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

Sourdeval, Matthieu; Lemaire, Christophe; Deniaud, Aurélien; Taysse, L.; Daulon, S.; Breton, P.; Brenner, Catherine; Boisvieux‐Ulrich, Emmanuelle; Marano, Francelyne

doi:10.1007/s10495-006-8764-1

Cited by 50 publications

(30 citation statements)

References 58 publications

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“…Surprisingly, our data showed no evidence that broad caspase inhibition after SM exposure had any effect on AChE activity or the percentage of TUNEL positive cells. The apparent discrepancies between our data and a previous report where zVAD showed marked protection against SM-induced apoptosis in 16HBEo − -cells (Sourdeval et al, 2006) may be due to the use of a different cell lines or due to differences in study design. In our protocol cells were not pre-treated or co-incubated with the inhibitor during SM exposure to avoid direct interaction of SM with zVAD.…”

Section: Discussioncontrasting

confidence: 99%

Apoptosis in sulfur mustard treated A549 cell cultures

et al. 2007

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Section: Discussioncontrasting

confidence: 99%

Apoptosis in sulfur mustard treated A549 cell cultures

et al. 2007

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“…Whether this oxidation is directly because of CEES, its metabolites, or the ROS that is formed is yet to be determined. The increased ROS we have seen in mitochondria may be because of mitochondrial dysfunctional, which we have seen in our CEES model and what others have seen after SM exposure (Sourdeval et al, 2006). The mitochondrion, specifically the respiratory chain, can produce a substantial amount of endogenous ROS (Fridovich, 1978;Drose and Brandt, 2008), and, if CEES causes mitochondrial uncoupling, this could explain oxidation products seen in other areas of the cell and markers of apoptosis (Dillman et al, 2005;Sourdeval et al, 2006).…”

Section: Discussionsupporting

confidence: 62%

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Gould¹,

White²,

Day³

2008

J Pharmacol Exp Ther

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Sulfur mustards (SMs) have been used as warfare agents since World War I and still pose a significant threat against civilian and military personnel. SM exposure can cause significant blistering of the skin, respiratory injury, and fibrosis. No antidote currently exists for SM exposure, but recent studies, using the SM analog 2-chloroethyl ethyl sulfide (CEES), have focused on the ability of antioxidants to prevent toxicity. Although antioxidants can prevent CEES-induced toxicity, the mechanisms by which these compounds are effective against SM agents are largely unknown. Using human bronchial epithelial (16HBE) cells and primary small airway epithelial cells, we show that CEES causes a significant increase in mitochondrial dysfunction as early as 4 h, which is followed by increases in mitochondrial reactive oxygen species (ROS), peaking 12 h after exposure. We also have identified a catalytic antioxidant metalloporphyrin that can rescue airway cells from CEES-induced toxicity when added 1 h after CEES exposure. In addition, the cytoprotective effects of the catalytic antioxidant are associated with correcting mitochondrial dysfunction ROS, DNA oxidation, and decreases in intracellular GSH. These findings suggest a role for oxidative stress in CEES toxicity and provide a rationale to investigate antioxidants as rescue agents in SM exposures.Bis(2-chloroethyl sulfide) or sulfur mustard (SM) was first synthesized in the late 1880s and since has been used as a warfare agent on a number of occasions. SM was first used in World War I and has been used in warfare as recently as the Iran-Iraq conflict of the late 1980s (Blanc, 1999). Although SM is less of a threat in warfare as it once was, it still posses a threat to military and civilian personnel because of current concerns for its deployment in a terrorist attack.Sulfur mustards are classic vesicating agents that mainly affect the skin, eyes, and respiratory system. There is no known antidote or specific treatment for SM exposure, and the current therapy is largely supportive. SM on the skin can be decontaminated with soap and water or a dilute bleach solution, but internal exposure, such as the respiratory system, is considerably more difficult to treat (Munro et al., 1990;Watson and Griffin, 1992). SM produces airway damage that includes necrosis, inflammation, and edema (Kehe and Szinicz, 2005). The exact mechanism of SM toxicity is unknown. 2-Chloroethyl ethyl sulfide (CEES; half mustard) is a monofunctional analog of SM (Fig. 1) that provides a useful model for SM injury without the need for a specialized containment facility. CEES, like SM, is an alkylating agent that can bind DNA and other macromolecules within the cell. Recent research into counteragents has focused on bolstering the endogenous antioxidant defenses by supplementation with N-acetyl-cysteine (McClintock et al

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“…Sourdeval et al indicated a mitochondrial pathway in the bronchial epithelial cell line, 16HBE, after an increase of p53, cytochrome c and the activation of caspase -2, -3, -8, -9 and -13 (Sourdeval et al, 2006). Also correlating with our results Ray et al demonstrated an activation of caspase 3 in undifferentiated normal human bronchial epithelial cells (Ray et al, 2008).…”

Section: Discussionsupporting

confidence: 91%