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.

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

“…Animal experiments showed that PARP inhibition and/or boosting of NAD+ levels can reduce SM induced pathology, suggesting that PARP inhibitors may be used as a medical countermeasure for SM related injuries (Cowan et at., 2003;Gross et al, 1985;Mol et al, 1991 ;Yourick et at., 1991Yourick et at., , 1993Zhang et al, 69 1995 ). Regarding the mechanism of action of such a treatment, it bas been suggestion, that PARP inhibition induces a switch in the mode of cell death by inhibiting necrosis but driving cells into apoptosis, which, in combination with inhibition ofNF KB related gene transcription, counteracts SM induced inflammatory responses (Bai and Virag, 2012a;Kehe et al, 2008;Meier and Millard, 1998;Rosenthal et al, 2001 ).…”

“…Based on the rationale that PARP inhibition preserves NAD + levels and counteracts inflammation, PARP inhibitors were tested as potential therapeutic agents for SM exposures. Interest ingly, in several animal models PARP inhibition and/or boosting of NAD + synthesis led to reduced pathological signs upon SM exposure (Cowan et al, 2003;Gross et al, 1985;Mol et al, 1991;Yourick et al, 1991Yourick et al, , 1993Zhang et al, 1995). Despite previous reports on the effect of PARP inhibitors on SM induced NAD + depletion, cell death and pathology, specific reports characterizing the actual PARylation response upon mustard treatment are incomplete and inconsistent.…”

The use of doxycycline as a protectant against sulphur mustard in HaCaT cells

“…The maintenance of cell viability in HD-exposed tissues may require the use of combined therapy with scavengers such as dimercaprol and with anti-inflammatory compounds such as octyl homovanillamide, both of which have proven effective in reducing HD-induced pathology in the mouse ear model (Cowan et al, 2003;Dillman et al, 2006). The combination of the anti-inflammatory compounds diclofenac and dexamethasone has been reported by Dachir et al (2004) to be particularly effective in that model.…”

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

“…It will be interesting to apply the optimized methodology as established in this work to study the PARylation response in cells treated with bifunctional sulfur and nitrogen mustards. This will have significant implica tions towards the question if PARP inhibitors may be used as a therapeutic option to mitigate SM induced pathologies, as suggested by several animal studies (Cowan et al, 2003;Gross et al, 1985;Mol et al, 1991;Yourick et al, 1991Yourick et al, , 1993Zhang et al, 1995) or to sensitize cancer cells to nitrogen mustard treatment, as tested in preclinical and clinical settings (Donawho et al, 2007;Norris et al, 2014). Several of these aspects are addressed in in an accompanying article (c.f.…”

“…Interest ingly, PARP inhibition did not influence cell survival in general, but shifted the mode of cell death, from necrotic to apoptotic cell death (Kehe et al, 2008;Meier et al, 1987;Papirmeister et al, 1985). It has been hypothesized that this shift is responsible for reduced mustard induced pathologies under conditions of PARP inhibition in a rodent animal model (Cowan et al, 2003).…”