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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 -
Ecotoxicology and Environmental Safety Dec 2021As a natural heme protein catalyzing the oxidation of sulfides to sulfoxides without sulfone formation, chloroperoxidase (CPO) is well suited for the degradation of...
As a natural heme protein catalyzing the oxidation of sulfides to sulfoxides without sulfone formation, chloroperoxidase (CPO) is well suited for the degradation of sulfur mustard (HD), a persistent chemical warfare agent that has been widely disposed since World War II and continuously leaks into aquatic environments. Herein, we report the first systematic investigation of CPO-catalyzed degradation of HD and the potential application of CPO in destroying chemical weapons under mild conditions. The related Michaelis-Menten parameters (K=0.17 mM, V=0.06 mM s (R =0.935), and k= 2717 s) indicated nearly a prominent enzymatic efficiency. Under optimal conditions, 80% of HD was transformed to bis(2-chloroethyl) sulfoxide as identified by mass spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. Other metabolites were also generated during the decontamination process. A plausible oxidation mechanism was proposed based on the degradation products, NMR titration experiments, and molecular dynamics simulations. CPO also promoted the degradation of other chemical weapon agents, namely, Lewisite (L) and venomous agent X (VX), thereby exhibiting a broad substrate scope. The high potential of the developed system for the decontamination of aquatic environments was demonstrated by the successful hatching of zebrafish embryos after HD degradation and the survival of zebrafish (Danio rerio, AB strain) larvae after the degradation of Agent Yellow (L+HD).
Topics: Animals; Catalysis; Chloride Peroxidase; Mustard Gas; Oxidative Stress; Zebrafish
PubMed: 34500382
DOI: 10.1016/j.ecoenv.2021.112715 -
Toxicology Letters Sep 2018Phosgene Oxime (CX, ClCNOH), a halogenated oxime, is a potent chemical weapon that causes immediate acute injury and systemic effects. CX, grouped together with... (Review)
Review
Phosgene Oxime (CX, ClCNOH), 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 instantaneous and severe damage. For this reason, it could be produced as a weaponized mixture with other chemical warfare agents to enhance their deleterious effects. The immediate devastating effects of CX and easy synthesis makes it a dangerous chemical with both military and terrorist potentials. Although CX is the most potent vesicating agent, it is one of the least studied chemical warfare agents and the pathophysiology as well as long term effects are largely unknown. CX exposure results in immediate pain and inflammation, and it mainly affects skin, eye and respiratory system. There are no antidotes available against CX-induced injury and the treatment is only supportive. This review summarizes existing knowledge regarding exposure, toxicity and the probable underlying mechanisms of CX compared to other important vesicants' exposure.
Topics: Animals; Antidotes; Arsenic Poisoning; Arsenicals; Blister; Chemical Warfare Agents; Humans; Irritants; Mustard Gas; Phosgene; Poisoning; Skin Diseases
PubMed: 29141200
DOI: 10.1016/j.toxlet.2017.11.011 -
Journal of Cellular and Molecular... Aug 2023Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress...
Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell-derived exosomes (HMSCs-Ex). We noted that HMSCs-Ex-derived miR-199a-5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS-2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR-199a-5p in HMSCs-Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs-Ex administration. In summary, miR-199a-5p was one of the key molecules in HMSCs-Ex that attenuated SM-associated oxidative stress via regulating CAV1/NRF2 signalling pathway.
Topics: Animals; Humans; Mice; Exosomes; Mesenchymal Stem Cells; MicroRNAs; Mustard Gas; NF-E2-Related Factor 2; Oxidative Stress
PubMed: 37386746
DOI: 10.1111/jcmm.17803 -
Annals of the New York Academy of... Aug 2016In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the... (Review)
Review
In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the duration of exposure. Initial responses include erythema, pruritus, edema, and xerosis; this is followed by an accumulation of inflammatory leukocytes in the tissue, activation of mast cells, and the release of mediators, including proinflammatory cytokines and bioactive lipids. These proinflammatory mediators contribute to damaging the epidermis, hair follicles, and sebaceous glands and to disruption of the epidermal basement membrane. This can lead to separation of the epidermis from the dermis, resulting in a blister, which ruptures, leading to the formation of an eschar. The eschar stimulates the formation of a neoepidermis and wound repair and may result in persistent epidermal hyperplasia. Epidermal damage and repair is associated with upregulation of enzymes generating proinflammatory and pro-growth/pro-wound healing mediators, including cyclooxygenase-2, which generates prostanoids, inducible nitric oxide synthase, which generates nitric oxide, fibroblast growth factor receptor 2, and galectin-3. Characterization of the mediators regulating structural changes in the skin during SM-induced tissue damage and wound healing will aid in the development of therapeutic modalities to mitigate toxicity and stimulate tissue repair processes.
Topics: Animals; DNA Damage; Inflammation Mediators; Mice; Mustard Gas; Skin; Skin Diseases; Wound Healing
PubMed: 27371823
DOI: 10.1111/nyas.13125 -
BMJ Open May 2024People with mustard gas lung disease experience cough, sputum, breathlessness and exercise limitation. We hypothesised that pulmonary rehabilitation (PR) would be... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
People with mustard gas lung disease experience cough, sputum, breathlessness and exercise limitation. We hypothesised that pulmonary rehabilitation (PR) would be beneficial in this condition.
DESIGN
An assessor-blind, two-armed, parallel-design randomised controlled clinical trial.
SETTING
Secondary care clinics in Iran.
PARTICIPANTS
60 men with breathlessness due to respiratory disease caused by documented mustard gas exposure, mean (SD) age 52.7 (4.36) years, MRC dyspnoea score 3.5 (0.7), St. George's Respiratory Questionnaire (SGRQ) 72.3 (15.2).
INTERVENTIONS
Participants were allocated either to a 6-week course of thrice-weekly PR (n=31) or to usual care (n=29), with 6-week data for 28 and 26, respectively.
OUTCOME MEASURES
Primary endpoint was change in cycle endurance time at 70% baseline exercise capacity at 6 weeks. Secondary endpoints included 6 min walk distance, quadriceps strength and bulk, body composition and health status. For logistical reasons, blood tests that had been originally planned were not performed and 12-month follow-up was available for only a small proportion.
RESULTS
At 6 weeks, cycle endurance time increased from 377 (140) s to 787 (343) s with PR vs 495 (171) s to 479 (159) s for usual care, effect size +383 (231) s (p<0.001). PR also improved 6 min walk distance+103.2 m (63.6-142.9) (p<0.001), MRC dyspnoea score -0.36 (-0.65 to -0.07) (p=0.016) and quality of life; SGRQ -8.43 (-13.38 to -3.48) p<0.001, as well as quadriceps strength+9.28 Nm (1.89 to 16.66) p=0.015.
CONCLUSION
These data suggest that PR can improve exercise capacity and quality of life in people with breathlessness due to mustard gas lung disease and support the wider provision of this form of care.
TRIAL REGISTRATION NUMBER
IRCT2016051127848N1.
Topics: Humans; Male; Iran; Mustard Gas; Middle Aged; Exercise Tolerance; Quality of Life; Dyspnea; Lung Diseases; Adult; Outpatients; Treatment Outcome; Chemical Warfare Agents
PubMed: 38806414
DOI: 10.1136/bmjopen-2023-083085 -
Seminars in Ophthalmology May 2021The investigations discussed in this review indicate that iron may exacerbate different eye diseases. Therefore, it is plausible that reducing cellular or body iron... (Review)
Review
The investigations discussed in this review indicate that iron may exacerbate different eye diseases. Therefore, it is plausible that reducing cellular or body iron stores could influence disease pathogenesis, so it is logical to consider the iron chelators' potential protective role in the various ophthalmic diseases in the form of topical eye drops or slow releasing injectable compounds as an adjuvant treatment.
Topics: Eye Diseases; Humans; Iron; Iron Chelating Agents; Macular Degeneration; Ophthalmic Solutions
PubMed: 33621147
DOI: 10.1080/08820538.2021.1887900 -
Disaster Medicine and Public Health... Dec 2020Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged as a health problem...
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged as a health problem worldwide. It seems that COVID-19 is more lethal for Iranian veterans with a history of exposure to mustard gas. There are some similarities in the pathogenesis of SARS-CoV-2 and mustard gas in immune system disruption and pulmonary infection. SARS-CoV-2 and mustard gas inducing oxidative stress, immune system dysregulation, cytokine storm, and overexpression of angiotensin-converting enzyme II (ACE2) receptor in lungs that act as functional entry receptors for SARS-CoV-2. Moreover, Iranian survivors of mustard gas exposure are more susceptible and vulnerable to COVID-19. It is suggested that the principles of COVID-19 infection prevention and control be adhered to more stringently in Iranian survivors of mustard gas exposure than others who have not been exposed to mustard gas. Therefore, in this review, we discuss the different pathologic aspects of lung injury caused by mustard gas and also the relationship between this damage and the increased susceptibility of Iranian mustard gas exposed survivors to COVID-19.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Cytokines; Humans; Iran; Lung; Mustard Gas; Oxidative Stress; SARS-CoV-2; Survivors; Veterans
PubMed: 32418550
DOI: 10.1017/dmp.2020.156