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-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.
Chatterjee
Diptendu
D
Department of Biochemistry, Meharry Medical College, Nashville, TN 37208, USA.
Mukherjee
Shyamali
S
Smith
Milton G
MG
Das
Salil K
SK
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006168:Guinea Pigs; D007442:Intubation, Intratracheal; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002518:Ceramides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C031278:2-chloroethyl ethyl sulfide; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases; D009151:Mustard Gas