Mechanisms Mediating the Vesicant Actions of Sulfur Mustard after Cutaneous Exposure

Published on Mar 1, 2010in Toxicological Sciences3.703
· DOI :10.1093/TOXSCI/KFP253
Michael P. Shakarjian12
Estimated H-index: 12
(NYMC: New York Medical College),
Diane E. Heck38
Estimated H-index: 38
(NYMC: New York Medical College)
+ 7 AuthorsJeffrey D. Laskin69
Estimated H-index: 69
(UMDNJ: University of Medicine and Dentistry of New Jersey)
Sulfur mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. SM is a bifunctional alkylating agent which reacts with many targets including lipids, proteins, and DNA, forming both intra- and intermolecular cross-links. Despite the relatively nonselective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of SM-induced cytotoxicity and the intracellular and extracellular targets of this vesicant. In this review, the effects of SM exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for SM poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action.
📖 Papers frequently viewed together
4 Authors (Kai Kehe, ..., Horst Thiermann)
192 Citations
339 Citations
108 Citations
#1Arttatrana Pal (University of Colorado Denver)H-Index: 12
#2Neera Tewari-Singh (University of Colorado Denver)H-Index: 17
Last. Rajesh Agarwal (University of Colorado Denver)H-Index: 104
view all 8 authors...
A monofunctional analog of the chemical warfare agent sulfur mustard (HD), 2-chloroethyl ethyl sulfide (CEES), induces tissue damage similar to HD. Herein we studied the molecular mechanisms associated with CEES-induced skin inflammation and toxicity in SKH-1 hairless mice. Topical CEES exposure caused an increase in oxidative stress as observed by enhanced 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrroline N-oxide protein adduct formation and an increase in protein oxidation. The...
69 CitationsSource
#1Patrick HaydenH-Index: 20
#2John P. Petrali (DA: United States Department of the Army)H-Index: 17
Last. Mitchell KlausnerH-Index: 15
view all 9 authors...
Abstract Bis-(β-chloroethyl) sulfide (SM) is a potent skin vesicant previously used for chemical warfare. Progress in determination of the mechanistic basis of SM pathology, and development of prophylactic and/or therapeutic countermeasures to SM exposure has been hampered by lack of physiologically relevant models of human skin. The current work evaluated a newly developed tissue engineered full-thickness human skin model in a completely in vitro approach to investigation of SM-induced dermal p...
30 CitationsSource
Abstract For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology—blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topi...
23 CitationsSource
#1Christian Ries (LMU: Ludwig Maximilian University of Munich)H-Index: 22
#2Tanja Popp (LMU: Ludwig Maximilian University of Munich)H-Index: 15
Last. Marianne Jochum (LMU: Ludwig Maximilian University of Munich)H-Index: 61
view all 5 authors...
Matrix metalloproteinases (MMPs), especially MMP-9 and MMP-2, degrade various proteins of the extracellular matrix, including collagen type IV the major component of basement membranes which also separate the epidermis from the dermis. Although previous work indicates the contribution of MMPs and their inhibitors (TIMPs) to the pathophysiology of skin lesions induced by the toxic chemical warefare agent sulphur mustard (SM), little is known about the underlying molecular and cellular mechanisms....
42 CitationsSource
#1Jennifer A. Price (Battelle Memorial Institute)H-Index: 8
#2James V. Rogers (Battelle Memorial Institute)H-Index: 16
Last. John S. GrahamH-Index: 18
view all 6 authors...
Severe cutaneous injuries continue to result from exposure to sulfur mustard [bis(2-chloroethyl)sulfide; HD] and thermal burns. Microarray analysis was utilized in this study to evaluate transcriptional changes in porcine skin assessing the underlying repair mechanisms of HD and thermal injury involved in wound healing. Four ventral abdominal sites on each of 4 weanling swine were exposed to 400 μL undiluted HD or a heated brass rod (70°C) for 8 minutes and 45–60 seconds, respectively. At 7 days...
15 CitationsSource
#1Dirk SteinritzH-Index: 22
#2A. ElischerH-Index: 2
Last. Kai KeheH-Index: 30
view all 8 authors...
Abstract Sulphur mustard (SM) is a chemical warfare agent that causes erythema and blistering of the skin with a latency of several hours. Although SM is known for almost 200 years the cellular mechanisms involved in the damaging process are not fully understood. There is evidence that changes in nitric oxide (*NO), reactive oxygen species (ROS) and reactive nitrogen species (RNS) might be involved in the damaging process. Aim To find out more about the pathophysiology of SM, we investigated the...
27 CitationsSource
The skin functions as a barrier protecting the body from dehydration and environmental insults. This barrier function is mainly provided by the outermost layer of the skin, the epidermis. The epidermis is maintained by epidermal stem cells which reside in the basal layer and which generate daughter cells that move upward toward the surface of the skin. During this journey, keratinocytes undergo a series of biochemical and morphological changes that result in the formation of the various layers o...
72 CitationsSource
#1M. MolH-Index: 6
Last. Henk P. BenschopH-Index: 2
view all 3 authors...
While skin is a major target for sulphur mustard (HD), a therapy to limit HD-induced vesication is currently not available. Since it is supposed that apoptotic cell death and proteolytic digestion of extracellular matrix proteins by metalloproteases are initiating factors for blister formation, we have explored whether inhibition of these processes could prevent HD-induced epidermal–dermal separation using adult human skin in organ culture. Involvement of the caspase and the metalloprotease fami...
32 CitationsSource
#1Paul A. Jowsey (Newcastle University)H-Index: 9
#2Faith M. Williams (Newcastle University)H-Index: 29
Last. Peter G. Blain (Newcastle University)H-Index: 28
view all 3 authors...
Sulphur mustard (SM) is a blistering agent that is directly toxic to the skin and mucosal surfaces of the eye and respiratory system. Symptoms take several hours to develop and the mechanism of action is poorly understood although SM is able to alkylate nucleic acids and proteins. The ability of SM to form adducts with DNA has been documented, although there are limited data demonstrating how cells respond to this insult to repair the damage. This study used the sulphur mustard surrogate 2-chlor...
48 CitationsSource
#1Neera Tewari-Singh (University of Colorado Denver)H-Index: 17
#2Sumeet RanaH-Index: 1
Last. Rajesh AgarwalH-Index: 104
view all 7 authors...
Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES...
66 CitationsSource
Cited By151
#1Feng Ye (Third Military Medical University)H-Index: 8
#2Guorong Dan (Third Military Medical University)H-Index: 5
Last. Zhongmin Zou (Third Military Medical University)H-Index: 18
view all 8 authors...
Sulfur mustard (a type of vesicant) can directly damage lung bronchial epithelium via aerosol inhalation, and prevalent cell death is an early event that obstructs the respiratory tract. JNK/c-Jun is a stress response pathway, but its role in cell death of the injured cells is not clear. Here, we report that JNK/c-Jun was activated in immortalized human bronchial epithelial (HBE) cells exposed to a lethal dose (20 μM) of nitrogen mustard (NM, a sulfur mustard analog). c-Jun silencing using small...
#1Angela Cruz-Hernandez (UM: University of Montana)
#2Ryan P. Mendoza (UM: University of Montana)H-Index: 4
Last. Jared M. Brown (UM: University of Montana)H-Index: 36
view all 8 authors...
Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we h...
#1Satyendra K. Singh (MSU: Michigan State University)H-Index: 9
#2Dinesh G Goswami (Anschutz Medical Campus)H-Index: 8
Last. Kathryn PateH-Index: 1
view all 11 authors...
Abstract null null With a possibility for the use of chemical weapons in battlefield or in terrorist activities, effective therapies against the devastating ocular injuries, from their exposure, are needed. Oxygen plays a vital role in ocular tissue preservation and wound repair. We tested the efficacy of supersaturated oxygen emulsion (SSOE) in reducing ex vivo corneal and keratocyte injury from chloropicrin (CP). CP, currently used as a pesticide, is a chemical threat agent like the vesicating...
#1Satyendra K. Singh (MSU: Michigan State University)H-Index: 9
#2Joshua A. Klein (MSU: Michigan State University)H-Index: 1
Last. Neera Tewari-Singh (MSU: Michigan State University)H-Index: 1
view all 4 authors...
Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as potential chemical weapons. In addition, their accidental release can lead to chemical emergencies and mass casualties. CX, an urticant, or nettle agent, grouped with vesicating agents, causes instant pain, injury and systemic effects, which can lead to mortality. With faster cutaneous penetration, corrosive properties, and more p...
2 CitationsSource
#1Andrea DeSantis-Rodrigues (RU: Rutgers University)H-Index: 2
#2Rita A. Hahn (RU: Rutgers University)H-Index: 8
Last. Marion K. Gordon (RU: Rutgers University)H-Index: 21
view all 8 authors...
Amino-Plex (SM1997) is a spray or liquid cosmeceutical that has been used for skin dryness, aging, or sun exposure. Its formulation includes electrolytes, trace minerals, amino acids, peptides, nucleosides and nucleotides, all substances that are less than 10 kDa. It is designed to increase oxygen levels in cells, improve glucose transport, stimulate ATP synthesis, and stimulate collagen formation, actions that can help facilitate repair of damaged cells. It also supports collagen synthesis and ...
#1Thomas W. Sawyer (DRDC: Defence Research and Development Canada)H-Index: 16
#2Yushan Wang (DRDC: Defence Research and Development Canada)H-Index: 11
Last. Andres Jimenez (DRDC: Defence Research and Development Canada)
view all 5 authors...
Abstract Sulphur mustard (H; bis(2-chloroethyl) sulphide) is a vesicant chemical warfare (CW) agent that has been well documented as causing acute injury to the skin, eyes and respiratory system. Although a great deal of research effort has been expended to understand how H exerts these effects, its mechanism of action is still poorly understood. At high exposures, H also causes systemic toxicity with chronic and long-term effects to the immune, cardiovascular and central nervous systems, and th...
#1Rama Malaviya (RU: Rutgers University)H-Index: 14
#2Howard M. Kipen (RU: Rutgers University)H-Index: 44
Last. Debra L. Laskin (RU: Rutgers University)H-Index: 71
view all 5 authors...
Abstract Pulmonary fibrosis is characterized by destruction and remodeling of the lung due to an accumulation of collagen and other extracellular matrix components in the tissue. This results in progressive irreversible decreases in lung capacity, impaired gas exchange and eventually, hypoxemia. A number of inhaled and systemic toxicants have been identified that cause pulmonary fibrosis including bleomycin, silica, asbestos, nanoparticles, mustard vesicants, nitrofurantoin, amiodarone, and ioni...
3 CitationsSource
#1Thomas W. Sawyer (DRDC: Defence Research and Development Canada)H-Index: 16
Abstract In the long and intensive search for effective treatments to counteract the toxicity of the chemical warfare (CW) agent sulphur mustard (H; bis(2-chloroethyl) sulphide), the most auspicious and consistent results have been obtained with the drug N-acetylcysteine (NAC), particularly with respect to its therapeutic use against the effects of inhaled H. It is a synthetic cysteine derivative that has been used in a wide variety of clinical applications for decades and a wealth of informatio...
1 CitationsSource
#1Dauren Biyashev (NU: Northwestern University)H-Index: 10
#2U.V. Onay (NU: Northwestern University)H-Index: 2
Last. Kurt Q. Lu (NU: Northwestern University)H-Index: 9
view all 7 authors...
Injury of the skin from exposure to toxic chemicals leads to the release of inflammatory mediators and the recruitment of immune cells. Nitrogen mustard (NM) and other alkylating agents cause severe cutaneous damage for which there are limited treatment options. Here, we show that combined treatment of vitamin D3 (VD3) and spironolactone (SP), a mineralocorticoid receptor antagonist, significantly improves the resolution of inflammation and accelerates wound healing after NM exposure. SP enhance...
2 CitationsSource
#1Jared Radbel (RU: Rutgers University)H-Index: 8
#2Debra L. Laskin (RU: Rutgers University)H-Index: 71
Last. Howard M. Kipen (RU: Rutgers University)H-Index: 44
view all 4 authors...
Acute respiratory distress syndrome (ARDS) is a highly morbid lung pathology induced by exposure to chemical warfare agents, including vesicants, phosgene, chlorine, and ricin. In this review, we describe the pathology associated with the development of ARDS in humans and experimental models of acute lung injury following animal exposure to these high-priority threat agents. Potential future approaches to disease-modifying treatment used in preclinical animal studies, including antioxidants, ant...
3 CitationsSource