2-Chloroethyl ethyl sulfide causes microvesication and inflammation-related histopathological changes in male hairless mouse skin.

Published on Apr 11, 2011in Toxicology4.099
· DOI :10.1016/J.TOX.2011.01.021
Anil K. Jain22
Estimated H-index: 22
(University of Colorado Denver),
Neera Tewari-Singh17
Estimated H-index: 17
(University of Colorado Denver)
+ 2 AuthorsRajesh Agarwal104
Estimated H-index: 104
(University of Colorado Denver)
Sources
Abstract
Sulfur mustard (HD) is a vesicating agent that has been used as a chemical warfare agent in a number of conflicts, posing a major threat in both military conflict and chemical terrorism situations. Currently, we lack effective therapies to rescue skin injuries by HD, in part, due to the lack of appropriate animal models, which are required for conducting laboratory studies to evaluate the therapeutic efficacy of promising agents that could potentially be translated in to real HD-caused skin injury. To address this challenge, the present study was designed to assess whether microvesication could be achieved in mouse skin by an HD analog 2-chloroethyl ethyl sulfide (CEES) exposure; notably, microvesication is a key component of HD skin injury in humans. We found that skin exposure of male SKH-1 hairless mice to CEES caused epidermal-dermal separation indicating microvesication. In other studies, CEES exposure also caused an increase in skin bi-fold thickness, wet/dry weight ratio, epidermal thickness, apoptotic cell death, cell proliferation, and infiltration of macrophages, mast cells and neutrophils in male SKH-1 hairless mouse skin. Taken together, these results establish CEES-induced microvesication and inflammation-related histopathological changes in mouse skin, providing a potentially relevant laboratory model for developing effective countermeasures against HD skin injury in humans.
📖 Papers frequently viewed together
66 Citations
147 Citations
330 Citations
References46
Newest
#1Neera Tewari-Singh (University of Colorado Denver)H-Index: 17
#2Mallikarjuna GuH-Index: 18
Last. Rajesh Agarwal (University of Colorado Denver)H-Index: 104
view all 5 authors...
Effective medical treatment and preventive measures for chemical warfare agent sulfur mustard (HD)-caused incapacitating skin toxicity are lacking, because of limited knowledge of its mechanism of action. The proliferating basal epidermal cells are primary major sites of attack during HD-caused skin injury. Therefore, employing mouse JB6 and human HaCaT epidermal cells, here, we investigated the molecular mechanism of HD analogue 2-chloroethyl ethyl sulfide (CEES)-induced skin cytotoxicity. As c...
56 CitationsSource
#1Adrienne T. Black (RU: Rutgers University)H-Index: 12
#2Laurie B. Joseph (RU: Rutgers University)H-Index: 12
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
view all 8 authors...
Abstract Dermal exposure to sulfur mustard causes inflammation and tissue injury. This is associated with changes in expression of antioxidants and eicosanoids which contribute to oxidative stress and toxicity. In the present studies we analyzed mechanisms regulating expression of these mediators using an in vitro skin construct model in which mouse keratinocytes were grown at an air–liquid interface and exposed directly to 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. CEE...
47 CitationsSource
#1Michael P. Shakarjian (NYMC: New York Medical College)H-Index: 12
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 38
Last. Jeffrey D. Laskin (UMDNJ: University of Medicine and Dentistry of New Jersey)H-Index: 69
view all 10 authors...
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 mecha...
147 CitationsSource
#1Arttatrana Pal (University of Colorado Denver)H-Index: 5
#1Arttatrana Pal (University of Colorado Denver)H-Index: 5
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...
66 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
#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...
31 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
#1Kai KeheH-Index: 30
#2Frank BalszuweitH-Index: 15
Last. Horst ThiermannH-Index: 50
view all 6 authors...
Objective: Sulfur mustard (SM) is a bifunctional alkylating substance being used as chemical warfare agent (vesicant). It is still regarded as a significant threat in chemical warfare and terrorism. Exposure to SM produces cutaneous blisters, respiratory and gastrointestinal tract injury, eye lesions, and bone marrow depression. Victims of World War I as well as those of the Iran-Iraq war have suffered from devastating chronic health impairment. Even decades after exposure, severe long-term effe...
73 Citations
#1Victor Paromov (ETSU: East Tennessee State University)H-Index: 7
Last. William L. Stone (ETSU: East Tennessee State University)H-Index: 34
view all 4 authors...
Objective: Sulfur mustard (bis-2-(chloroethyl) sulfide) is a chemical warfare agent (military code: HD) causing extensive skin injury. The mechanisms underlying HD-induced skin damage are not fully elucidated. This review will critically evaluate the evidence showing that oxidative stress is an important factor in HD skin toxicity. Oxidative stress results when the production of reactive oxygen (ROS) and/or reactive nitrogen oxide species (RNOS) exceeds the capacity of antioxidant defense mechan...
100 Citations
#1Mallikarjuna Gu (Anschutz Medical Campus)H-Index: 18
#2Rana P. SinghH-Index: 73
Last. Rajesh AgarwalH-Index: 104
view all 5 authors...
Sunscreens partially filter UVB and, therefore, could partially prevent skin cancer; however, efficient approaches are desired to effectively prevent photocarcinogenesis. It is hypothesized that nontoxic pharmacologically active natural compounds can increase photoprotective effects. Our completed studies suggest that silibinin, a bioactive phytochemical, strongly prevents photocarcinogenesis; however, its mechanism is not fully understood. Herein, for the first time, we used a clinically releva...
127 CitationsSource
Cited By32
Newest
#1Xi Cheng (National University of Defense Technology)H-Index: 1
#2Chang-Cai LiuH-Index: 4
Last. Yihe Li (National University of Defense Technology)
view all 9 authors...
Abstract Sulfur mustard (SM) is a blister chemical warfare agent with severe cytotoxicity and genotoxicity. It can extensively alkylate important macromolecules in organisms, such as proteins, DNA, and lipids, and produce a series of metabolites, among which the characteristic ones can be used as biomarkers. The exact toxicological mechanisms of SM remain unclear but mainly involve the DNA lesions induced by alkylation and oxidative stress caused by glutathione depletion. Various methods have be...
Source
#1Somaye Sadeghi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 2
#2Mahtab Tapak (Shahid Beheshti University of Medical Sciences and Health Services)
Last. Nariman Mosaffa (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 12
view all 4 authors...
Abstract Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as w...
Source
#1Peng Wang (SYSU: Sun Yat-sen University)H-Index: 2
#1Peng Wang (SYSU: Sun Yat-sen University)H-Index: 11
Last. Bing Tang (SYSU: Sun Yat-sen University)H-Index: 12
view all 9 authors...
Abstract Excessive inflammation and reduced angiogenesis are two major obstacles in burn wound healing and skin regeneration. Here we report the fabrication and application of a sophisticated hydrogel from chemically modified hyaluronic acid (HA), dextran (Dex), and β-cyclodextrin (β-CD) integrating resveratrol (Res) and vascular endothelial growth factor (VEGF) plasmid as the anti-inflammatory and pro-angiogenic components for burn wounds. Firstly, covalent alterations were conducted to obtain ...
39 CitationsSource
#1Dinesh G Goswami (UM: University of Montana)H-Index: 8
#2Rajesh Agarwal (UM: University of Montana)H-Index: 104
Last. Neera Tewari-Singh (UM: University of Montana)H-Index: 17
view all 3 authors...
Abstract Phosgene Oxime (CX, Cl 2 CNOH), a halogenated oxime, is a potent chemical weapon that causes immediate acute injury and systemic effects. CX, grouped together with vesicating agents, is an urticant or nettle agent with highly volatile, reactive, corrosive, and irritating vapor, and has considerably different chemical properties and toxicity compared to other vesicants. CX is absorbed quickly through clothing with faster cutaneous penetration compared to other vesicating agents causing i...
5 CitationsSource
#1Laurie B. Joseph (RU: Rutgers University)H-Index: 12
#2Gabriella M. Composto (RU: Rutgers University)H-Index: 5
Last. Diane E. Heck (NYMC: New York Medical College)H-Index: 38
view all 13 authors...
Abstract Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal app...
8 CitationsSource
#1Dorothee Rose (University of Lübeck)H-Index: 3
#2Annette M. SchmidtH-Index: 40
Last. Johannes Boltze (University of Lübeck)H-Index: 34
view all 6 authors...
Abstract Sulfur mustard (SM) is a chemical warfare, which has been used for one hundred years. However, its exact pathomechanisms are still incompletely understood and there is no specific therapy available so far. In this systematic review, studies published between January 2000 and July 2017 involving pathomechanisms and experimental treatments of SM-induced skin lesions were analyzed to summarize current knowledge on SM pathology, to provide an overview on novel treatment options, and to iden...
8 CitationsSource
#2Daniel Béracochéa (University of Bordeaux)H-Index: 30
Last. Christophe PiérardH-Index: 27
view all 4 authors...
Abstract Cognitive and emotional disorders have been reported in veterans intoxicated with sulfur mustard (SM) a chemical weapon belonging to the category of vesicating agents. However, the intense stress associated with the SM intoxication may render difficult determining the exact role played by SM intoxication itself on the emergence and maintaining of cognitive disorders. Animal's model would allow overcoming this issue. So far, we presently investigated the cognitive and emotional impact of...
3 CitationsSource
#1Neera Tewari-Singh (UM: University of Montana)H-Index: 17
#2Dinesh G Goswami (UM: University of Montana)H-Index: 8
Last. Rajesh Agarwal (UM: University of Montana)H-Index: 104
view all 7 authors...
Abstract Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 ha...
7 CitationsSource
#1Carl W. White (CU: University of Colorado Boulder)H-Index: 64
#2Raymond C. Rancourt (CU: University of Colorado Boulder)H-Index: 14
Last. Livia A. Veress (CU: University of Colorado Boulder)H-Index: 12
view all 3 authors...
Acute lung injury due to sulfur mustard (SM) inhalation causes the formation of airway fibrin casts that obstruct airways at multiple levels, leading to acute respiratory failure and death. These pathophysiological effects are seen in rodent models of acute SM vapor inhalation, as well as in human victims of acute SM inhalation. In rat models, the initial steps in activation of the coagulation system at extravascular sites depend on tissue factor (TF) expression by airway cells, especially in th...
9 CitationsSource
#1Dinesh G Goswami (UM: University of Montana)H-Index: 8
#2Neera Tewari-Singh (UM: University of Montana)H-Index: 17
Last. Rajesh Agarwal (UM: University of Montana)H-Index: 104
view all 3 authors...
The vesicating agents sulfur mustard (SM) and lewisite (LEW) are potent chemical warfare agents that primarily cause damage to the ocular, skin, and respiratory systems. However, ocular tissue is the most sensitive organ, and vesicant exposure results in a biphasic injury response, including photophobia, corneal lesions, corneal edema, ulceration, and neovascularization, and may cause loss of vision. There are several reports on ocular injury from exposure to SM, which has been frequently used i...
17 CitationsSource