Putative roles of inflammation in the dermatopathology of sulfur mustard

Cowan, Fred M.; Broomfield, Clarence A.

doi:10.1007/bf00755599

Cited by 61 publications

(31 citation statements)

References 48 publications

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“…On the basis of this information, several groups investigated the beneficial effects of agents that scavenge free radicals and other oxidant species. They monitored the beneficial effects of those agents mainly by showing the recovery from damaged skin [12] or by showing inhibition of the induction of proteolytic enzymes [13]. Favorable response of systemic cortisone and local hydrocortisones on rabbit skin lesions, produced after sulfur mustard application, was obtained by Vogt et al [6].…”

Section: Introductionmentioning

confidence: 98%

Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

Das

Mukherjee

Smith³

et al. 2003

J Biochem & Molecular Tox

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Mustard gas exposure causes adult respiratory distress syndrome associated with lung injury. The purpose of this study was to investigate whether an antioxidant, such as N-acetylcysteine (NAC), has any protective effect. Guinea pigs were given single exposure (0.5-6 mg/kg body weight) of 2-chloroethyl ethyl sulfide (CEES) as a mustard analogue intratracheally and maintained for various lengths of time (1 h to 21 days). Within 1 h of CEES infusion at 4 mg/kg, high levels of tumor necrosis factor alpha (TNF-alpha), ceramides, and nuclear factor kappaB accumulated in lung and alveolar macrophages. Both acid and neutral sphingomyelinases were activated within 4 h. These signal transduction events were associated with alteration in the oxygen defense system. Within 1 h of exposure to CEES (6 mg/kg body weight), there was 10-fold increase in the (125)I-BSA leakage into lung tissue, indicating severe lung injury. Although low level of CEES exposure (0.5 mg/kg body weight) produced symptoms of chemical burn in lung as early as 1 h after exposure, the severity of edema, congestion, hemorrhage, and inflammation increased progressively with time (1 h to 21 days). Feeding of single dose of NAC (0.5 g) by gavage just before the CEES infusion was ineffective to counteract these effects. However, consumption of the antioxidant in drinking water for 3 or 30 days prior to CEES exposure significantly inhibited the induction of TNF-alpha, activation of neutral and acid sphingomyelinases, production of ceramides, activation of caspases, leakage of (125)I-bovine serum albumin ((125)I-BSA) into lung tissue, and histological alterations in lung. Pretreatment with NAC for 3 and 30 days protected against 69-76% of the acute lung injury. Therefore, NAC may be an antidote for CEES-induced lung injury.

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Section: Introductionmentioning

confidence: 98%

Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

Das

Mukherjee

Smith³

et al. 2003

J Biochem & Molecular Tox

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“…Studies on the mechanism of blister formation caused by HD and various blister skin diseases such as the genetic disease epidermolysis bullosa (EB) (Zambruno, 1999) have indicated that vesication caused by HD involves proteolysis and inflammation (Cowan and Broomfield, 1993;Arroyo et al, 1999). It was recently shown that AChE expression is induced at the initiation of apoptosis by various stimuli (Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning

et al. 2005

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Certain organophosphorus (OP) nerve agents (e.g. soman) induce neuroinflammatory processes during acute poisoning. An increased level of typical inflammation markers was also observed in poisoning by alkylating agents such as sulfur mustard (HD). The therapeutic potential of new bifunctional compounds was investigated, eliciting activity of non-steroidal anti-inflammatory drug (NSAID) and anti-cholinesterase (anti-ChE) activity, as an antidotal treatment for both soman and HD poisoning in mice. Three bifunctional compounds were used that include the ChE inhibitor pyridostigmine (PYR) coupled to either ibuprofen (IBU) or diclofenac (DICLO) through an eight (octyl) or ten (decyl) hydrocarbon chain spacer: IBU-PO, IBU-PD and DICLO-PD. These compounds are 15-25 fold less toxic than PYR in mice and exert peripheral and central anti-inflammatory and anti-ChE activity in vivo. IBU-PO (4 mg kg(-1), i.p.), IBU-PD (4 mg kg(-1), i.p.) and PYR (0.13 mg kg(-1), i.p.) reduced to control levels the brain edema in soman-poisoned mice (1.1 LD50, s.c.). Pre-treatment with IBU-PO, IBU-PD and DICLO-PD 4-5 h before soman challenge (2.2-2.3 LD50, s.c.) combined with antidotal treatment (atropine, 11 mg kg(-1), 2-PAM-Cl, 25 mg kg(-1), i.m.) afforded a longer 24 h survival rate (SR) than with PYR pre-treatment. DICLO-PD exhibited the largest protection efficacy (SR = 70% vs 17% with PYR). These results indicate a longer duration of action of bifunctional compounds compared with PYR. DICLO-PD (5% in propyleneglycol) reduced significantly the HD-induced edema in mouse ear-skin (51% increase in biopsy weight compared with 100% without treatment). Quantitative evaluation of ear-skin sections showed that only following DICLO-PD treatment was there a marked decrease in edema. DICLO-PD also elicited a significant decrease in HD-induced vesication as displayed by the reduced sub-epidermal blister level. The data indicate possible use of NSAID-ChEI bifunctional compounds for the medical treatment of both nerve and alkylating chemical agents.

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“…It exerts local action on the eyes, skin, and respiratory tissues and then impairs the nervous, cardiac, and digestive systems in humans and laboratory animals [1][2][3][4]. Previous studies with rats and mice have shown that mustard gas action on the lungs, skin, and other organs involves DNA alkylation; cross-linking of DNA [5]; activation of proteases, resulting in proteolysis of several important enzymes and structural proteins [6]; production of free radicals and induction of free radicalmediated oxidative stress [7,8]; inflammation [9]; and activation of TNF-␣, part of the inflammatory cytokine cascade [10,11]. Recently, we demonstrated that the downstream signal transduction events in lung following chloroethyl ethyl sulfide (CEES) exposure involve the induction of TNF-␣, which in turn activates both acid and neutral sphingomyelinases, resulting in the subsequent accumulation of ceramides in the lung [12].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cholinephosphotransferase activity in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard analog

Roy

Mukherjee

Kabir

et al. 2005

J. Biochem. Mol. Toxicol.

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Exposure to mustard gas causes inflammatory lung diseases including acute respiratory distress syndrome (ARDS). A defect in the lung surfactant system has been implicated as a cause of ARDS. A major component of lung surfactant is dipalmitoyl phosphatidylcholine (DPPC) and the major pathway for its synthesis is the cytidine diphosphocholine (CDP-choline) pathway. It is not known whether the ARDS induced by mustard gas is mediated by its direct effects on some of the enzymes in the CDP-choline pathway. In the present study we investigated whether mustard gas exposure modulates the activity of cholinephosphotransferase (CPT) the terminal enzyme by CDP-choline pathway. Adult guinea pigs were intratracheally infused with single doses of 2-chloroethyl ethyl sulfide (CEES) (0.5 mg/kg b.wt. in ethanol). Control animals were injected with vehicles only. The animals were sacrificed at different time and the lungs were removed after perfusion with physiological saline. CPT activity increased steadily up to 4 h and then decreased at 6 h and stabilized at 7 days in both mitochondria and microsomes. To determine the dose-dependent effect of CEES on CPT activity we varied the doses of CEES (0.5-6.0 mg/kg b.wt.) and sacrificed the animals at 1 h and 4 h. CPT activity showed a dose-dependent increase of up to 2.0 mg/kg b.wt. of CEES in both mitochondria and microsomes then decreased at 4.0 mg/kg b.wt. For further studies we used a fixed single dose of CEES (2.0 mg/kg b.wt.) and fixed exposure time (7 days). Lung injury was determined by measuring the leakage of iodinated-bovine serum albumin into lung tissue and expressed as the permeability index. CEES exposure (2.0 mg/kg b.wt. for 7 days) caused a significant decrease of both CPT gene expression (approximately 1.7-fold) and activity (approximately 1.5-fold) in the lung. This decrease in CPT activity was not associated with any mutation of the CPT gene. Previously we reported that CEES infusion increased the production of ceramides which are known to modulate PC synthesis. To determine whether ceramides affect microsomal CPT activity the lung microsomal fraction was incubated with different concentrations of C(2)-ceramide prior to CPT assay. CPT activity decreased significantly with increasing dose and time. The present study indicates that CEES causes lung injury and significantly decreases CPT gene expression and activity. This decrease in CPT activity was not associated with any mutation of the CPT gene is probably mediated by accumulation of ceramides. CEES induced ceramide accumulation may thus play an important role in the development of ARDS by modulating CPT enzyme.

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Putative roles of inflammation in the dermatopathology of sulfur mustard

Cited by 61 publications

References 48 publications

Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning

Inhibition of cholinephosphotransferase activity in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard analog

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