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Cells Jun 2023Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported...
Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in >90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Naïve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2/3, pSMAD, and ɑSMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGFβ, pSMAD3, and SMAD2/3 levels. On the contrary, inhibition of SMAD2/3 signaling by SIS3 treatment significantly reduced SMAD2/3, pSMAD3, and ɑSMA expression in hCSFs. We conclude that SMAD2/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure.
Topics: Humans; Animals; Rabbits; Mustard Gas; Myofibroblasts; Chemical Warfare Agents; Cornea; Mechlorethamine; Signal Transduction; Smad2 Protein
PubMed: 37296653
DOI: 10.3390/cells12111533 -
RSC Advances Jul 2022By combining the anionic salt meso-tetra(4-carboxyphenyl)porphyrin (TCPP) and the Keggin polyoxometalate cation cluster [AlO(OH)(HO)] a simple ion-exchange method, a...
Enhancing the quantum yield of singlet oxygen: photocatalytic degradation of mustard gas simulant 2-chloroethyl ethyl sulfide catalyzed by a hybrid of polyhydroxyl aluminum cations and porphyrin anions.
By combining the anionic salt meso-tetra(4-carboxyphenyl)porphyrin (TCPP) and the Keggin polyoxometalate cation cluster [AlO(OH)(HO)] a simple ion-exchange method, a hybrid (CHNO)[AlO(OH)(HO)](OH)·18HO (Al-TCPP) was prepared and thoroughly characterized as a prototype of polyoxometalate-porphyrin hybrids for the photocatalytic degradation of the mustard gas simulant 2-chloroethyl ethyl sulfide (CEES). The experimental results showed that the catalytic degradation rate of CEES in the presence of Al-TCPP reached 96.16 and 99.01% in 180 and 90 min in methanol and methanol-water solvent mixture (v/v = 1 : 1), respectively. The reaction followed first-order reaction kinetics, and the half-life and kinetic constant in methanol and solvent mixture were 39.8 min, -0.017 min and 14.7 min, -0.047 min. Mechanism analysis indicated that under visible light irradiation in air, CEES was degraded through a combination of oxidation and alcoholysis/hydrolysis in methanol and the methanol-water solvent mixture. The superoxide radical (O˙) and singlet molecular oxygen (O) generated by Al-TCPP selectively oxidized CEES into a non-toxic sulfoxide. The singlet oxygen capture experiments showed that Al-TCPP ( = 0.236) had a higher quantum yield of singlet oxygen generation than HTCPP ( = 0.135) under visible light irradiation in air. The material Al-TCPP has good reusability, and the degradation rate of CEES can still reach 98.37% after being recycled five times.
PubMed: 35919596
DOI: 10.1039/d2ra01821g -
Annals of the New York Academy of... Jun 2016Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of... (Review)
Review
Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents.
Topics: Animals; Humans; Irritants; Models, Biological; Mustard Gas; Silybin; Silymarin; Skin
PubMed: 27326543
DOI: 10.1111/nyas.13099 -
Annals of the New York Academy of... Jun 2016Corneal injuries resulting from ocular exposure to sulfur mustard (SM) vapor are the most prevalent chemical warfare injury. Ocular exposures exhibit three distinct,... (Review)
Review
Corneal injuries resulting from ocular exposure to sulfur mustard (SM) vapor are the most prevalent chemical warfare injury. Ocular exposures exhibit three distinct, dose-dependent clinical trajectories: complete injury resolution, immediate transition to a chronic injury, or apparent recovery followed by the subsequent development of persistent ocular manifestations. These latter two trajectories include a constellation of corneal symptoms that are collectively known as mustard gas keratopathy (MGK). The etiology of MGK is not understood. Here, we synthesize recent findings from in vivo rabbit SM vapor studies, suggesting that tissue-specific damage during the acute injury can decrement the regenerative capacities of corneal endothelium and limbal stem cells, thereby predisposing the cornea to the chronic or delayed forms of MGK. This hypothesis not only provides a mechanism to explain the acute and MGK injuries but also identifies novel therapeutic modalities to mitigate or eliminate the acute and long-term consequences of ocular exposure to SM vapor.
Topics: Animals; Cornea; Corneal Injuries; Disease Models, Animal; Environmental Exposure; Humans; Mustard Gas; Volatilization
PubMed: 27310673
DOI: 10.1111/nyas.13105 -
BMJ (Clinical Research Ed.) Feb 2002
Review
Topics: Chemical Warfare Agents; Decontamination; Humans; Mustard Gas; Organophosphate Poisoning; Phosgene; Poisoning
PubMed: 11834561
DOI: 10.1136/bmj.324.7333.332 -
Environmental Health Perspectives Dec 1999The two major threat classes of chemical weapons are mustard gas and the nerve agents, and this has not changed in over 50 years. Both types are commonly called gases,... (Review)
Review
The two major threat classes of chemical weapons are mustard gas and the nerve agents, and this has not changed in over 50 years. Both types are commonly called gases, but they are actually liquids that are not remarkably volatile. These agents were designed specifically to harm people by any route of exposure and to be effective at low doses. Mustard gas was used in World War I, and the nerve agents were developed shortly before, during, and after World War II. Our perception of the potency of chemical weapons has changed, as well as our concern over potential effects of prolonged exposures to low doses and potential target populations that include women and children. Many of the toxicologic studies and human toxicity estimates for both mustard and nerve agents were designed for the purpose of quickly developing maximal casualties in the least sensitive male soldier. The "toxicity" of the chemical weapons has not changed, but our perception of "toxicity" has.
Topics: Animals; Chemical Warfare; Chemical Warfare Agents; Hazardous Substances; Humans
PubMed: 10585902
DOI: 10.1289/ehp.99107985 -
Free Radical Biology & Medicine Dec 2020In 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),... (Review)
Review
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 information exists on its safety and protective properties against a broad range of toxicants and disease states. Its primary mechanism of action is as a pro-drug for the synthesis of the antioxidant glutathione (GSH), particularly in those circumstances where oxidative stress has exhausted intracellular GSH stores. It impacts a number of pathways either directly or through its GSH-related antioxidant and anti-inflammatory properties, which make it a prime candidate as a potential treatment for the wide range of deleterious cellular effects that H is acknowledged to cause in exposed individuals. This report reviews the available literature on the protection afforded by NAC against the toxicity of H in a variety of model systems, including its efficacy in treating the long-term chronic lung effects of H that have been demonstrated in Iranian veterans exposed during the Iran-Iraq War (1980-1988). Although there is overwhelming evidence supporting this drug as a potential medical countermeasure against this CW agent, there is a requirement for carefully controlled clinical trials to determine the safety, efficacy and optimal NAC dosage regimens for the treatment of inhaled H.
Topics: Acetylcysteine; Chemical Warfare Agents; Glutathione; Humans; Iran; Mustard Gas
PubMed: 32980537
DOI: 10.1016/j.freeradbiomed.2020.09.020 -
Annals of the New York Academy of... Aug 2016Acute lung injury due to sulfur mustard (SM) inhalation causes the formation of airway fibrin casts that obstruct airways at multiple levels, leading to acute... (Review)
Review
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 the microparticle fraction, and these effects can be inhibited by TF pathway inhibitor protein. Not only does the procoagulant environment of the acutely injured lung contribute to airway cast formation, but these lesions persist in airways because of the activation of multiple antifibrinolytic pathways, including plasminogen activator inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin. Airway administration of tissue plasminogen activator can overwhelm these effects and save lives by preventing fibrin-dependent airway obstruction, gas-exchange abnormalities, and respiratory failure. In human survivors of SM inhalation, fibrotic processes, including bronchiolitis obliterans and interstitial fibrosis of the lung, are among the most disabling chronic lesions. Antifibrotic therapies may prove useful in preventing either or both of these forms of chronic lung damage.
Topics: Acute Lung Injury; Animals; Blood Coagulation; Fibrinolytic Agents; Humans; Inhalation Exposure; Mustard Gas
PubMed: 27384912
DOI: 10.1111/nyas.13130 -
Proteome Science Aug 2022Understanding the molecular and cellular mechanisms involved in the pathogenesis of ocular injured induced by mustard gas can help better identify complications and...
Understanding the molecular and cellular mechanisms involved in the pathogenesis of ocular injured induced by mustard gas can help better identify complications and discover appropriate therapies. This study aimed to analyze the proteomics of tears of chemical warfare victims with mustard gas ocular injuries and compare it with healthy individuals. In this case-control research, 10 mustard gas victims with long-term ocular difficulties (Chronic) were included in the patient group, while 10 healthy persons who were age and sex matched to the patients were included in the control group. Schirmer strips were used to collect the tears of the participants. Proteomics experiments were performed using the high-efficiency TMT10X method to evaluate the tear protein profile, and statistical bioinformatics methods were used to identify the differently expressed proteins. 24 proteins had different expressions between the two groups. Among these 24 proteins, 8 proteins had increased expression in veterans' tears, while the remaining 16 proteins had decreased expression. Reactome pathways were used to look at proteins with various expressions, and 13 proteins were found to be engaged in the immune system, 9 of which were effective in the innate immune system, and 5 proteins were effective in the complement cascade. Ocular mustard gas exposure may cause a compromised immune system on the eye's surface, exposing the cornea to external and endogenous infections, and eventually causing corneal opacity and reduced vision.
PubMed: 35948930
DOI: 10.1186/s12953-022-00195-1 -
BMC Pulmonary Medicine Aug 2008Exposure to mustard gas frequently results in long-term respiratory complications. However the factors which drive the development and progression of these complications...
BACKGROUND
Exposure to mustard gas frequently results in long-term respiratory complications. However the factors which drive the development and progression of these complications remain unclear. The Renin Angiotensin System (RAS) has been implicated in lung inflammatory and fibrotic responses. Genetic variation within the gene coding for the Angiotensin Converting Enzyme (ACE), specifically the Insertion/Deletion polymorphism (I/D), is associated with variable levels of ACE and with the severity of several acute and chronic respiratory diseases. We hypothesized that the ACE genotype might influence the severity of late respiratory complications of mustard gas exposure.
METHODS
208 Kurdish patients who had suffered high exposure to mustard gas, as defined by cutaneous lesions at initial assessment, in Sardasht, Iran on June 29 1987, underwent clinical examination, spirometric evaluation and ACE Insertion/Deletion genotyping in September 2005.
RESULTS
ACE genotype was determined in 207 subjects. As a continuous variable, FEV1 % predicted tended to be higher in association with the D allele 68.03 +/- 20.5%, 69.4 +/- 21.4% and 74.8 +/- 20.1% for II, ID and DD genotypes respectively. Median FEV1 % predicted was 73 and this was taken as a cut off between groups defined as having better or worse lung function. The ACE DD genotype was overrepresented in the better spirometry group (Chi2 4.9 p = 0.03). Increasing age at the time of exposure was associated with reduced FEV1 %predicted (p = 0.001), whereas gender was not (p = 0.43).
CONCLUSION
The ACE D allele is associated with higher FEV1 % predicted when assessed 18 years after high exposure to mustard gas.
Topics: Adult; Chemical Warfare; Chemical Warfare Agents; Environmental Exposure; Female; Forced Expiratory Volume; Gene Deletion; Humans; Iran; Iraq; Lung Diseases; Male; Middle Aged; Mustard Gas; Polymorphism, Genetic; Renin; Spirometry
PubMed: 18702808
DOI: 10.1186/1471-2466-8-15