Effects of sulfur mustard on the basal cell adhesion complex†

Werrlein, Robert J.; Madren-Whalley, Janna S.

doi:10.1002/1099-1263(200012)20:1+<::aid-jat682>3.0.co;2-q

Cited by 15 publications

(9 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our experiments showed that cell detachment and apoptosis occurred after a latency phase for the first morphological appearance of toxic effects upon human bronchial epithelial cell line as observed in other cells [34]. The two mustards clearly induced time-and concentrationdependent cell detachment which preceded apoptosis, as indicated by kinetics of time-and concentration-dependent responses.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

et al. 2006

View full text Add to dashboard Cite

In the present study, the toxicity of yperite, SM, and its structural analogue mechlorethamine, HN2, was investigated in a human bronchial epithelial cell line 16HBE. Cell detachment was initiated by caspase-2 activation, down-regulation of Bcl-2 and loss of mitochondrial membrane potential. Only in detached cells, mustards induced apoptosis associated with increase in p53 expression, Bax activation, decrease in Bcl-2 expression, opening of the mitochondrial permeability transition pore, release of cytochrome c, caspase-2, -3, -8, -9 and -13 activation and DNA fragmentation. Apoptosis, occurring only in detached cells, could be recognized as anoikis and the mitochondrion, involved both in cell detachment and subsequent cell death, appears to be a crucial checkpoint. Based on our understanding of the apoptotic pathway triggered by mustards, we demonstrated that inhibition of the mitochondrial pathway by ebselen, melatonin and cyclosporine A markedly prevented mustard-induced anoikis, pointing to these drugs as interesting candidates for the treatment of mustard-induced airway epithelial lesions.

show abstract

Section: Discussionsupporting

confidence: 69%

Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Our results leave open the possibility that SM destruction of the kIF network is the mechanism behind the vesicant action of SM. The concentration of CEES and MEC we have used is higher than used in some tissue culture models [11,16,17] but it is similar to the concentrations used in live animal studies [13,14,24,25,[29][30][31].…”

Section: Resultsmentioning

confidence: 99%

“…One hypothesis for vesicant action is the activation of an endogenous protease by SM [7][8][9][10] and an endogenous inhibitor of this protease has been identified [11,12]. Other investigators have analyzed the effects of SM on basal cell adhesion complex molecules [13][14][15][16][17], hypothesizing alkylation of basal cell adhesion complex molecules results in failure of the complex [16,18], leading to blister formation, similar to inherited skin blistering diseases [19].…”

Section: Introductionmentioning

confidence: 99%

Treatment of keratin intermediate filaments with sulfur mustard analogs

Hess

Fitzgerald

2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Sulfur mustard (SM) is an alkylating agent with a history of use as a chemical weapon. The chemical reactivity of sulfur mustard toward both proteins and nucleic acids coupled with the hours long delay between exposure and appearance of blisters has prevented the determination of the mechanism of blister formation. We have treated assembled keratin intermediate filaments with analogs of sulfur mustard to simulate exposure to SM. We find that treatment of intact filaments with chloroethyl ethyl sulfide (CEES) or mechlorethamine (MEC) produces aggregates of keratin filaments with little native appearing structure. Treatment of a mix of epidermal keratins 1/10 (keratin pair 1 and 10) and keratins 5/14 with a sulfhydryl-specific modification reagent also results in filament abnormalities. Our results are consistent with the hypothesis that modification of keratins by SM would result in keratin filament destruction, leading to lysis of epidermal basal cells and skin blistering.

show abstract

“…Epidermal keratinocytes rely on signals derived from the surrounding extracellular matrix for survival. In addition, Werrlein and Madren-Whalley (2000) found that SM caused rapid, significant decreases in immunodetection of keratins 5 and 14, an intermediate filament pair found in undifferentiated keratinocytes (Werrlein and Madren-Whalley, 2000). Several lines of evidence support this possibility.…”

Section: Apoptosismentioning

confidence: 97%

“…In support of this idea, Gentilhomme et al (1998) showed that SM treatment of human dermal equivalents reduced the ability of naïve keratinocytes to deposit laminin at the dermal-epidermal interface (Gentilhomme et al, 1998). SM and nitrogen mustard also reduce cell and tissue immunoreactivity for laminin-332, as well as integrin α6β4 and collagen XVII (also known as bullous pemphigoid antigen), two hemidesmosomal components that are critical for keratinocyte adherence (Smith et al, 1997a(Smith et al, ,b,c, 1998Zhang and Monteiro-Riviere, 1997;Werrlein and Madren-Whalley, 2000;Kan et al, 2003). This inhibitory action was determined to be alkylation-dependent, because it could be prevented by co-treatment with SM scavengers.…”

Section: Apoptosismentioning

confidence: 99%