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Clinically-Relevant Cutaneous Lesions by Nitrogen Mustard: Useful Biomarkers of Vesicants Skin Injury in SKH-1 Hairless and C57BL/6 Mice

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      A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, skin injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous injury endpoints in screening and optimization of therapies for skin injuries by vesicating agents.

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      Medical aspects of sulphur mustard poisoning.

      Sulphur mustard is one of the major chemical warfare agents developed and used during World War I. Large stockpiles are still present in several countries. It is relatively easy to produce and might be used as a terroristic weapon. Sulphur mustard is a vesicant agent and causes cutaneous blisters, respiratory tract damage, eye lesions and bone marrow depression. The clinical picture of poisoning is well known from the thousands of victims during World War I and the Iran-Iraq war. In the latter conflict, sulphur mustard was heavily used and until now about 30,000 victims still suffer from late effects of the agent like chronic obstructive lung disease, lung fibrosis, recurrent corneal ulcer disease, chronic conjunctivitis, abnormal pigmentation of the skin, and several forms of cancer. Despite enormous research efforts during the last 90 years, no specific sulphur mustard antidote has been found. The prospering knowledge and developments of modern medicine created nowadays new chances to minimize sulphur mustard-induced organ damage and late effects.
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        Comparison of early and late toxic effects of sulfur mustard in Iranian veterans.

        Sulfur mustard is an alkylating agent that reacts with ocular, respiratory, cutaneous, and bone marrow tissues, resulting in early and late toxic effects. We compare these effects based on the experience in Iranian veterans exposed to the agent during the Iran-Iraq conflict (1983-88). The first clinical manifestations of sulfur mustard poisoning occurred in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. Respiratory effects appeared as rhinorhea, laryngitis, tracheobronchitis, and dyspnoea. Skin lesions varied from erythema to bullous necrotization. Initial leukocytosis and lymphopenia returned to normal within four weeks in recovered patients, but marked cytopenia with bone marrow failure occurred in fatal cases. Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes. Main respiratory complications were chronic obstructive pulmonary disease, bronchiectasis, asthma, large airway narrowing, and pulmonary fibrosis. Late skin lesions were hyperpigmentation, dry skin, atrophy, and hypopigmentation. Fifteen of the severely intoxicated patients were diagnosed with delayed keratitis, having corneal vascularization, thinning, and epithelial defect. Respiratory complications exacerbated over time, while cutaneous and ocular lesions decreased or remained constant. Both the severity and frequency of bronchiectatic lesions increased during long-term follow-up. The only deteriorating cutaneous complication was dry skin. The maximum incidence of delayed kaeratitis was observed 15 to 20 years after initial exposure. Being suggested as the main cause ofassociated with malignancies and recurrent infections, natural killer cells were significantly lower 16 to 20 years after intoxication.
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          The pharmacology, toxicology, and medical treatment of sulphur mustard poisoning.

          Sulphur mustard (SM) is regarded as one of the most important agents of chemical warfare because of its simple and cheap chemical synthesis that makes it readily available for both terrorist and military use. SM acts as an alkylating agent that induces disruption of nucleic acids and proteins, impairing cell homeostasis and eventually causing cell death. It rapidly reacts with ocular, respiratory and cutaneous tissues, as well as bone marrow and the mucosal cells of the gastrointestinal tract, resulting in several devastating long-term effects on human health, many of which are not clinically or pathologically well defined. In light of the possible threat of SM use against military and civilian populations, physicians should be aware of its grave effects and knowledgeable how to care for its victims. The pattern of immediate and long-term toxic effects following exposure to SM is reviewed in this article with special references to the recent data available from over 100,000 chemical casualties incurred during the Iran-Iraq conflict.

            Author and article information

            [1 ]Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, United States of America
            [2 ]Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
            Roswell Park Cancer Institute, United States of America
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Conceived and designed the experiments: NTS RA. Performed the experiments: NTS AKJ SI. Analyzed the data: NTS AKJ SI CWW RA. Contributed reagents/materials/analysis tools: NTS AKJ SI. Wrote the paper: NTS CWW RA.

            Role: Editor
            PLoS One
            PLoS ONE
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            24 June 2013
            : 8
            : 6

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Pages: 7
            This work was supported by the Countermeasures Against Chemical Threats (CounterACT) Program, Office of the Director National Institutes of Health (OD) and the National Institute of Environmental Health Sciences (NIEHS), [Grant Number U54 ES015678]. The study sponsors have no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
            Research Article
            Anatomy and Physiology
            Skin Physiology
            Animal Genetics
            Model Organisms
            Animal Models
            Toxic Agents
            Anatomy and Physiology
            Critical Care and Emergency Medicine
            Dermatologic Pathology
            Toxic Agents



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