Sulfur Mustard Increases Elastase-Like Activity in Homogenates of Hairless Guinea Pig Skin

Cowan, Fred M.; Bongiovanni, Rodolfo; Broomfield, Clarence A.; Yourick, Jeffrey J.; Smith, William J.

doi:10.3109/15569529409062922

Cited by 19 publications

(10 citation statements)

References 17 publications

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“…[2][3][4] The HD-exposed skin homogenate samples showed enhanced elastase and tryptase activities, whereas the chymase and Asp-ase activities in these samples were not increased. 3 In the mouse ear vesicant model, evaluation of the endpoint responses (e.g.…”

Section: Protease Activitiesmentioning

confidence: 99%

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Cutaneous protease activity in the mouse ear vesicant model†

Powers

Kam

Ricketts³

et al. 2001

J. Appl. Toxicol.

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Section: Protease Activitiesmentioning

confidence: 99%

“…3,4 The protease activities are inhibited by several protease inhibitors. 3,5 These results indicated that proteases may play a role in HD-induced inflammation and vesication.…”

Section: Introductionmentioning

confidence: 99%

Cutaneous protease activity in the mouse ear vesicant model†

Powers

Kam

Ricketts³

et al. 2001

J. Appl. Toxicol.

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“…However, the minority view for inflammation as a possible major factor in SM and nerve agent pathology was presented . Over the last decade experimental evidence has accumulated demonstrating SM-increased proteases and the expression of inflammatory enzymes, gene products, mediators and receptors in tissue or cell cultures and inflammatory enzymes and cytokines in the skin of SM-exposed animals (Papirmeister et al , 1985;Higuchi et al , 1988;Cowan et al , , 1994Cowan et al , , 1996Cowan et al , , 1997Cowan et al , , 2000aArroyo et al ., 1995;Sabourin and Casillas 1998). Our Institute in conjunction with Battelle has screened nearly 400 compounds in the mouse ear model for SM cutaneous injury; 19 compounds reduced SM histopathology by >50% (Table 1).…”

Section: Proteolysis and Inflammation In Sulfur Mustard Toxicitymentioning

confidence: 99%

“…The blister agent sulfur mustard (2,2 ′ -dichlorodiethyl sulfide, SM) increases proteolytic activity in tissue or cell cultures and in the skin of SM-exposed animals Cowan et al , 1994Cowan et al , , 1996Cowan et al , , 2001Powers, 2000). The nerve agent soman (pinacolyl methylphosphonofluoridate, GD) increased proteolytic activity associated with the muscle fiber necrosis observed in soman-intoxicated animals (Vanneste and Lison, 1993).…”

Section: Introductionmentioning

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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“…This C1q binding overlapped with the time course (4-24 h) and concentration (50-200 M HD) reported for HD-increased proteolytic activity and HD-enhanced FcR expression. 5,18 This time frame also correlates well with HD-increased proteolysis in hairless guinea-pig skin 6,19 and rat lung 20 and the ultrastructural demonstration of protease-like cleavage of adherent fibrils at the epidermal-dermal junction following HD exposure. 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.…”

Section: Discussionmentioning

confidence: 55%