Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering.
Sulfur mustard (SM) is a strong alkylating agent, which produces subepidermal blisters, erythema and inflammation after skin contact. Despite the well-described SM-induced gross and histopathological changes, the exact underlying molecular mechanisms of these events are still a matter of research. As part of an international effort to elucidate the components of cellular signal transduction pathways, a large body of data has been accumulated in the last decade of SM research, revealing deeper insight into SM-induced inflammation, DNA damage response, cell death signaling, and wound healing. SM potentially alkylates nearly every constituent of the cell, leading to impaired cellular functions. However, SM-induced DNA alkylation has been identified as a major trigger of apoptosis. This includes monofunctional SM-DNA adducts as well as DNA crosslinks. As a consequence, DNA replication is blocked, which leads to cell cycle arrest and DNA single and double strand breaks. The SM-induced DNA damage results in poly(ADP-ribose) polymerase (PARP) activation. High SM concentrations induce PARP overactivation, thus depleting cellular NAD(+) and ATP levels, which in consequence results in necrotic cell death. Mild PARP activation does not disturb cellular energy levels and allows apoptotic cell death or recovery to occur. SM-induced apoptosis has been linked both to the extrinsic (death receptor, Fas) and intrinsic (mitochondrial) pathway. Additionally, SM upregulates many inflammatory mediators including interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha) and others. Recently, several investigators linked NF-kappaB activation to this inflammatory response. This review briefly summarizes the skin toxicity of SM, its proposed toxicodynamic actions and strategies for the development of improved medical therapy.
Kehe
K
K
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, D-80937 Munich, Germany. kai.kehe@lrz.uni-muenchen.de
Balszuweit
F
F
Steinritz
D
D
Thiermann
H
H
D000478:Alkylation; D017209:Apoptosis / Q000187:drug effects; D001768:Blister / Q000139:chemically induced* / Q000473:pathology; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000378:metabolism / Q000506:poisoning*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D003875:Drug Eruptions / Q000209:etiology* / Q000473:pathology; D006801:Humans; D009151:Mustard Gas / Q000737:chemistry / Q000378:metabolism / Q000506:poisoning*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012869:Skin Absorption; D012883:Skin Ulcer / Q000139:chemically induced* / Q000473:pathology; D015854:Up-Regulation
D002619:Chemical Warfare Agents; D016207:Cytokines; D018736:DNA Adducts; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D009151:Mustard Gas