Characterization of acute and long-term pathologies of superficial and deep dermal sulfur mustard skin lesions in the hairless guinea pig model.

Published on Nov 1, 2012in Wound Repair and Regeneration3.617
· DOI :10.1111/J.1524-475X.2012.00830.X
Shlomit Dachir19
Estimated H-index: 19
(Israel Institute for Biological Research),
Maayan Cohen9
Estimated H-index: 9
(Israel Institute for Biological Research)
+ 6 AuthorsTamar Kadar26
Estimated H-index: 26
(Israel Institute for Biological Research)
Sources
Abstract
Sulfur mustard induces severe acute and prolonged damage to the skin and only partially effective treatments are available. We have previously validated the use of hairless guinea pigs as an experimental model for skin lesions. The present study aimed to characterize a model of a deep dermal lesion and to compare it with the previously described superficial lesion. Clinical evaluation of the lesions was conducted using reflectance colorimetry, trans-epidermal water loss and wound area measurements. Prostaglandin E2 content, matrix metalloproteinase-2 and 9 activity, and histopathology were conducted up to 4 weeks post-exposure. Sulfur mustard skin injury, including erythema and edema, impairment of skin barrier and wounds developed in a dose-dependent manner. Prostaglandin E2 content and matrix metalloproteinase-2 and 9 activities were elevated during the wound development and the healing process. Histological evaluation revealed severe damage to the epidermis and deep dermis and vesications. At 4 weeks postexposure, healing was not completed: significantly impaired stratum corneum, absence of hair follicles, and epidermal hyperplasia were observed. These results confirm the use of the superficial and deep dermal skin injuries in the hairless guinea pigs as suitable models that can be utilized for the investigation of the pathological processes of acute as well as long-term injuries. These models will be further used to develop treatments to improve the healing process and prevent skin damage and long-term effects.
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References41
Newest
#1Laurie B. Joseph (RU: Rutgers University)H-Index: 13
#2Donald R. Gerecke (RU: Rutgers University)H-Index: 19
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 71
view all 10 authors...
Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1–14 days later. After 1 da...
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#1Anil K. Jain (University of Colorado Denver)H-Index: 23
#2Neera Tewari-Singh (University of Colorado Denver)H-Index: 18
Last. Rajesh Agarwal (University of Colorado Denver)H-Index: 108
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Abstract Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-...
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#1Janet M. Benson (LRRI: Lovelace Respiratory Research Institute)H-Index: 29
#2JeanClare Seagrave (LRRI: Lovelace Respiratory Research Institute)H-Index: 31
Last. Thomas H. March (LRRI: Lovelace Respiratory Research Institute)H-Index: 23
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The objective of these studies was to provide detailed analyses of the time course of sulfur mustard (SM) vapor-induced clinical, histological, and biochemical changes following cutaneous exposure in hairless guinea-pigs. Three 6 cm2 sites on the backs of each guinea-pig were exposed to SM vapor (314 mg3) for 6 minutes (low dose) or 12 minutes (high dose). Animals were killed at 6, 24, and 48 hours, or 2 weeks postexposure. Erythema, edema, histopathology, and analysis of matrix metalloproteinas...
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#1Adrienne T. Black (RU: Rutgers University)H-Index: 12
#2Patrick J. HaydenH-Index: 2
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 71
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a r t i c l e i n f o Article history: Sulfur mustard is a potent vesicant that induces in! ammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sul" de, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100-1000 ! M) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes;...
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#1Rama Malaviya (RU: Rutgers University)H-Index: 17
#2Vasanthi R. Sunil (RU: Rutgers University)H-Index: 20
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Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4mg/kg SM by vapor inhalation. Animals were sacrificed 6h, 24h, 48h or 7 d post-exposure and bronchoalveolar lavage fluid (BAL) and l...
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#1Adrienne T. Black (RU: Rutgers University)H-Index: 12
#2Laurie B. Joseph (RU: Rutgers University)H-Index: 13
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 71
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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...
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#1Shlomit Dachir (Israel Institute for Biological Research)H-Index: 19
#2Maayan Cohen (Israel Institute for Biological Research)H-Index: 9
Last. Tamar Kadar (Israel Institute for Biological Research)H-Index: 26
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Background/purpose: Skin exposure to sulfur mustard (HD) results in erythema, edema and severe injury, which take long time to heal and might impose a heavy burden on the health system. Despite many years of research, there is no treatment that prevents the development of the cytotoxic effects of HD causing acute and prolonged damage to the skin. Therefore, it is of great importance to develop treatments that will ameliorate the extent of injury and improve as well as shorten the healing process...
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#1Nahum Allon (Israel Institute for Biological Research)H-Index: 11
#2Adina Amir (Israel Institute for Biological Research)H-Index: 16
Last. Tamar Kadar (Israel Institute for Biological Research)H-Index: 26
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Guinea pigs (GP) were exposed (head only) in individual plethysmographs to various concentrations of sulfur mustard vapor, determined online, using FTIR attached to flow chamber. The LCt{sub 50} and the inhaled LD{sub 50} were calculated at different time points post exposure. Surviving animals were monitored for clinical symptoms, respiratory parameters and body weight changes for up to 30 days. Clinical symptoms were noted at 3 h post exposure, characterized by erythematic and swelling nose wi...
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#1Tamar Kadar (Israel Institute for Biological Research)H-Index: 26
#2Shlomit Dachir (Israel Institute for Biological Research)H-Index: 19
Last. Adina Amir (Israel Institute for Biological Research)H-Index: 16
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Sulfur mustard (SM) is a potent vesicant, known for its ability to cause incapacitation and prolonged injuries to the eyes, skin and respiratory system. The toxic ocular events following sulfur mustard exposure are characterized by several stages: photophobia starting a few hours after exposure, an acute injury phase characterized by inflammation of the anterior segment and corneal erosions and a delayed phase appearing following a clinically silent period (years in human). The late injury appea...
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#1Mike RowellH-Index: 1
#2Kai KeheH-Index: 32
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Abstract Whilst the acute effects of sulfur mustard have been relatively well characterised, the chronic effects of short term but significant exposures are still evolving. The approximately 30,000 Iranian victims of CW exposure from the 1980 to 1988 Iran–Iraq war who are currently being followed form a key population who are now 20 years post-exposure. The key chronic findings in this population reflect the common acute effects of sulfur mustard, and are related to the skin, eye and respiratory...
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Abstract Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soa...
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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...
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AbstractSulfur mustard (SM) is an incapacitating chemical warfare agent used in numerous conflicts around the world and it is still a major threat for both, army troops and civilians. To evaluate its multiple targets effects in experimental setup, a model of whole body exposure (WBE) to SM vapor was established in rats and its simultaneous effects on lungs and eyes as well as on general wellbeing were examined. Rats were exposed to SM vapor. Evaluation (up to 10 weeks post-exposure) included bod...
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#1Dorothee Rose (University of Lübeck)H-Index: 3
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#1Shlomit Dachir (Israel Institute for Biological Research)H-Index: 19
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Data on the toxicity of lewisite (L), a vesicant chemical warfare agent, are scarce and conflicting, and the use of the specific antidote is not without drawbacks. This study was designed to evaluate if the SKH-1 hairless mouse model was suitable to study the L-induced skin injuries. We studied the progression of lesions following exposure to L vapors for 21 days using paraclinical parameters (color, transepidermal water loss (TEWL), and biomechanical measurements), histological assessments, and...
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