title: Putative role of proteolysis and inflammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures.
abstract: Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.
authors.affiliation: US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. fred.cowan@amedd.army.mil
authors.forename: F M
authors.initials: FM
authors.lastname: Cowan
authors.forename: C A
authors.initials: CA
authors.lastname: Broomfield
authors.forename: D E
authors.initials: DE
authors.lastname: Lenz
authors.forename: W J
authors.initials: WJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D006801:Humans; D009151:Mustard Gas / Q000633:toxicity*; D010447:Peptide Hydrolases / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000627:therapeutic use; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use; D012999:Soman / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015842:Serine Proteinase Inhibitors; D012999:Soman; D011065:Poly(ADP-ribose) Polymerases; D010447:Peptide Hydrolases; D009151:Mustard Gas