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

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-kappaB 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-kappaB were activated due to CEES exposure. However, NF-kappaB rapidly disappeared after 2 h. It is possible that the initial activation of NF-kappaB was an adaptive response to protect the cells from damage since NF-kappaB is known to inhibit TNF-alpha/ceramide-induced cell apoptosis. Since NF-kappaB disappeared after 2 h, the cells continued being damaged owing to accumulation of ceramides and activation of several caspases, leading to apoptosis. (C) 2003 Wiley Periodicals, Inc.