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      Cutaneous Injury-Related Structural Changes and Their Progression following Topical Nitrogen Mustard Exposure in Hairless and Haired Mice

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          Abstract

          To identify effective therapies against sulfur mustard (SM)-induced skin injuries, various animals have been used to assess the cutaneous pathology and related histopathological changes of SM injuries. However, these efforts to establish relevant skin injury endpoints for efficacy studies have been limited mainly due to the restricted assess of SM. Therefore, we employed the SM analog nitrogen mustard (NM), a primary vesicating and bifunctional alkylating agent, to establish relevant endpoints for efficient efficacy studies. Our published studies show that NM (3.2 mg) exposure for 12–120 h in both the hairless SKH-1 and haired C57BL/6 mice caused clinical sequelae of toxicity similar to SM exposure in humans. The NM-induced cutaneous pathology-related structural changes were further analyzed in this study and quantified morphometrically (as percent length or area of epidermis or dermis) of skin sections in mice showing these lesions. H&E stained skin sections of both hairless and haired mice showed that NM (12–120 h) exposure caused epidermal histopathological effects such as increased epidermal thickness, epidermal-dermal separation, necrotic/dead epidermis, epidermal denuding, scab formation, parakeratosis (24–120 h), hyperkeratosis (12–120 h), and acanthosis with hyperplasia (72–120 h). Similar NM exposure in both mice caused dermal changes including necrosis, edema, increase in inflammatory cells, and red blood cell extravasation. These NM-induced cutaneous histopathological features are comparable to the reported lesions from SM exposure in humans and animal models. This study advocates the usefulness of these histopathological parameters observed due to NM exposure in screening and optimization of rescue therapies against NM and SM skin injuries.

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          Most cited references39

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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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            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.
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              Doxycycline hydrogels with reversible disulfide crosslinks for dermal wound healing of mustard injuries.

              Doxycycline hydrogels containing reversible disulfide crosslinks were investigated for a dermal wound healing application. Nitrogen mustard (NM) was used as a surrogate to mimic the vesicant effects of the chemical warfare agent sulfur mustard. An 8-arm-poly(ethylene glycol) (PEG) polymer containing multiple thiol (-SH) groups was crosslinked using hydrogen peroxide (H(2)O(2) hydrogel) or 8-arm-S-thiopyridyl (S-TP hydrogel) to form a hydrogel in situ. Formulation additives (glycerin, PVP and PEG 600) were found to promote dermal hydrogel retention for up to 24 h. Hydrogels demonstrated high mechanical strength and a low degree of swelling (< 1.5%). Doxycycline release from the hydrogels was biphasic and sustained for up to 10-days in vitro. Doxycycline (8.5 mg/cm(3)) permeability through NM-exposed skin was elevated as compared to non vesicant-treated controls at 24, 72 and 168 h post-exposure with peak permeability at 72 h. The decrease in doxycycline permeability at 168 h correlates to epidermal re-epithelialization and wound healing. Histology studies of skin showed that doxycycline loaded (0.25% w/v) hydrogels provided improved wound healing response on NM-exposed skin as compared to untreated skin and skin treated with placebo hydrogels in an SKH-1 mouse model. In conclusion, PEG-based doxycycline hydrogels are promising for dermal wound healing application of mustard injuries. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 January 2014
                : 9
                : 1
                : e85402
                Affiliations
                [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 Pathology, School of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
                [3 ]Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
                University of California Irvine, United States of America
                Author notes

                Competing Interests: Please note that co-author Rajesh Agarwal is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: NTS CWW RA. Performed the experiments: NTS AKJ. Analyzed the data: NTS DO CWW RA. Wrote the paper: NTS AKJ DO CWW RA.

                Article
                PONE-D-13-41538
                10.1371/journal.pone.0085402
                3885697
                179be8ec-a153-4d93-943e-7fee0247ffc7
                Copyright @ 2014

                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.

                History
                : 7 October 2013
                : 27 November 2013
                Page count
                Pages: 10
                Funding
                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 funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Skin
                Skin Physiology
                Histology
                Model Organisms
                Animal Models
                Mouse
                Toxicology
                Toxic Agents
                Medicine
                Anatomy and Physiology
                Skin
                Skin Physiology
                Clinical Research Design
                Epidemiology
                Critical Care and Emergency Medicine
                Toxicology
                Dermatology
                Diagnostic Medicine
                Pathology
                Anatomical Pathology
                Histopathology
                Clinical Pathology
                Epidemiology
                Clinical Epidemiology
                Toxicology
                Toxic Agents

                Uncategorized
                Uncategorized

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