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Metabolomics significantly impacts drug discovery and precise disease management. This study meticulously assesses the metabolite profiles of cells treated with Crocin, Dexamethasone, and mesenchymal stem cells (MSCs) under oxidative stress induced by 2-chloroethyl ethyl sulfide (CEES). Gas chromatography/mass spectrometry (GC/MS) analysis unequivocally identified substantial changes in 37 metabolites across the treated groups. Notably, pronounced alterations were observed in pathways associated with aminoacyl-tRNA biosynthesis and the metabolism of aspartate, serine, proline, and glutamate. These findings demonstrate the potent capacity of the analyzed treatments to effectively reduce inflammation, mitigate reactive oxygen species production, and enhance cell survival rates. SIGNIFICANCE., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Sulphur mustard (SM) is a chemical weapon agent that was extensively used by Iraqi troops during the Iran-Iraq war (1980-1988), resulting in exposure among Iranian military personnel and civilians. However, there is limited and conflicting information about the long-term mortality effects of SM exposure. This study aimed to determine the standardised mortality ratios (SMRs) in individuals exposed to SM gas during the Iran-Iraq war., Study Design: This was a retrospective follow-up study., Methods: Data were obtained from the Veterans and Martyr Affair Foundation of Iran (VMAF) regarding all confirmed individuals who were exposed to SM during the Iran-Iraq war (1980-1988) up to 30 March 2019. The mortality rate, cumulative mortality and SMR with 95 % confidence intervals (CIs) were calculated to assess mortality in chemical warfare survivors (CWS), and results were compared with the general Iranian population. Overall survival was analysed using the Kaplan-Meier curve, and the log-rank test was employed to compare survival probability across different categories., Results: Among the 48,067 confirmed CWS, a total of 4358 (9.1 %) individuals had died by the end of the study period (30 March 2019), with a mean age of 55.5 ± 14.4 years at the time of death. Overall, at the 39-year follow-up, the mortality rate due to all causes of death for people who were exposed to SM was lower than the general Iranian population (SMR: 0.70, 95 % CI: 0.68-0.72). However, cause-specific SMR analysis showed that the mortality rate due to liver cancer (SMR: 1.98, 95 % CI: 1.59-2.45), poisonings (SMR: 1.92, 95 % CI: 1.52-2.38), respiratory disorders (SMR: 1.59, 95 % CI: 1.46-1.73) and multiple myeloma (SMR: 1.72, 95 % CI: 1.06-2.62) were approximately twofold higher in CWS than the general population., Conclusions: This study provides valuable insights into the mortality effects of SM exposure among the Iranian population affected by the Iran-Iraq war. The results emphasise the importance of continued monitoring and support for individuals exposed to SM, particularly in the context of managing and addressing the heightened risks associated with liver cancer, poisonings, respiratory disorders and multiple myeloma. Further research and interventions may be necessary to mitigate these specific health challenges in the affected population., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Sulfur Mustard (SM) is a chemical warfare agent that has serious short-term and long-term effects on health. Thousands of Iranians were exposed to SM during the eight-year Iran-Iraq conflict and permanently injured while the socioeconomic imbalance in their healthcare utilization (HCU) and health expenditures remains. This study aims to describe the HCU of SM-exposed survivors in Iran from 2018 to 2021; identify high-risk areas; and apply an inequality analysis of utilization regarding the socioeconomic groups to reduce the gap by controlling crucial determinants., Methods: From Oct 2018 to June 2021, the Veterans and Martyrs Affairs Foundation (VMAF) recorded 58,888 living war survivors with eye, lung, and skin ailments. After cleaning the dataset and removing junk codes, we defined 11 HCU-related variables and predicted the HCU for the upcoming years using Bayesian spatio-temporal models. We explored the association of individual-level HCU and determinants using a Zero-inflated Poisson (ZIP) model and also investigated the provincial hotspots using Local Moran's I., Results: With ≥ 90% confidence, we discovered eleven HCU clusters in Iran. We discovered that the expected number of HCU 1) rises with increasing age, severity of complications in survivors' eyes and lungs, wealth index (WI), life expectancy (LE), and hospital beds ratio; and 2) decreases with growing skin complications, years of schooling (YOS), urbanization, number of hospital beds, length of stay (LOS) in bed, and bed occupancy rate (BOR). The concentration index (CInd) of HCU and associated costs in age and wealth groups were all positive, however, the signs of CInd values for HCU and total cost in YOS, urbanization, LOS, and Hospital beds ratio groups were not identical., Conclusions: We observed a tendency of pro-rich inequity and also higher HCU and expenditures for the elderly population. Finally, health policies should tackle potential socioeconomic inequities to reduce HCU gaps in the SM-exposed population. Also, policymakers should allocate the resources according to the hotspots of HCU., (© 2023. The Author(s).)

Sulfur mustard (SM) is an alkylating and forming chemical that was widely used by Iraqi forces during the Iran-Iraq wars. One of the target organs of SM is the skin. Understanding the mechanisms involved in the pathogenesis of SM may help better identify complications and find appropriate treatments. The current study collected ten SM-exposed patients with long-term skin complications and ten healthy individuals. Proteomics experiments were performed using the high-efficiency TMT10X method to evaluate the skin protein profile, and statistical bioinformatics methods were used to identify the differentially expressed proteins. One hundred twenty-nine proteins had different expressions between the two groups. Of these 129 proteins, 94 proteins had increased expression in veterans' skins, while the remaining 35 had decreased expression. The hub genes included RPS15, ACTN1, FLNA, HP, SDHC, and RPL29, and three modules were extracted from the PPI network analysis. Skin SM exposure can lead to oxidative stress, inflammation, apoptosis, and cell proliferation., (© 2022. The Author(s).)

Background: Mustard gas (MG) is one of the most widely used chemical weapons in the past century. However, little information exists concerning long-term mortality from MG exposure. In this study, we investigated mortality rate among civilian people exposed to MG during Iran-Iraq war in Sardasht in Iran after 32 years.  METHODS: In this retrospective cohort study, data of people exposed to MG in Sardasht in 1987 were extracted from the Veterans and Martyr Affair Foundation of Iran up to March 20, 2019. Mortality rate, cumulative mortality and standardized mortality ratio with 95% confidence interval were calculated to explain mortality in the cohort, and then compared with general Iranian population. Cox regression analysis was used to indicate factor affecting the risk of death in the cohort.  RESULTS: Out of 1,203 exposed people at the beginning of the period, 148 people died by the end of the study, with an average age of 66.42 at the time of death. Total person-years of the people up to end of the study were 38,198.63 and mortality rate was equal to 387 per 100,000 persons-years. Total number of observed deaths was less than expected death and the all-cause standardized mortality ratio (SMR) was determined as 0.680 (95% CI: 0.574 - 0.798). Cause-specific SMR showed that observed death due to respiratory diseases was higher than expected (SMR: 1.75) (95% CI: 1.145 - 2.569). The results of univariate and multivariate cox regression analysis showed that increasing age and having severe late complications in lung were associated with increased risk of death among people in the cohort., Conclusion: In general, this result indicated that acute exposure to MG, even without wearing protective clothing and masks, could not increase all-cause mortality after 32 years if accompanied by special and ongoing care for those exposed., (© 2022. The Author(s).)

Background: This study aims to explore the healthcare utilization (HCU) and expenditures from complementary health insurance among Iranian people who survived sulfur mustard (SM) exposure during the Iran-Iraq war., Methods: This study was conducted between March 21, 2018 and March 21, 2019 using secondary data. Data on the HCU and expenditure of war survivors after their exposure to SM were obtained from the Iran Veterans and Martyr Affair Foundation (VMAF) database and the national complementary insurance organization that covers their medical expenses. Multiple linear and zero-inflated poison regression (ZIP) models were used to estimate the costs and HCU. Analyses were performed in R software version 3.6.3., Results: Among 58880 survivors who were included in study, 36383 (61.7%) used at least one service during a year. The total frequency of HCU was 15.6 services per person per year. The annual mean medical cost of each survivor was US$807.6 (±2901.2). The highest number of utilizations was related to medicine and physician visits. The highest median cost was related to rehabilitation (US$151.7), medical equipment (US$84.5), medicine (US$83.3) and inpatient services (US$ 48.8). With increasing age, disability, weight, severity of injury in lung or eye injuries, the rate of health service utilization rose significantly., Conclusion: Over 30 years after the Iran-Iraq war, Iranian people who were exposed to SM and survived still suffer from injuries and pose a significant drain on healthcare resources., (2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Blister agents damage the skin, eyes, mucous membranes and subcutaneous tissues. Other toxic effects may occur after absorption. The response of the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) to a request from the OPCW Director-General in 2013 on the status of medical countermeasures and treatments to blister agents is updated through the incorporation of the latest information. The physical and toxicological properties of sulfur mustard and clinical effects and treatments are summarised. The information should assist medics and emergency responders who may be unfamiliar with the toxidrome of sulfur mustard and its treatment., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Importance: The prevalence and severity of long-term health complications after exposure to sulfur mustard are unknown., Objective: To investigate the long-term health outcomes among survivors exposed to sulfur mustard during the Iran-Iraq War., Design, Setting, and Participants: In this retrospective cohort study, late-onset health complications of 64 190 Iranian survivors exposed to sulfur mustard during the Iran-Iraq War from 1980 to 1988 were investigated using descriptive statistics. Data involving affected organs and symptom severity were extracted from the Veterans and Martyr Affair Foundation (VMAF) database from 1980 to 2019. Assessments were conducted across 3 groups depending on whether survivors were (1) evacuated and admitted (EA) to a hospital; (2) not evacuated or admitted (NEA) to a hospital; or (3) evacuation or admission status was not documented., Exposures: Analysis of chronic symptom severity following exposure to sulfur mustard., Main Outcomes and Measures: Mild, moderate, or severe rankings of symptoms in lungs, eyes, and skin of survivors exposed to sulfur mustard using data from the VMAF database., Results: Of 64 190 chemical survivors registered in the VMAF database, 60 861 met the inclusion criteria. Of the included survivors, 98.0% were male, and the mean (SD) age was 23.5 (7.7) years. Most survivors (53 675 [88.2%]) had no symptoms or mild lesions, and 7186 survivors (11.8%) had moderate or severe complications. Moderate to severe lung (6540 [10.7%]), eye (335 [0.6%]), or skin (725 [1.2%]) injuries were documented in the exposed population. The proportion of moderate plus severe late complications in eyes was 3 times as high in male survivors compared with female survivors (0.6% [95% CI, 0.53%-0.65%] vs 0.2% [95% CI, 0.09%-0.73%]; P < .001), whereas dermal complications were significantly more common in female survivors (3.9% [95% CI, 2.92%-5.11%] vs 1.14% [95% CI, 1.06%-1.23%]; P < .001). Mild lung lesions were more prevalent in the NEA group than in the EA group (73.9% [95% CI, 73.4%-74.4%] vs 11.0% [95% CI, 10.6%-11.3%]; P < .001). In the NEA group, 83.2% (n = 23 866) developed lung injuries that were mostly mild or moderate, whereas 77% (n = 24 766) of the EA group did not develop lung injuries (P < .001)., Conclusions and Relevance: The present study found sex differences in the frequencies of eye and skin complications following sulfur mustard exposure, and lung complications were more prevalent years after sulfur mustard exposure than soon after exposure. Mild lung lesions were observed more frequently among sulfur mustard-exposed survivors who had not been evacuated or hospitalized than among those who had been evacuated or hospitalized. These differences may be due to physiological response or dose of exposure. Close monitoring over an extended period may be required for detection of late pulmonary complications in individuals exposed to sulfur mustard.

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.

Background: Autophagy is an intracellular hemostasis mechanism, responding to extracellular or intracellular stresses. Sulfur mustard (SM) induces cellular stress. Iranian soldiers exposed to SM gas, during the Iraq-Iran war, suffer from delayed complications even 30 years after exposure. In this study, for exploring the SM effect on autophagy pathway, gene and protein expression of autophagy markers are evaluated in the lung of SM-exposed people., Methods: 52 FFPE lung tissues of SM-exposed people and 33 lung paraffin blocks of non-exposed patients to SM were selected. LC3 and Beclin-1 mRNA expressions were evaluated by QRT-PCR. LC3-B protein and LC3II/LC3I proteins ratio were detected by Immunohistochemistry and immunoblotting method. The collected data were analyzed in SPSS, and P value ≤ 0.05 was considered significant., Results: LC3 gene expression in SM-exposed subjects (median CT value = 4.97) increased about 4 fold compared with the control group (median CT value = 0.46, P = 0.025). Beclin-1 mRNA expression had not significant difference between two groups. After adjusting the confounding variables such as drug usage, LC3-B protein (P = 0.041) and LC3II/LC3I ratio (P = 0.044) were found significantly lower in the lung cells of SM-exposed group., Conclusion: Upon exposure to SM gas, the lung cells are affected by acute cellular stress such as oxidative stress. The study results show that LC3 mRNA level increases in these patients, but, surprisingly, LC3-B protein via unknown mechanism has been down-regulated. N-acetyl cysteine and salbutamol drugs could induce the autophagy, and help to reduce the SM effects and improve the clinical condition of SM-injured patients., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest in this study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Context: Sulfur mustard (SM) is a strong alkylating toxicant that targets different organs, particularly human lung tissue. Change in genes expression is one of the molecular mechanisms of SM toxicity in damaged tissue., Objective: The purpose of this investigation is to characterize the expression of cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LO), inducible nitric oxide synthase 2 (iNOS2), and surfactant protein D (SFTPD) in lungs of patients who exposed to SM., Methods: Lung biopsies were provided from SM-exposed patients (n = 6) and controls (n = 5). Total RNA were extracted from all specimens and then cDNA was synthesized for each sample. Changes in gene expression were measured using RT 2 Profiler ™PCR Array., Results: Pulmonary function tests revealed more obstructive and restrictive spirometric patterns among patients compared to the control group. Expression of COX-2 and 12-LO in the lung of patients was increased by 6.2555 (p = 0.004) and 6.2379-folds (p = 0.002), respectively. In contrast, expression of SF-D and iNOS genes was reduced by 8.5869-fold (p = 0.005) and 2.4466-folds (p = 0.011), respectively., Conclusions: Mustard lungs were associated with overexpression of COX-2 and 12-LO, which are responsible for inflammation, overproduction of free radicals and oxidative stress. Downregulation of iNOS2 and SF-D are probably the reason for lung disease and dysfunction among these patients. Therefore, the expression of these genes could be an important, routine part of the management of such patients.

Background: More than 60,000 people have health problems due to chemical weapons exposure during the Iran-Iraq war. Respiratory consequences of mustard gas exposure are common and disabling; medical interventions have limited effect. Patients complain of cough, sputum, breathlessness and exercise limitation. We hypothesized that patients with this condition would benefit from pulmonary rehabilitation., Methods: We outline the protocol for an assessor-blind, two-armed, parallel-design randomized controlled clinical trial (IRCT2016051127848N1). Sixty patients with respiratory disease due to documented sulfur mustard gas exposure will be randomized to either take part in a 6-week pulmonary rehabilitation programme or receive usual care. Inclusion criteria include forced expiratory volume in 1 second < 80% predicted and Medical Research Council dyspnoea score ≥ 3. The primary endpoint will be the change in cycle endurance time at 70% baseline exercise capacity at 6 weeks. Lung function, physical activity, the strength and endurance of the quadriceps muscle, and quality of life will also be compared. Outcomes will be assessed at 6 weeks and 12 months. Health care utilization will also be assessed., Discussion: If the study confirms that rehabilitation is effective for patients with mustard gas lung disease this should prompt provision of the intervention to this patient group., Trial Registration: Iranian Registry of Clinical Trials, IRCT2016051127848N1 . Registered on 24 May 2016.

Sulfur mustard (SM) is a mutagenic compound that targets various organs. Although it causes a wide range of abnormalities, cellular and molecular mechanisms of its action are not-well-understood. Oxidation of DNA, proteins, lipids, as well as depletion of cellular nicotinamide adenine dinucleotide (NAD), antioxidants and increase of intracellular calcium are the hypothesized mechanisms of its action at the acute phase of injury. In this review, the proteome analysis of SM toxicity has been considered. We selected articles that considered proteomics analysis of SM toxicity with two-dimensional gel electrophoresis (2DE) followed by mass spectrometry. Our search yielded nine related articles, four original in vitro and five human studies. The results of these studies have revealed a change in expression pattern of various proteins such as haptoglobin, amyloid A1, surfactant proteins, S100 proteins, apolipoprotein, Vit D binding protein, transferrin, alpha 1 antitrypsin, protein disulfide isomerase and antioxidant enzymes in patients who were exposed to SM about 30 years ago. Most of these proteins are up- or down-regulated in response to excessive production of reactive oxygen species (ROS) and oxidative stress (OS). There is a tight link between the expression pattern of these proteins with accumulation of leukocytes, inflammatory conditions, antioxidant depletion, mitochondrial deficiency, as well as increased expression or activity of several proteases such as caspases and matrix metalloproteinases (MMPs). Therefore, excessive production of ROS and OS along with chronic inflammatory may be the long-term toxic effects of SM following acute exposure.

Sulfur mustard (SM) is a toxic agent which causes severe abnormalities in an airway system such as necrosis and inflammation, oxidative stress, chronic bronchitis, shortness of breath, and chronic obstructive pulmonary disease. Although possible mechanisms of SM toxicity have been extensively considered, there is still need to find an appropriate clinical treatment to decrease chronic lung injuries caused by SM. Due to extensive progresses and achievement in tissue repairing through stem cells therapy, the importance of cell therapy for the treatment of lung injuries has been increased. However, several factors such as types of stem cells, necessary conditions for growth and proliferation of stem cells, and their homing into the target tissues are considered as the most important problems in this issue. Mesenchymal stem cells (MSCs) are a class of multipotent stem cells with proliferative and self-renewal capacity which are able to differentiate into different cell lines such as lung epithelial cells. They have a potential repairing and immune modulatory properties which make them as a good candidate for the regeneration of bronchioles tract in SM-exposed patients. Unlike chemical drugs, the differentiation and high-level safety properties of MSCs can be considered as a new strategy for the treatment of SM-injured patients with pulmonary complications. This review aims to consider the therapeutic effects of MSCs in the treatment of SM-induced pulmonary injuries in both animals and humans.

Despite many years having passed since exposure to sulfur mustard (SM) gas, there are many exposed subjects who are still suffering from delayed pulmonary complications. The levels of pro-inflammatory cytokines in the lung of these subjects have not been investigated in delay phase. In this study, we evaluated mRNA expression of pro-inflammatory  cytokines (tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor type 1 (TNFR1), and interleukin 1 beta (IL-1β)  ) in lung biopsy of SM-exposed subjects and compared them with control (non-exposed) subjects. We used formalin-fixed, paraffin-embedded (FFPE) tissue for this purpose. Lung FFPE blocks of SM-exposed subjects (30 samples) and a control group (30 samples) were collected from archival pathology department. The total mRNA of FFPE tissues were extracted and the mRNA expression of pro-inflammatory  cytokines were determined by quantitative Real Time PCR (RT-qPCR). The obtained results from two groups were compared to each other and non-parametric statistical analyses were carried out on them. Our studies showed that the mRNA expression of TNFα, TNFR1 and IL-1β  in lung tissue of SM injured and control people have no significant difference (p-value= 0.159, 0.832 and 0.314 respectivly). TNFR1 showed direct correlation with TNFα (r=0.867, p=0.002) and IL-1β (r= 0.65, p=0.006). The evaluation of mRNA expression in pro-inflammatory cytokines in lung of SM-exposed subjects after 20 years showed that these mediators are similar to those of non-exposed group and there was no acute inflammation in lung of these patients.

Sulfur mustard (SM) is a chemical alkylating compound that primary targets lung tissue. It causes a wide variety of pathological effects in respiratory system such as chronic bronchitis, bronchiolitis obliterans, necrosis of the mucosa and inflammation, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. However, molecular and cellular mechanisms for these pathologies are still unclear. Oxidative stress (OS) induced by reactive oxygen species (ROS) is likely a significant mechanism by which SM leads to cell death and tissues injury. SM can trigger various molecular and cellular pathways that are linked to ROS generation, OS, and inflammation. Hypoxia-induced oxidative stress, reduced activity of enzymatic antioxidants, depletion of intercellular glutathione (GSH), decreased productivity of GSH-dependent antioxidants, mitochondrial dysfunction, accumulation of leukocytes and proinflammatory cytokines, and increased expression of ROS producing-related enzymes and inflammatory mediators are the major events in which SM leads to massive production of ROS and OS in pulmonary system. Therefore, understanding of these molecules and signaling pathways gives us valuable information about toxicological effects of SM on injured tissues and the way for developing a suitable clinical treatment. In this review, we aim to discuss the possible mechanisms by which SM induces excessive production of ROS, OS, and antioxidants depletion in lung tissue of exposed patients.

Sulfur mustard (SM) is a vesicating agent that has been employed as a chemical warfare agent. High-dose exposure to sulfur mustard may lead to the damage of rapidly proliferating cells of bone marrow and, therefore, suppression of the immune system. This may be continued as dysfunction of the immune system, and ultimately result in secondary immune disorders. Studies have suggested a role for T cells in SM-induced lung injury. Moreover, observations from animal studies indicate a delayed-type hypersensitivity (DTH) response after skin exposure to SM, providing an understanding that SM can stimulate specific T cell-mediated immune responses. On the other hand, T helper (Th) 17 cells, which are a subset of CD4+ T cells, have recently been reported to be involved in a number of inflammatory, autoimmune, and chronic fibrotic lung diseases. Furthermore, a strong association has been established between the overproduction of profibrotic cytokines like transforming growth factor (TGF)-β and Th17 cell number. In this review, we aimed to go through the new findings about the involvement and interactions of TGF-β and Th17 in SM-related injuries., (© 2017 Wiley Periodicals, Inc.)

Introduction: Mustard gas (MG) is a chemical warfare agent widely used in the Iran-Iraq War. Its catastrophic effects on the lungs, eyes, and skin have been well studied. However, it also affects the cardiovascular system. We aimed to evaluate the long-term effect of MG on right ventricular (RV) function., Methods: All patients presenting to the university clinics between May 2014 and September 2015 were consecutively evaluated to enter the study based on the inclusion criteria (documented proof of chemical injury, no past or present cardiovascular disease, not a current smoker, and no history of sleep apnea). A comparable control group of veterans without MG exposure was randomly selected. All patients underwent echocardiographic measurement of RV size and function by a blinded cardiologist., Results: We included 23 patients in the MG-exposed group and 19 subjects in the control group, with a mean age of 48.6 years. Mean chemical injury severity score was 29.7% and mean time from the MG exposure was 29.2 years. The main complaint of MG-exposed patients pertained to respiratory symptoms (91%). Pulmonary artery pressure was higher (32.83 vs. 28.95 mmHg) and RV strain was lower (-17.05% vs. -20.72%) in the MG-exposed than in the control group (P < .05)., Conclusion: Our results present baseline RV values for MG-exposed patients and show mild but significant changes after 3 decades. Further cellular and molecular studies are needed to evaluate underlying mechanisms of MG cardiotoxicity., (© 2017 Wiley Periodicals, Inc.)

Among the most readily existing chemical warfare agents, sulphur mustard (SM), also known as mustard gas, is the most commonly used agent owing to its ease of synthesis and stockpiling. Unprotected exposure mostly results in debilitation rather than lethal injuries, leaving an exposed victim incapacitated for days to even months. Although acute toxicity of sulphur mustard has been fairly established, the long-term post-exposure effects either chronic or short-term but significant are still evolving. A total of 30,000 Iranian victims of the Iran-Iraq imposed war have now - after 30 years - formed the key population demonstrating long-term effects from sulphur mustard exposure. Recent studies have shown that the prevalence of several long-term cardiovascular disorders (CVDs) has significantly increased among SM-exposed victims including coronary artery disorders (CAD), coronary artery ectasia (CAE), congestive heart failure (CHF) and myocardium abnormalities. The more important point is the lack of a determinant biomarker for early screening, recognizing, treating, monitoring and estimating exposed victims' response to applied therapy. Additionally, unidentified risk factors significantly decrease the chance of a successful therapy and result in undesired failure of a comprehensive therapeutic strategy. In this MiniReview, we examined the literature in detail to evaluate relevant reports considering long-term cardiovascular complications of SM, detecting possible risk factors and determining possible preventing events., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: This study investigated the efficacy and safety of supplementation with probiotics in improving chronic pulmonary symptoms due to sulfur mustard (SM) exposure., Methods: In a randomized double-blind placebo-controlled study, 65 subjects suffering from chronic pulmonary complications of SM were assigned to one probiotic capsule (1 × 10 9 CFU containing seven strains of lactic acid-producing bacteria) every 12 h or an identical placebo for six weeks. Serum high-sensitivity C-reactive protein (CRP) concentrations, pulmonary function tests (FEV1, FEV1/FVC and MMEF 25-75%) and COPD assessment test (CAT) were assessed at baseline and at the end of trial., Results: The groups were comparable in baseline characteristics. There were significant improvements in FEV1/FVC in the probiotic but not in placebo group. CAT scores were decreased in both study groups. However, between-group comparison of changes in the assessed parameters reached statistical significance only for CAT score (p < 0.001). There was no report of adverse events during the course of trial., Conclusions: Findings of the present trial favor the efficacy of probiotic supplementation in improving the pulmonary symptoms of SM-exposed subjects.

More than a century after the introduction of sulfur mustard (SM), as a chemical warfare agent, it has affected thousands of military and civilians on several occasions. The most notable toxic effects of this easily produced chemical, are lung damage ranges from necrotic, hemorrhagic, and infectious acute-lung injury to chronic conditions (i.e., mustard lung). While there is no definite treatment for individuals exposed to sulfur mustard, corticosteroids, mucolytics, bronchodilators, antibiotics, immunosuppressive medicines, and magnesium are being used to help victims. In the pathophysiology of SM-induced lung conditions, oxidative stress and inflammation play undeniable roles; thus, N-acetyl-L-cysteine (NAC) has been used as a treatment. In this narrative review article, we discuss the mechanisms involved in SM-induced lung damage along with the properties of NAC that can help patients recover from these deleterious effects.

Sulfur mustard (SM; mustard gas) is a classic chemical warfare agent that has been used in several wars and is still a potential threat especially in the Middle-East region. Victims experience acute symptoms in airexposed organs including skin, respiratory tract and the eyes. Survivors of the acute stage might develop chronic or delayed-onset complications in the exposed organs. The exact mechanism(s) of SM-induced tissue damage is still unknown, however DNA alkylation and oxidative damage are the most relevant mechanisms. Eye is the most sensitive organ to the SM vapor and ocular symptoms usually precede other manifestations. Ocular findings including blepharitis, dry eye disease, corneal vascularization, persistent epithelial defects, limbal ischemia, limbal stem cell deficiency, corneal thinning, corneal opacity and corneal innervation abnormalities have been reported several years after SM exposure. In this review, mechanisms of acute and chronic/delayed ocular manifestations of SM and their current management and potential future therapies have been discussed. We have also included recent advances in amniotic membrane transplantation, cultivated stem cell transplantation and anti-angiogenic therapies which might be considered as therapeutic options in SM-induced ocular damage in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oxidative stress and inflammation are one of the main pathological consequences of sulfur mustard on human lungs. Unfortunately, there is no effective treatment to mitigate pathological effects of sulfur mustard in mustard lungs. Here, we aimed to evaluate potential efficacy of systemic mesenchymal stem cells administration on expression of oxidative stress- and inflammation-related genes in sulfur mustard-exposed patients. Our patient received 100 million cells per injection, which was continued for four injections within 2 months. Sputum samples were provided after each injection. Oxidative stress was evaluated by determining sputum levels of malondialdehyde and glutathione. Furthermore, changes in expression of several oxidative stress- (metallothionein 3, glutathione reductase, oxidative stress responsive 1, glutathione peroxidase 2, lacto peroxidase, forkhead box M1) and inflammation-related genes (matrix metallopeptidase 2, matrix metallopeptidase 9, transforming growth factor-β1, vascular endothelial growth factor, metallopeptidase inhibitor 1, metallopeptidase inhibitor 2) were also evaluated using real-time PCR after treatments. Two-lung epithelial-specific proteins including Clara cell protein 16 and Mucin-1 protein levels were measured using enzyme immunoassay method. No significant differences were found between serum levels of Clara cell protein 16 and serum Mucin-1 protein in patient before and after cell therapy. Most of the oxidative stress responsive genes, particularly oxidative stress responsive 1, were overexpressed after treatments. Expressions of antioxidants genes such as metallothionein 3, glutathione reductase and glutathione peroxidase 2 were increased after cell therapy. Upon comparison of inflammation-related genes, we observed upregulation of vascular endothelial growth factor and matrix metallopeptidase 9 after mesenchymal stem cells therapy. Additionally, a trend for increased value of glutathione and decreased levels of malondialdehyde was observed from baseline to final evaluation times. Mesenchymal stem cells administration mitigates oxidative stress and inflammation in sulfur mustard-exposed patients.

In this study, we investigated expression changes of Th17/Treg-related cytokine in transbronchial lung biopsy (TBLBs) of sulfur mustard (SM) exposure, stable chronic obstructive pulmonary disease (COPD) patients and also compared it with a healthy control (HC) group. Here, ROR-γt, FoxP3, and Treg/Th17-related cytokines (IL-10, IL-17A, IL-6, and TGF-β1) were assessed using a combination of RT-QPCR and ELISA in 11 SM-exposed cases, 9 patients with GOLD stage II COPD diagnosed, and 8 HC. Our results showed that the levels of Foxp3 expression were lower and ROR-γt expression was higher in SM and COPD patients when compared with HC (all p values were less than 0.001). The relative Foxp3 expressions and Foxp3/ROR-γt ratio were positively correlated with FEV1 (%) pred (R = 0.682 and R = 0.602, respectively; p ≤ 0.001). However, the relative ROR-γt expressions were inversely correlated with FEV1 (%) pred (R= -0.75, p = 0.003) and relative Foxp3 expression (R= -0.704, p = 0.003). The mRNA and protein expression of IL-10 were significantly decreased in SM and COPD patients compared with HC (p < 0.001). An increase of IL-17A (∼7.2 fold) and TGF-β1 (∼5.6 fold) are involved in the lung exacerbation of SM and COPD patients. The expression of IL-6 was variable between three groups (p ≥ 0.05). In addition, an inverse correlation were observed between FEV1 (%) pred and expressions of IL-17A (R= -0.741), IL-6 (R= -0.673) and TGF-β1 (R= -0.632) (p ≤ 0.001). Instead, positive correlation was found between IL-10 ratios and FEV1 (%) pred (R = 0.777, p = 0.001). These findings suggest that Treg/Th17-mediated distributions are involved in the progression of chronic lung injury of SM and COPD patients.

The aim of this study is to analyze oxidative stress (OS) and changes in expression of reactive oxygen species (ROS) producing-related genes in mustard lungs. Human lung biopsies provided from controls (n=5) and sulfur mustard (SM)-exposed patients (n=6). Changes in expression of dual oxidases (DUOXs), aldehyde oxidase 1 (AOX1), thyroid peroxidase (TPO), myeloperoxidase (MPO) and eosinophil Peroxidase (EPO) were measured using RT(2) Profiler(™) PCR Array. OS was evaluated by determining bronchoalveolar lavage fluids (BALF) levels of total antioxidant capacity (TAC) and malondialdehyde (MDA). Higher TAC value was observed in BALF of controls compared with patients (0.138±0.02683μmol/l vs 0.0942±0.01793μmol/l), whereas a significant increase in MDA concentration was found in patients (0.486±0.04615 nmol/l vs 0.6467±0.05922 nmol/l). All ROS producing-related genes were overexpressed in the order AOX1>MPO>DUOX2>DUOX1>TPO>EPO. Upregulation of these genes may be a reason for overproduction of ROS, oxidants/antioxidants imbalance, OS and respiratory failures in mustard lungs., (Copyright © 2016. Published by Elsevier B.V.)

Background: Sulfur mustard (SM) is a potent and mutagenic agent that targets human lung tissue., Purpose of the Study: The purpose of this investigation is to characterize the expression of sulfiredoxin-1 (SRXN1) and peroxiredoxin (PRDXs) genes and oxidative stress (OS) status in human lung after exposure to SM., Materials and Methods: Lung biopsy specimens bronchoalveolar lavage (BAL) fluids were provided from SM-exposed patients (n = 6) and controls (n = 5). Changes in gene expression were measured using RT(2) Profiler PCR Array. OS was considered by measuring BAL fluid levels of malondialdehyde (MDA) and protein carbonyls (PC)., Results: Mean of MDA and PC values in BAL fluid of patients (0.6467 ± 0.05922 nmol/l and 1.391 ± 0.421 nmol/mg, respectively) was higher than in controls (0.486 ± 0.04615 nmol/l and 0.949 ± 0.149 nmol/mg, respectively). Expression of all examined genes was in the order PRDX1> PRDX3> PRDX6> SRXN1> PRDX2> PRDX4> PRDX5. Among the most upregulated genes was the PRDX1, which was overexpressed by 10.1029-fold (p = 0.000634). SM-exposed individuals demonstrated expression of PRDX3 4.6231 (p = 0.000134), PRDX6 3.4964 (p = 0.001102), SRXN1 3.3719 (p < 0.0001) and PRDX2 2.7725-folds (p = 0.000383) higher than those of controls that reveal., Conclusions: Upregulation of PRDXs and SRXN1 genes may be because of reactive oxygen species (ROS) production and OS in lung tissue of patients after SM exposure. Expression of SRXN1 and PRDXNs genes, especially I, II, III, and VI is increased in SM-injured lungs, suggesting the induction of cellular responses to increased production of ROS and OS in lung of the patients. Therefore, sulfiredoxin and peroxiredoxins can be targeted as biomarkers of OS in these patients.

Sulfur mustard (SM) is a potent alkylating agent that targets several organs, especially lung tissue. Although pathological effects of SM on mustard lung have been widely considered, molecular and cellular mechanisms for these pathologies are poorly understood. We investigated changes in expression of genes related to oxidative stress (OS) and antioxidant defense caused by SM in lung tissue of patients. We performed gene expression profiling of OS and antioxidant defense in lung tissue samples from healthy controls (n=5) and SM-exposed patients (n=6). Changes in gene expression were measured using a 96-well RT(2) Profiler ™PCR Array: Human Oxidative Stress and Antioxidant Defense, which arrayed 84 genes functionally involved in cellular OS response. 47 (55.95%) genes were found to be significantly upregulated in patients with mustard lung compared with controls (p<0.05), whereas 7 (8.33%) genes were significantly downregulated (p<0.05). Among the most upregulated genes were OS responsive-1 (OXSR1), forkhead box M1 (FOXM1), and glutathione peroxidase-2 (GPX2), while metallothionein-3 (MT3) and glutathione reductase (GSR) were the most downregulated genes. Expression of hypoxia-induced genes (CYGB and MB), antioxidants and reactive oxygen species (ROS)-producing genes were significantly altered, suggesting an increased oxidative damage in mustard lungs. Mustard lungs were characterized by hypoxia, massive production of ROS, OS, disruption of epithelial cells, surfactant dysfunction, as well as increased risk of lung cancer and pulmonary fibrosis. Oxidative stress induced by ROS is the major mechanism for direct effect of SM exposure on respiratory system. Antioxidant treatment may improve the main features of mustard lungs., (Copyright © 2016. Published by Elsevier B.V.)

Oxidative stress plays a key role in the development of chronic pulmonary complications of sulfur mustard (SM). Curcuminoids are polyphenols with documented safety and antioxidant activity. The present study aimed to investigate the efficacy of short-term supplementation with curcuminoids (co-administered with piperine to enhance the bioavailability of curcuminoids) in alleviating systemic oxidative stress and clinical symptoms, and improvement of health-related quality of life (HRQoL) in subjects suffering from chronic pulmonary complications due to SM exposure who are receiving standard respiratory treatments. Eighty-nine subjects were recruited to this randomized double-blind placebo-controlled trial, being randomly allocated to either curcuminoids (1500 mg/day) + piperine (15 mg/day) combination (n = 45) or placebo (n = 44) for a period of 4 weeks. High-resolution computed tomography suggested the diagnosis of bronchiolitis obliterans in all subjects. Efficacy measures were changes in serum levels of reduced glutathione (GSH) and malonedialdehyde (MDA). The severity and frequency of respiratory symptoms and HRQoL were also assessed using St. George respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) indices. Serum levels of GSH were increased whilst those of MDA decreased by the end of trial in both groups. Likewise, there were significant improvements in the total as well as subscale (symptoms, activity and impact) SGRQ and CAT scores in both groups. However, comparison of magnitude of changes revealed a greater effect of curcuminoids-piperine combination compared to placebo in elevating GSH, reducing MDA and improving CAT and SGRQ (total and subscale) scores (p < 0.001). Regarding the promising effects of curcuminoids on the measures of systemic oxidative stress, clinical symptoms and HRQoL, these phytochemicals may be used as safe adjuvants in patients suffering from chronic SM-induced pulmonary complications who are receiving standard treatments.

Background: Sulfur mustard (SM)-induced airway injuries and chronic obstructive pulmonary disease (COPD) are characterized by chronic inflammation of the respiratory tract and share some similarities regarding the cellular and molecular mechanisms orchestrating airway destruction. Since available data regarding the immunobiology of COPD is much more known compared with SM-mediated injuries, and considering the similarities in the immunopathogenesis of these diseases, comparison of the immunopathogenesis of COPD and SM-induced respiratory complications can help designing new therapeutic approaches for treatment of SM-induced injuries., Methods: A multi-database search was performed to identify articles dealing with the role of immune system function in the pathogenesis of COPD and mustard mustard-induced respiratory complications., Results: This review outlines the role of different components of the immune system in the pathogenesis of COPD and mustard-induced respiratory complications, and suggests therapeutic implication for improving the management of the latter condition as the most common chronic complication of sulfur mustard exposure., Conclusion: Although COPD and mustard lung are overlapping phenotypes and have shared pathophysiologic features, there are certain differences between these two diseases that necessitate further scrutiny. Combination therapies to counterbalance inflammation, oxidative stress and immune imbalance hold promise for the management of SM-induced respiratory complications but the success of such combined treatments need to be confirmed in proof-ofconcept trials.

Sulphur mustard is an alkylating agent that reacts with different cellular components, causing acute and delayed complications that may remain for decades after exposure. This study aimed to identify differentially expressed metabolites between mustard-exposed individuals suffering from chronic complications compared with unexposed individuals as the control group. Serum samples were obtained from 15 mustard-exposed individuals and 15 apparently healthy unexposed individuals. Metabolomic profiling was performed using (1)H nuclear magnetic resonance spectroscopy, and analyses were carried out using Chenomex and MATLAB softwares. Metabolites were identified using Human Metabolome Database, and the main metabolic pathways were identified using MetaboAnalyst software. Chemometric analysis of serum samples identified 11 differentially expressed metabolites between mustard-exposed and unexposed groups. The main pathways that were influenced by sulphur mustard exposure were related to vitamin B6 (down-regulation), bile acid (up-regulation) and tryptophan (down-regulation) metabolism. Metabolism of vitamin B6, bile acids and tryptophan are the most severely impaired pathways in individuals suffering from chronic mustard-induced complications. These findings may find implications in the monitoring of exposed patients and identification of new therapeutic approaches., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: In patients with short-term exposure to the sulfur mustard gas, the delayed cellular effects on lungs have not been well understood yet. The lung pathology shows a dominant feature consistent with obliterative bronchiolitis, in which fibroblasts play a central role. This study aims to characterize alterations to lung fibroblasts, at the cellular level, in patients with delayed respiratory complications after short-term exposure to the sulfur mustard gas., Methods: Fibroblasts were isolated from the transbronchial biopsies of patients with documented history of exposure to single high-dose sulfur mustard during 1985-7 and compared with the fibroblasts of control subjects., Results: Compared with controls, patients' fibroblasts were thinner and shorter, and showed a higher population doubling level, migration capacity and number of filopodia. Sulfur mustard decreased the in vitro viability of fibroblasts and increased their sensitivity to induction of apoptosis, but did not change the rate of spontaneous apoptosis. In addition, higher expression of alpha smooth muscle actin showed that the lung's microenvironment in these patients is permissive for myofibroblastic differentiation., Conclusions: These findings suggest that in patients under the study, the delayed pulmonary complications of sulfur mustard should be considered as a unique pathology, which might need a specific management by manipulation of cellular components.

Pulmonary problems are among the most frequent chronic complications of sulfur mustard (SM) intoxication and are often accompanied by deregulated production of pro-inflammatory cytokines. Curcuminoids, comprising curcumin, demethoxycurcumin and bisdemethoxycurcumin, are phytochemicals with remarkable anti-inflammatory properties that are derived from dried rhizomes of the plant Curcuma longa L. (turmeric). The present pilot study aimed to investigate the clinical effects of supplementation with curcuminoids on markers of pulmonary function and systemic inflammation in SM-intoxicated subjects. In a randomized double-blind placebo-controlled trial, 89 male subjects who were suffering from chronic SM-induced pulmonary complications were recruited and assigned to either curcuminoids (500 mg TID per oral; n=45) or placebo (n=44) for a period of 4 weeks. Efficacy measures were changes in the spirometric parameters (FVC, FEV1, FEV1/FVC) and serum levels of inflammatory mediators including interleukins 6 (IL-6) and 8 (IL-8), tumor necrosis factor-α (TNFα), transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). 78 subjects completed the trial. Although FEV1 and FVC remained comparable between the groups, there was a greater effect of curcuminoids vs. placebo in improving FEV1/FVC (p=0.002). Curcuminoids were also significantly more efficacious compared to placebo in modulating all assessed inflammatory mediators: IL-6 (p<0.001), IL-8 (p=0.035), TNFα (p<0.001), TGFβ (p<0.001), substance P (p=0.016), hs-CRP (p<0.001), CGRP (p<0.001) and MCP-1 (p<0.001). Curcuminoids were safe and well-tolerated throughout the trial. Short-term adjunctive therapy with curcuminoids can suppress systemic inflammation in patients suffering from SM-induced chronic pulmonary complications., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Noninvasive ventilation (NIV) has been shown to improve numerous clinical measures in subjects with COPD, including gas exchange, exercise tolerance, dyspnea, hospitalizations, health-related quality of life (HRQOL), and functional status. Although useful for classical COPD, NIV has not been validated specifically as a treatment option for mustard airway disease. Our aim was to assess the efficacy of NIV in subjects with severe mustard airway disease., Methods: This study was performed over the course of 12 months on 20 subjects with severe mustard airway disease (Global Initiative for Chronic Obstructive Lung Disease criteria). Subjects were selected from the pulmonary clinic of Baqiyatallah Hospital in Tehran, Iran. Body mass index, lung function, dyspnea, exercise tolerance, HRQOL, sleep quality, and hospitalization measures were assessed before and after NIV treatment., Results: NIV improved HRQOL (P = .03) and sleep quality (P = .06) in very severe subjects and reduced hospitalizations (P = .003) and exacerbations (P = .01) in severe subjects. Chest imaging studies showed that these subjects had heterogeneous airway disease, the main finding of which was bronchiolitis obliterans., Conclusions: NIV can be used as an effective new palliative method in the treatment of mustard airway disorders. Subjects with very severe and severe disease benefitted differently from NIV., (Copyright © 2015 by Daedalus Enterprises.)

Sulfur mustard (SM) is a potent alkylating agent that targets several organs, especially lung tissue. Although pathological effects of SM have been widely considered, molecular and cellular mechanisms for these pathologies are not well understood, yet. General cellular and molecular events such as inflammation, DNA damage, cell membrane disintegrity, apoptosis and cell death were observed either in in vitro or in vivo models exposed to SM. However, it is not obvious that which specific molecules and signaling pathways are relevant to the pathogenesis of mustard lung. Oxidative stress (OS) and antioxidants depletion induced by SM seem to be one of these factors. SM can trigger several molecular and cellular pathways linked to oxidative stress and inflammation that can cause cell necrosis and apoptosis as well as loss of tissue structure and function. Identification of these signaling pathways and molecules gives us valuable information regarding the toxic mechanisms of SM on injured tissues and the way for developing a better clinical approach. In this review we aimed to discuss the proposed cellular and molecular mechanisms of SM on pulmonary damage, the importance of oxidative stress and the mechanisms by which SM induces OS and antioxidants depletion along with research on antioxidant therapy as a suitable antidote.

Introduction: Sleep-related breathing disorders are associated with unusual respiratory pattern or an abnormal reduction in gas exchange during sleep that is common in sulfur mustard (SM) exposure., Methods: We compared 57 Iranian male patients injured with SM and had any complaints of sleep problems with an age-matched group of 21 Iranian male patients who had complaints of sleep problems and were not chemically injured; this group had Epworth Sleepiness Scale (ESS) above 10 and whom referred for polysomnography. Split-night studies were performed for patients with diagnostic polysomnography for obstructive sleep apnea (OSA) and respiratory events. We then studied respiratory events including episodes of OSA, apnea-hypopnea index (AHI) and respiratory disturbance index (RDI)., Results: The mean age in mustard-exposed patients was 48.14±8.04 years and in age-matched group, 48.19±8.39 years. In mustard exposed patients, there were statistical differences for the episodes of OSA (p=0.001), AHI (p=0.001), and RDI (p=0.001) between two segments of split-night studies. In the age-matched group, there were statistically differences for each parameter (episodes of OSA (p=0.001), AHI (p=0.001), and RDI (p=0.001)). There were no significant differences between two groups., Conclusion: This study indicated that the incidence of respiratory events and nocturnal hypoxemia during sleep in mustard-exposed patients were high and treatment with CPAP significantly reduced all these events.

Context: Sulfur mustard exposure, as the most widely used chemical weapon, can lead to acute and long-term pulmonary complications via various pathways, such as triggering an imbalance between the oxidant and antioxidant system. Currently, there is no validated antidote, chemoprophylaxis and curative modality for pulmonary toxicities secondary to sulfur mustard exposure., Objective: The aim of this literature review is to collect available experimental and clinical data on the efficacy of N-acetylcysteine (NAC), as a prominent antioxidant agent, in the prevention and/or treatment of sulfur mustard-induced acute and chronic pulmonary toxicities., Methods: A literature search was performed by the relevant keywords like "N-acetyl cysteine", "Sulfur mustard" and "Lung injury" in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. No time limitation was considered. Nineteen articles were selected for review., Results: A number of in vitro and experimental studies concluded that oral, intravenous, intraperitoneal and intra-tracheal administration of NAC is effective in the management of sulfur mustard-induced acute lung injury, in a time-dependent manner, via direct scavenging, inhibition of oxidative stress, inflammatory responses and apoptosis. In addition, oral NAC alone (1200 or 1800 mg/day for 4 months) or at a dose 600 mg/day for 6 months in combination with clarithromycin (500 mg/day) have led to improvements of clinical and paraclinical pulmonary parameters of patients with bronchiolitis obliterans due to sulfur mustard, through undetermined mechanisms., Conclusion: Despite limitations of relevant experimental and clinical studies, NAC can be considered as a candidate agent for prevention and/or treatment of sulfur mustard-induced acute lung injuries, as well as its long-term pulmonary toxicities, especially bronchiolitis obliterans.

There is much data about the acute effects of sulfur mustard gas on humans, animals and cells. But less is known regarding the molecular basics of chronic complications in humans. Basically, mustard gas, as an alkylating agent, causes several chronic problems in the eyes, skin and more importantly in the pulmonary system which is the main cause of death. Although recent proteomic research has been carried out on bronchoalveolar lavage (BAL) and serum, but high-throughput transcriptomics have not yet been applied to chronic airway remodeling. This is the first cDNA-microarray report on the chronic human mustard lung disease, 25 years after exposure during the Iran-Iraq war. Microarray transcriptional profiling indicated that a total of 122 genes were significantly dysregulated in tissues located in the airway of patients. These genes are associated with the extracellular matrix components, apoptosis, stress response, inflammation and mucus secretion.

Context: Sulfur mustard (SM) is an alkylating agent identified as a potent chemical warfare agent. More recently, SM was used in the Iraq conflict against Iranian troops and civilians. At present, there are many people suffering from chronic obstructive pulmonary disease (COPD) due to mustard gas in Iran. SM increases the endogenous production of reactive oxygen species (ROS). The oxidant/antioxidant imbalance present in the lungs of these patients also results from the impaired capacity of the antioxidant/detoxification enzymes to detoxify the harmful reactive oxygen metabolites., Objective: One of the major antioxidants in human airways is glutathione S-transferase. They facilitate the detoxification of various environmental of oxidative stress. In this study, we attempted to understand the significance different in expression of GSTs in airway wall of chemical patients and control., Materials and Methods: Seven normal and 20 SM induced COPD individuals were studied. Bronchoscopy was performed in all subjects and two specimens were taken from the main bronchus for mRNA extraction, PCR analysis and immunohistochemistry., Results: SM-induced COPD individuals showed expression of GSTA1 2.51 ± 0.83-, GSTM1 2.84 ± 1.71- and GSTP1 5.61 ± 2.59-folds higher than those of controls that revealed. GSTP1-immunoreactivity was strongly expressed in luminal border of normal samples. SM patient samples immunoreactivity for GSTP1 in the same area were negative., Discussion and Conclusion: According to these findings, we speculated that overexpression of GSTs mRNA in patients revealed that GSTs plays an important role in cellular protection against oxidative stress of MS in airway wall of patients.

Pulmonary problems are among the most common chronic complications of sulfur mustard (SM) intoxication and adversely affect patients' quality-of-life. The present trial investigated the impact of immunotherapy with interferon (IFN)-γ on quality-of-life, respiratory symptoms, and circulating immunologic and oxidative parameters in patients suffering from chronic SM-induced complications. Patients (n = 15) were administered IFNγ (100 μg) every other day for a period of 6 months. Assessment of quality-of-life [using St. George respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) indices], the severity and frequency of respiratory symptoms, and serum levels of immunologic [including interleukin (IL)-2, IL-4, IL-6, IL-10, IFNγ, calcitonin gene related peptide (CGRP), matrix metallopeptidase (MMP)-9, and tumor necrosis factor (TNF)-α], oxidative stress [malondialdehyde (MDA) as well as total and reduced glutathione, and catalase and superoxide dismutase (SOD) activity], and fibrogenic [transforming growth factor (TGF)-β] parameters were performed at baseline and at trial end. The results indicated that IFNγ therapy is associated with improvements in SGRQ (p < 0.001) and CAT (p < 0.001) scores, decreased severity of cough (p = 0.001), dyspnea (p < 0.001), and morning dyspnea (p < 0.001), reduced frequency of sputum production (p < 0.001) and hemoptysis (p < 0.001), and elevated FEV1 (p = 0.065). Serum levels of IL-4 (p < 0.001), IL-6 (p < 0.001), IL-10 (p < 0.001), CGRP (p < 0.001), MMP-9 (p = 0.001), TNFα (p < 0.001), TGFβ (p < 0.001) and MDA (p = 0.001) were decreased while those of IL-2 (p < 0.001), IFNγ (p < 0.001), and both total (p = 0.005) and reduced glutathione (p = 0.061) increased by the end of the trial. It was concluded that IFNγ has favorable effects on the quality-of-life and alleviates respiratory symptoms in patients suffering from chronic SM-induced pulmonary complications. A modulation of cytokines and oxidative stress appears responsible for the clinical efficacy of IFNγ.

Late respiratory complications in patients suffering from pulmonary lesions due to sulfur mustard (SM) gas are asthma, chronic obstructive pulmonary disease and bronchiectasis. Recently PON1 antioxidant activity draws attention as the enzyme which prevents the oxidation of lipoproteins during oxidative stress. In this study we aimed to investigate PON1 192 polymorphisms and paraoxonase and arylesterase activity in the serum of SM-exposed lung disease patients. Also, we examined the detection of PON1 and apoA1 proteins in BAL fluid. 101 male patients were included who were categorized to three groups of mild, moderate and severe suffering from pulmonary lesions due to SM. Significant reduction in paraoxonase activity [Healthy: 412.46 ± 89.1 U/L, Severe: 89.66 ± 20.7 U/L] (p < 0.0001) and arylesterase activity [Healthy: 25826.4 ± 4425.23 U/L, Severe: 16760.43 ± 3814.9 U/L] (p < 0.0001) with increase in severity of disease was demonstrated statistically. With respect to the distribution of the PON1 polymorphism, the RR genotype was more frequent in severe patients [37.2%] than healthy group [10%] (p < 0.05) and no significant regression was found between genotype and PON1 activity. On the other hand, the results of PON1 and apoA1 detection illustrated that only apoA1 protein was found in BAL fluid. According to our findings it seems that increase in the stress oxidative in chemical injured veterans with pulmonary complications comes with reduction in PON1 enzyme activity and appearance of RR genotype rises up with the increase in disease severity. Since a significant correlation between enzyme activity and genotype was not observed altering these two variables with each other requires more studies.

Sulfur mustard (SM) has been identified as an important chemical weapon. During the Iran-Iraq war of 1980-88, the extensive usage of SM against Iranian civilians and military forces was proven. This agent has been shown to cause severe damage mainly in the skin, eyes, lungs, and respiratory tract in Iranian veterans. The most common disease is bronchiolitis obliterans (BO)). SM increases the endogenous production of reactive oxygen species (ROS). Superoxide dismutases (SODs) are known as protective antioxidants against the harmful effects of ROS. Twenty exposed SM individuals (43.2±6.4 years), and 10 normal controls (41.3±2.5 years) were enrolled in this study. Evaluation of SODs was performed by semiquantitative RT-PCR and immunohistochemistry. Our results demonstrated that CuZnSOD and MnSOD mRNA were up-regulated 2.79±1.09 and 2.49±1.11 folds, respectively in SM-injured patients in comparison with control levels. In contrast, Immunohistochemistry results showed downregulation of CuZnSOD protein expression in SM injured patients. Our results revealed that SODs may play an important role in cellular protection against oxidative stress due to mustard gas toxicity in airway wall of SM exposed patients.

The widespread use of sulfur mustard (SM) as a chemical warfare agent in the past century has proved its long-lasting toxic effects. Despite a lot of research over the past decades on Iranian veterans, there are still major gaps in the SM literature. Transforming growth factor (TGF-β), a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of chronic airway diseases, especially with respect to airway remodeling in mustard lung. Primary airway fibroblasts from epibronchial biopsies were cultured, and gene expression of TGF-β1, TGF-β2, TbR-I and TbR-II in fibroblasts of SM injured patients and controls were investigated. Expression of TGF-βs and receptors was measured by RT-PCR. Protein level of TGF-β1 was surveyed by western blot. Our findings revealed that expression levels of TGF-β1, TGF-β2, TbR-I and TbR-II were upregulated in the airway fibroblasts of SM exposed patients in comparison with control samples. TGF-β1 expression was shown to be markedly increased in primary lung fibroblasts of chemically injured patients. Our novel data, suggested that over-expression of TGF-β molecule and receptors in primary airway fibroblasts of mustard gas injured patients may be involved in progression of airway remodeling of these patients.

Background/aim: Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls., Materials and Methods: In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values., Result: The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23) compared with healthy subjects (0.13 ± 0.07; P ± 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls ( P = 0.5)., Conclusion: Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.

Purpose: To review the acute and chronic pathological effects of sulfur mustard on the genitourinary system and male fertility., Materials and Methods: We searched PubMed and Google Scholar to find studies related to the sulfur mustard-induced genitourinary effects and male infertility. Information in the abstracts of non-English related papers as well as those in the proceedings of congresses on sulfur mustard were reviewed as well., Results: In acute phase after sulfur mustard exposure, evidences are in favor of microscopic and macroscopic renal lesions, very low androgen levels, and impaired spermatogenesis. Several years following sulfur mustard exposure, the long-term pathological effects vary from the renal function impairment to the gonadal damage, in particular the spermatogenesis. Nevertheless, carcinogenic effect of sulfur mustard on the genitourinary system as well as the prevalence of male infertility among sulfur mustard-exposed veterans in the chronic post-exposure phase is still unclear., Conclusion: Sulfur mustard causes both acute and chronic injuries to different parts of the genitourinary system.

To review long-term respiratory effects of mustard gas on Iranian veterans having undergone Iraq-Iran war. Electronic databases of Scopus, Medline, ISI, IranMedex, and Irandoc sites were searched. We accepted articles published in scientific journals as a quality criterion.The main pathogenic factors are free radical mediators. Prevalence of pulmonary involvement is approximately 42.5%. The most common complaints are cough and dyspnea. Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma. Spirometry results can reveal restrictive and obstructive pulmonary disease. Plain chest X-ray does not help in about 50% of lung diseases. High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi. There is no definite curative treatment for mustard lung. The effective treatment regimens consist of oxygen administration, use of vaporized moist air, respiratory physiotherapy, administration of mucolytic agents, bronchodilators, corticosteroids, and long-acting beta-2 agonists, antioxidants, surfactant, magnesium ions, therapeutic bronchoscopy, laser therapy, placement of respiratory stents, early tracheostomy in laryngospasm, and ultimately lung transplantation. High-resolution CT of the lung is the most accurate modality for the evaluation of the lung parenchyma and bronchi. The treatment efficacy of patients exposed to mustard gas depends on patient conditions (acute or chronic, upper or lower respiratory tract involvement). There are various treatment protocols, but unfortunately none of them is definitely curable.

Introduction: It is estimated that during the Iraq-Iran war of the 1980s, over 100,000 Iranians (military or civilian) were exposed to sulfur mustard (SM), and a considerable proportion of them are still suffering with long-term consequences of exposure. The aim of the present article is to address carcinogenesis of SM following these acute exposures., Methods: Using a cohort study, we estimated and compared the incidence rates of malignant disorders in 7,570 veterans exposed to SM and 7,595 unexposed comrades in a 25-year follow-up period. We also determined the hazard ratio of cancer occurrence for SM exposure during the follow-up period., Results: Cancer incidence was significantly increased with exposure to SM. The incidence rate ratio of cancer for SM exposure was 1.81 (95 % CI 1.27-2.56), and the age-adjusted incidence rate ratio was 1.64 (95 % CI 1.15-2.34).The hazard ratio of cancer was 2.02 (95 % CI 1.41-2.88)., Conclusion: Present study suggests carcinogenesis of SM following acute exposure during war. With respect to this finding, it is reasonable to improve care programs such as routine screening schemes for exposed veterans.

It is well documented that inhalation of sulfur mustard (SM) causes injury to the respiratory system. Many Iranian civilians and war veterans are suffering from late respiratory complications of SM exposure. Recent studies have shown that bronchiolitis obliterans (BO) is the major cause of respiratory complications following SM exposure. In this review, we focus on the clinical, pulmonary, radiological, immunological and pathological manifestations in SM-induced BO with intent to provide a practical, clinical and paraclinical guideline for diagnosis and step-wise workup of these patients, which may be used to manage similar lung injuries induced by other similar inhaled toxins.