Inflammatory Biomarkers of Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide–Induced Skin Injury in SKH-1 Hairless Mice

Published on Mar 1, 2009in Toxicological Sciences3.703
· DOI :10.1093/TOXSCI/KFN261
Neera Tewari-Singh17
Estimated H-index: 17
(University of Colorado Denver),
Sumeet Rana1
Estimated H-index: 1
+ 4 AuthorsRajesh Agarwal104
Estimated H-index: 104
Sources
Abstract
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-induced skin injury in dose- (0.05–2 mg) and time- (3–168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.
📖 Papers frequently viewed together
330 Citations
147 Citations
66 Citations
References58
Newest
#1Byung Ju Kim (NU: Northeastern University)H-Index: 3
#2Hoyun Lee (Northern Ontario School of Medicine)H-Index: 24
Background information. PCNA (proliferating cell nuclear antigen) is required for a wide range of cellular functions, including DNA replication and damage repair. To be functional, PCNA must associate with the replication and repair foci. In addition, PCNA also mediates targeting of certain replication and repair proteins to these foci. However, the mechanism is not yet known by which PCNA is imported into the nucleus, and then localized to the replication and repair foci. Results. We have found...
17 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
#2Angela L. AdkinsH-Index: 1
Last. John S. GrahamH-Index: 18
view all 4 authors...
Objective: Sulfur mustard (SM) causes blisters on the human skin. These blisters delay healing of the skin and make the victims more susceptible to infection. In vitro models have been used for protection studies against SM injury, but study on wound healing after SM exposure has not been explored. The purpose of this study was to test whether the addition of exogenous growth factors could improve the rate of SM wound healing. Methods: The model consisted of normal human epidermal keratinocytes ...
19 Citations
#1Valentina Loria (UCSC: Catholic University of the Sacred Heart)H-Index: 3
#2Ilaria DatoH-Index: 9
Last. Luigi M. BiasucciH-Index: 69
view all 4 authors...
Myeloperoxidase (MPO) is an enzyme stored in azurophilic granules of polymorphonuclear neutrophils and macrophages and released into extracellular fluid in the setting of inflammatory process. The observation that myeloperoxidase is involved in oxidative stress and inflammation has been a leading factor to study myeloperoxidase as a possible marker of plaque instability and a useful clinical tool in the evaluation of patients with coronary heart disease. The purpose of this review is to provide ...
212 CitationsSource
#1Adil Anwar (Anschutz Medical Campus)H-Index: 20
#2Mallikarjuna Gu (Anschutz Medical Campus)H-Index: 18
Last. Mayumi Fujita (Anschutz Medical Campus)H-Index: 28
view all 10 authors...
UVB exposure of skin results in various biologic responses either through direct or indirect damage to DNA and non-DNA cellular targets via the formation of free radicals, reactive oxygen species (ROS) and inflammation. Bucillamine [N-(2-mercapto-2-methylpropionyl)-L-cysteine] is a cysteine-derived compound that can replenish endogenous glutathione due to its two donatable thiol groups, and functions as an antioxidant. In this study, we investigated the effects of bucillamine on UVB-induced phot...
8 CitationsSource
#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
#1R.R. Bell (Pfizer)H-Index: 1
#2R.W. Dunstan (Pfizer)H-Index: 1
Last. N.K. Khan (Pfizer)H-Index: 1
view all 3 authors...
Summary Background The inducible isoform of the nitric oxide (NO) synthase (NOS) enzyme (iNOS) is upregulated by inflammatory mediators and/or other pathological stresses, generating high, sustained levels of NO. Cumulative data suggest a role for NO in the regulation of skin wound healing, although it is not clear to what extent NO generated by iNOS, and possibly endothelial NOS (eNOS), contribute to that healing process. Because of the current lack of understanding regarding the contribution o...
10 CitationsSource
#1Myriane A. Isidore (WRAIR: Walter Reed Army Institute of Research)H-Index: 1
#2Michael P. Castagna (WRAIR: Walter Reed Army Institute of Research)H-Index: 1
Last. Madhusoodana P. Nambiar (USU: Uniformed Services University of the Health Sciences)H-Index: 32
view all 5 authors...
To evaluate stem cell-derived therapeutics for cutaneous vesicant injuries, we developed a dorsal exposure model using C57BL/6 black mice and half-mustard, 2-chloroethyl ethyl sulfide (CEES). The dorsal side of a mouse was exposed to 1–5 μl of CEES for 10 minutes and then decontaminated. The data demonstrate that 3 μl of CEES induced edema and erythema that peaked 24 h post exposure. Histopathology showed a central area of deep injury characterized by severe necrosis of epidermis and dermis. The...
15 CitationsSource
#1John S. GrahamH-Index: 18
#2Robert S StevensonH-Index: 4
Last. Robyn B. LeeH-Index: 14
view all 7 authors...
Objective: The objective was to examine the efficacy of several treatment regimens in improving wound healing of cutaneous sulfur mustard (HD) injuries. Methods: Wound healing studies were conducted in weanling pigs. Superficial dermal HD injuries were debrided at 48 hours postexposure using an erbium-doped yttrium aluminum garnet (Er:YAG) laser, followed by application of a treatment adjunct. A variety of noninvasive bioengineering methods were conducted during the postsurgical observation peri...
19 Citations
#1Mahdi Balali-Mood (MUMS: Mashhad University of Medical Sciences)H-Index: 25
#2Mehrdad Hefazi (MUMS: Mashhad University of Medical Sciences)H-Index: 9
Abstract: 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 appe...
247 CitationsSource
Cited By66
Newest
#1Satyendra Kumar Singh (MSU: Michigan State University)
#1Satyendra K. Singh (MSU: Michigan State University)H-Index: 9
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...
1 CitationsSource
#1Silpa Sabnam (KIIT: KIIT University)H-Index: 4
#2Huma Rizwan (KIIT: KIIT University)H-Index: 4
Last. Arttatrana Pal (KIIT: KIIT University)H-Index: 5
view all 4 authors...
Abstract Reactive oxygen species (ROS) is mainly produced as a by-product from electron transport chain (ETC) of mitochondria and effectively eliminated by cellular antioxidants. However, 2-chloroethyl ethyl sulfide (CEES) exposure to keratinocytes declined antioxidant capacity and increased accumulation of ROS triggered alteration of mitochondrial activity and apoptosis is lacking. Our findings demonstrated that the electron leakage from the impaired ETC, leading to the accumulation of ROS was ...
3 CitationsSource
#1Gabriella Wahler (RU: Rutgers University)H-Index: 1
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 4
Last. Laurie B. Joseph (RU: Rutgers University)H-Index: 12
view all 6 authors...
Abstract Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mi...
1 CitationsSource
#1Silpa Sabnam (KIIT: KIIT University)H-Index: 4
#2Arttatrana Pal (KIIT: KIIT University)H-Index: 5
2-Chloroethyl ethyl sulfide (CEES) is a well-known chemical warfare agent that induces cellular stress in exposed individuals. However, molecular mechanisms of CEES-induced oxidative stress–mediated metabolic deregulation are not clearly elucidated. Here we investigated CEES-induced free radical production act as key functional mediators of metabolic stress via Erk1/2 mitogen–activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K/Akt) signaling cascades in keratinocytes. We ob...
6 CitationsSource
#1Megha Bansal (IITR: Indian Institute of Toxicology Research)H-Index: 2
#2Neha Singh (IITR: Indian Institute of Toxicology Research)H-Index: 4
Last. Kausar M. Ansari (IITR: Indian Institute of Toxicology Research)H-Index: 18
view all 7 authors...
Abstract Alternariol (AOH) is a mycotoxin that contaminates various food stuffs as well as animal feed and may cause toxicity after consumption. However, a dermal toxic potential of AOH has not been explored so far. In the present study, skin toxicity after topical exposure of AOH and the involved mechanism/s are revealed. Single topical application of different AOH doses (12.5, 25, 50 μg/animal) caused increased bi-fold thickness as well as hyperplasia and higher production of prostaglandin E2 ...
7 CitationsSource
#1Yoke Chen Chang (RU: Rutgers University)H-Index: 3
#2Melannie Soriano (RU: Rutgers University)H-Index: 1
Last. Donald R. Gerecke (RU: Rutgers University)H-Index: 18
view all 7 authors...
Abstract Sulfur mustard (2,2′-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemok...
5 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
#1Dinesh G Goswami (Anschutz Medical Campus)H-Index: 8
#2Rama Kant (Anschutz Medical Campus)H-Index: 8
Last. Rajesh Agarwal (Anschutz Medical Campus)H-Index: 104
view all 4 authors...
Abstract Vesicating agent, Sulfur mustard (SM), causes devastating eye injury; however, there are no effective antidotes available. Using nitrogen mustard (NM), a bi-functional analog of SM, we have earlier reported that NM-induced corneal injury in ex vivo rabbit cornea organ culture model parallels corneal injury reported with SM. Using this model, we have demonstrated the therapeutic efficacy of dexamethasone (DEX), doxycycline (DOX) and silibinin (SB) in reversing NM (2 h exposure)-induced c...
7 CitationsSource