Blunting Nature's Swiss Army Knife

Seife, Charles

doi:10.1126/science.277.5332.1602

Cited by 44 publications

(32 citation statements)

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“…Protease inhibitors are under investigation for numerous and varied pathologies (Siefe, 1997). Both of these classes of compounds can have anti-inflammatory actions and are existing examples of crossover between neuronal and vesicant pathology associated with nerve and blister agents, respectively (Siefe, 1997;Dery et al, 1998;Bal-Price and Brown, 2001;Mabely et al, 2001).…”

Section: Protease and Parp Inhibitorsmentioning

confidence: 99%

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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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.

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Section: Protease and Parp Inhibitorsmentioning

confidence: 99%

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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“…Disproportion in the ratios of proteinases to inhibitors caused by genetic defects, inflammation or certain harmful impacts may lead to severe pathological effects [1]. Thus, proteinases and their specific inhibitors represent worthwhile targets for the development of drugs [2,3].…”

Section: Introductionmentioning

confidence: 99%

Recombinant production, purification and biochemical characterization of domain 6 of LEKTI: a temporary Kazal-type-related serine proteinase inhibitor

Kreutzmann

Schulz

Ständker

et al. 2004

Journal of Chromatography B

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“…1,2 Drugs reported to inhibit cutaneous histopathology in HD-exposed rodents include niacinamide, 21 Protease inhibitors and soluble immune receptors for complement components, cytokines and soluble FcR to reduce pathology in conditions as varied as cancer, rheumatoid arthritis and infectious diseases are two major areas of drug discovery. [24][25][26] Serine and cysteine protease inhibitors can inhibit HD-increased proteolysis in human peripheral blood lymphocytes 6 and prevent the epidermal-dermal separation in human skin explants 24 h after HD exposure. 27 Matrix metalloproteinase inhibitors can greatly reduce neutrophil infiltration and alkali-induced corneal lesions, and show inflammatory and proteolytic mechanisms similar to those proposed for HD.…”

Section: Discussionmentioning

confidence: 99%

Exposure of human epidermal keratinocyte cell cultures to sulfur mustard promotes binding of complement C1q: implications for toxicity and medical countermeasures†‡

Cowan¹,

Broomfield²,

Smith³

2001

J. Appl. Toxicol.

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Blunting Nature's Swiss Army Knife

Cited by 44 publications

References 0 publications

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Recombinant production, purification and biochemical characterization of domain 6 of LEKTI: a temporary Kazal-type-related serine proteinase inhibitor

Exposure of human epidermal keratinocyte cell cultures to sulfur mustard promotes binding of complement C1q: implications for toxicity and medical countermeasures†‡

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