Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies.

UNASSIGNED: Sulfur mustard (SM) exposure causes acute and chronic respiratory diseases. The extent of small airway dysfunction (SAD) in individuals exposed to SM is unclear. This study evaluated and compared SAD in SM-exposed and SM-unexposed participants using noninvasive lung function tests assessing small airway function.
UNASSIGNED: This retrospective cohort study involved SM-exposed (n = 15, mean age: 53 ± 8 years) and SM-unexposed (n = 15, mean age: 53 ± 7 years) Kurdish-Swedish individuals in Sweden. Small airway resistance and reactance were assessed using impulse oscillometry (IOS). Nitrogen (N2) multiple breath washout (MBW) was employed to assess lung ventilation heterogeneity. The gas-exchanging capacity of the lungs was assessed using the diffusing capacity of the lungs for the carbon monoxide (DLCO) test. Lung function outcomes were reported as absolute values and z-scores. Group comparisons were performed using the Mann-Whitney U test.
UNASSIGNED: No statistically significant differences in age, height, or body mass index were observed between the two groups. IOS showed significantly increased small airway resistance, while N2MBW exhibited significantly increased global and acinar ventilation heterogeneity in SM-exposed individuals compared to that in unexposed individuals. SAD was identified in 14 of 15 SM-exposed individuals, defined as at least one abnormal IOS difference between resistance at 5 and 20 Hz (R5-R20) and/or area of reactance (AX) or N2MBW lung\'s acinar zone (Sacin), and DLCO adjusted to the alveolar volume (DLCO/VA) outcome. Of these 14 individuals, only 5 demonstrated concordant findings across the IOS and N2MBW tests.
UNASSIGNED: Exposure to SM was positively associated with long-term impairment of respiratory tract function in the small airways in the majority of the previously SM-exposed individuals in the present study. Furthermore, both IOS and N2MBW should be employed to detect SAD in SM-exposed survivors as they provide complementary information. Identifying and characterizing the remaining pathology of the small airways in survivors of SM exposure is a first step toward improved treatment and follow-up.

UNASSIGNED: Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.
UNASSIGNED: Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.
UNASSIGNED: Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).
UNASSIGNED: The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.

Although chemical and radiological agents cause toxicity through different mechanisms, the multiorgan injuries caused by these threats share similarities that convene on the level of basic biological responses. This publication will discuss these areas of convergence and explore \"multi-utility\" approaches that could be leveraged to address common injury mechanisms underlying actions of chemical and radiological agents in a threat-agnostic manner. In addition, we will provide an overview of the current state of radiological and chemical threat research, discuss the US Government\'s efforts toward medical preparedness, and identify potential areas for collaboration geared toward enhancing preparedness and response against radiological and chemical threats. We also will discuss previous regulatory experience to provide insight on how to navigate regulatory paths for US Food and Drug Administration (FDA) approval/licensure/clearance for products addressing chemical or radiological/nuclear threats. This publication follows a 2022 trans-agency meeting titled, \"Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures,\" sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH). Discussions from this meeting explored the overlapping nature of radiation and chemical injury and spurred increased interest in how preparedness for one threat leads to preparedness for the other. Herein, subject matter experts from the NIAID and the Biomedical Advanced Research and Development Authority (BARDA), a part of the Administration for Strategic Preparedness and Response (ASPR), summarize the knowledge gained from recently funded biomedical research, as well as insights from the 2022 meeting. These topics include identification of common areas for collaboration, potential use of biomarkers of injury to identify injuries caused by both hazards, and common and widely available treatments that could treat damage caused by radiological or chemical threats.

UNASSIGNED: The primary objective of this study was to analyze the long-term survival of 48,067 chemical warfare survivors who suffered from pulmonary, cutaneous, and ocular lesions in the decades following the Iran-Iraq war.
UNASSIGNED: The data for this study were obtained from the Veterans and Martyr Affair Foundation (VMAF) database. The survivors were divided into two groups based on whether they were evacuated/admitted (EA) to a hospital or not evacuated/admitted (NEA) to a hospital. The proportional hazard (PH) assumption for age categories, gender, exposure statuses, and eye severity was not satisfied. Therefore, we used a Generalized Gamma (GG) distribution with an Accelerated Failure Time (AFT) model for analysis.
UNASSIGNED: The study included a total of 48,067 observations, and among them, 4342 (9.03 %) died during the study period. The mean (SD) age of the survivors was 55.99 (7.9) years. The mortality rate increased with age, and higher rates were observed in males. Survival probabilities differed significantly among age categories, provinces, lung severity, and eye severity based on log-rank tests (p-value<0.05 for all). The GG model results showed that higher age and being male were associated with a shorter time to death. The study also found that the mortality rate was significantly higher in the EA group compared to the NEA group.
UNASSIGNED: The present study showed no significant difference in survival time between the EA and NEA groups. The findings suggest that pulmonary lesions caused by mustard gas are more likely to be fatal compared to skin and eye lesions. The results also indicate a potential association between survival time and the severity of lung damage.

Sulfur mustard (SM), a bi-functional alkylating agent, was used during World War I and the Iran-Iraq war. SM toxicity is ten times higher in eyes than in other tissues. Cornea is exceptionally susceptible to SM-injuries due to its anterior positioning and mucous-aqueous interphase. Ocular SM exposure induces blepharitis, photosensitivity, dry eye, epithelial defects, limbal ischemia and stem cell deficiency, and mustard gas keratopathy leading to temporary or permanent vision impairments. We demonstrated that dexamethasone (Dex) is a potent therapeutic intervention against SM-induced corneal injuries; however, its mechanism of action is not well known. Investigations employing proteomic profiling (LC-MS/MS) to understand molecular mechanisms behind SM-induced corneal injury and Dex efficacy were performed in the rabbit cornea exposed to SM and then received Dex treatment. PEAKS studio was used to extract, search, and summarize peptide identity. Ingenuity Pathway Analysis was used for pathway identification. Validation was performed using immunofluorescence. One-Way ANOVA (FDR < 0.05; p < 0.005) and Student\'s t-test (p < 0.05) were utilized for analyzing proteomics and IF data, respectively. Proteomic analysis revealed that SM-exposure upregulated tissue repair pathways, particularly actin cytoskeleton signaling and inflammation. Prominently dysregulated proteins included lipocalin2, coronin1A, actin-related protein2, actin-related protein2/3 complex subunit2, actin-related protein2/3 complex subunit4, cell division cycle42, ezrin, bradykinin/kininogen1, moesin, and profilin. Upregulated actin cytoskeleton signaling increases F-actin formation, dysregulating cell shape and motility. Dex reversed SM-induced increases in the aforementioned proteins levels to near control expression profiles. Dex aids corneal wound healing and improves corneal integrity via actin cytoskeletal signaling and anti-inflammatory effects following SM-induced injuries.

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.

Chemical agents have been utilized for centuries in warfare and pose a health threat to civilians and military personnel during armed conflict. Despite treaties and regulations against their use, chemical agent exposure remains a threat and measures to understand their effects and countermeasures for systemic and organ-specific health are needed. Many of these agents have ocular complications, both acute and chronic. This mini-review focuses on key chemical agents including vesicants (mustards, lewisite), nerve agents (sarin, VX), knockdown gasses (hydrogen cyanide), and caustics (hydrofluoric acid). Their ophthalmic manifestations and appropriate treatment are emphasized. Acute interventions include removal of the source and meticulous decontamination, as well as normalization of pH to 7.2-7.4 if alteration of the ocular pH is observed. Besides vigorous lavage, acute therapies may include topical corticosteroids and non-steroid anti-inflammatory therapies. Appropriate personal protective equipment (PPE) and strict donning and doffing protocols to avoid healthcare provider exposure are also paramount in the acute setting. For more severe disease, corneal transplantation, amniotic membrane graft, and limbal stem cell transplantation may be needed. Orbital surgery may be required in patients in whom cicatricial changes of the ocular surface have developed, leading to eyelid malposition. Multidisciplinary care teams are often required to handle the full spectrum of findings and consequences associated with emerging chemical threats.

Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD+ supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD+ depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD+ booster nicotinamide riboside (NR) and NAD+ synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD+ levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD+ via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD+ levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD+ levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD+ is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD+ booster.

Sulfur mustard (SM) is a lethal chemical agent that affects many organs, particularly the eyes, respiratory system and skin. Even asymptomatic patients with documented SM vapor exposure may develop organ disorder many years later. Patients with even minor signs in the acute stage may experience late complications that necessitate surgery. Early decontamination and conservative measures could help the patients and decrease the complications. Despite decades of research, there is still no effective treatment for either acute or long-term SM-induced ocular complications. Even after multiple medications and surgical procedures, the majority of patients continue to have symptoms. For dry eye, punctual occlusion, autologous eye drops, and aggressive lubrication are used; for persistent epithelial defects (PED), tarsorrhaphy, amniotic membrane transplant, and stem cell transplantation are used; for total limbal stem cell deficiency (LSCD), living-related conjunctivolimbal allograft and keratolimbal allograft are used; for corneal vascularization, steroids, non-steroidal anti-inflammatory drugs, and anti-vascular endothelial growth factor prescribed; and for corneal opacities, corneal transplantation is done. Platelet rich plasma and topical drops containing stem cell transplantation for LSCD, photodynamic therapy paired with subconjunctival or topical anti-vascular endothelial growth factors for corneal vascularization, topical curcumin and topical ciclosporin-A for dry eye, and orbital fat-derived stem cells for PED are all alternative treatments that can be suggested. Despite the experimental and clinical research on the complications of SM exposure over the past decades, there is still no effective treatment for eye complications. However, supportive medical and surgical management has been applied with relatively good outcome.