied by E6, sensitizes keratinocytes to apoptosis.

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Sulfur Mustard Induces Apoptosis and Necrosis in Endothelial Cells

Cited by 94 publications

References 0 publications

Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-κB and inflammatory response in lung epithelial cells

The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis

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