Signal transduction events in lung injury induced by 2‐chloroethyl ethyl sulfide, a mustard analog

Abstract

Sulfur mustard has been used as a vesicant chemical warfare agent. To understand the mechanism by which mustard gas exposure causes respiratory damage, we have used 2-chloroethyl ethyl sulfide (CEES) as a mustard analog. Our initial studies have shown that guinea pigs exposed to CEES intratracheally accumulate high levels of TNF-alpha. Accumulation of TNF-alpha leads to activation of both acid and neutral sphingomyelinases, resulting in high accumulation of ceramides, a second messenger involved in cell apoptosis. In addition, NF-kappa B was activated for a short period (1-2 h after exposure) as determined by mobility shift assay. Supershift assays indicated that both p50 and p65 of NF-kappa B were activated due to CEES exposure. However, NF-kappa B rapidly disappeared after 2 h. It is possible that the initial activation of NF-kappa B was an adaptive response to protect the cells from damage since NF-kappa B is known to inhibit TNF-alpha/ceramide-induced cell apoptosis. Since NF-kappa B disappeared after 2 h, the cells continued being damaged owing to accumulation of ceramides and activation of several caspases, leading to apoptosis.

Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

“…Recent studies indicated that within 30 min of the mustard gas exposure, induction of tumor necrosis factor ␣ (TNF-␣) occurs that initiates a series of signaling events leading to apoptosis [19][20][21]. Inhibition of the initiation of signaling events has not been previously demonstrated.…”

Induction of neuronal damage in guinea pig brain by intratracheal infusion of 2‐chloroethyl ethyl sulfide, a mustard gas analog

“…Our laboratory has developed a guinea pig model of mustard gas exposure used to study the induction of lung toxicity by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. Inhalation of CEES is known to cause hemorrhagic inflammation of the tracheobronchial tree in addition to severe pulmonary complications such as adult respiratory distress syndrome [2,3].…”

Topical Application of Liposomal Antioxidants for Protection Against CEES Induced Skin Damage

“…Signal transduction has also been demonstrated for CEES, wherein TNF-alpha, sphingomyelinase levels, caspase 3, 8, and 9 were all elevated [10]. Stone et al [5] have found that inflammatory cytokines exacerbate the toxicity of CEES.…”