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Sulfur mustard (SM)-exposed individuals develop late pulmonary complications, which are associated with chronic inflammation and fibrotic changes in the lung tissue. MicroRNAs are known to act as important regulators of inflammatory responses, including inflammation and fibrosis-related cytokine signaling. In this study, we investigated the expression miR-15b-5p and miR-21-5p, two regulators of TGF-β signaling, as well as their target molecule, SMAD7, in lung tissues from SM-exposed and control individuals. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) lung tissue biopsies obtained during surgery from SM-exposed (n=20) or control (n=20) cases. Quality of the extracted RNA was evaluated by an Agilent Bioanalyzer and RNA was quantified using a NanoDrop. MiR-21-5p, miR-15b-5p and SMAD7 expression levels were measured by real-time RT-PCR. miR-21-5p expression levels were significantly decreased (2.7 fold) in the lung tissues from SM-exposed individuals compared with tissues obtained from the control group (p=0.02). There were no significant differences in miR-15b-5p expression levels between the two groups (p=0.94). Interestingly, SMAD7 expression levels were significantly higher (5.8 fold) in SM-exposed individuals' lung tissues compared with the control group (p=0.045). Our data indicate that exposure to sulfur mustard affects the expression of miR-21-5p as well as its target, SMAD7, in lung tissues many years after exposure. Considering the role of SMAD7 in the regulation of TGF-β signaling, these changes might point to a potential mechanism by which SM-exposure regulates inflammatory/fibrotic alterations in lung tissue.

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1β, IL-18, and IL-1βR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.

The spectrum of pulmonary pathology in the Middle East is as versatile as its civilizations and cultures. In this review, we outline the key challenges confronting pulmonologists in the Middle East. We shed light on the diverse conditions commonly encountered in the region, from the centuries-old illnesses of tuberculosis, to contemporary problems such as lung complications from chemical warfare. We specifically highlighted unique aspects related to respiratory illnesses in the Middle East, for example, climate factors in the desert region, cultural habits, for example, water-pipe smoking and disorders unique to the region, such as Behçet's disease. Pulmonologists are also faced with the consequences of modernization, including large immigrant population and associated social and health issues, rising incidence of obesity and sleep apnoea, and drug-resistant tuberculosis. Tackling these health issues will require an integrated approach involving public health, primary care as well as specialist pulmonology input, taking into consideration the unique cultural and environmental factors to ensure effective management and compliance to medical care., (© 2011 The Authors; Respirology © 2011 Asian Pacific Society of Respirology.)

Objective: The purpose of this study was to examine whether the degree of air trapping in high resolution computed tomography (HRCT) of patients with histories of sulfur mustard gas exposure during suspended full expiration correlated with various parameters of the cardiopulmonary exercise test as the gold standard for assessment of pulmonary function., Methods: In this analytic study 75 male patients, each with a history of sulfur mustard gas exposure, were investigated. Each participant underwent an incremental cardiopulmonary exercise test, pulmonary function test and arterial oxygen saturation for hemoglobin measurement. For HRCT examination, both lungs were divided into three parts (upper, middle, and lower) and in each part images were separately observed from the involved area point of view (<25% ≤6/24; >25% ≥6/24)., Results: A total of 49.3% of the patients (37/75) had evidence of air trapping in over 25% of their lung segments. The mean age±SD in the patients with air trapping of =25% or <25% were 41.1±6.8 and 39.7±4.0 years, respectively (P=0.281). In our study there was no significant difference in pulmonary function test findings (FEV1, FVC and FEV1/FVC) between the two groups. There was no significant correlation with air trapping of =25% and any of the exercise test parameters. Also, no correlation was found between significant air trapping and exercise test findings in maximum exercise and anaerobic situations., Conclusions: No correlation was found between HRCT and cardiopulmonary exercise test findings. HRCT is neither pathognomic of the disease nor a good predictor of disease severity but it might be suggestive of mustard lung injuries.

Sulfur mustard (SM) is highly toxic for various organs. The eyes, skin, respiratory tract, as well hematopoietic and immune systems are the main organs affected by SM. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a potent cytokine that plays an important role in the hematopoietic and immune system. The aim of this study was to determine the serum levels of GM-CSF and its relation to blood cell count and other inflammatory cytokines 20 years after SM exposure. The association of GM-CSF with the clinical severity of pulmonary, ophthalmic and dermatologic complications has also been studied. In this historical cohort study named as Sardasht-Iran Cohort Study (SICS), 369 SM exposed male participants and 125 unexposed volunteers were studied. The serum concentrations of cytokines were measured by ELISA technique. The severity of clinical complications was graded according to the criteria verified by the Medical Committee of the Foundation of Martyr and Veterans Affairs. The serum levels of GM-CSF in the SM exposed group did not display any significant differences with the control group. Median of GM-CSF was 7.33 and 9.39 pg/ml in the SM exposed group and the controls respectively. There was a positive correlation between the serum levels of GM-CSF and the percent of eosinophils only in the exposed group. Moreover, positive correlations were found between circulating levels of GM-CSF with IL-1alpha, IL-1beta, TNF-alpha and IL-6. This correlation was not observed between GM-CSF and IL-8 in both study groups. The serum levels of GM-CSF did not show any significant association with clinical complications.

IL-10 is an anti-inflammatory cytokine that is important in the regulation of inflammatory processes in different conditions. Sulfur mustard (SM) intoxicated patients are suffering from different inflammatory diseases in their lung, skin and eyes. Physical activity (PA) is reported to control inflammation by reducing pro-inflammatory and inducing anti-inflammatory cytokines. Our previous study revealed lower PA and more sedentary lifestyle among SM exposed population. This study aimed to determine the relationship of PA with IL-10 production in SM exposed subjects. Baseline, mitogen-induced and the serum levels of IL-10 were evaluated. In a historical cohort study, Sardasht-Iran Cohort Study (SICS), 372 SM exposed participants were studied 20 years after exposure and were compared with 128 unexposed control participants. The Global Physical Activity Questionnaire (GPAQ; developed by WHO) was used to obtain a self-reported measure of physical activity. Whole blood culture supernatants and serum samples were used for IL-10 measurement by ELISA technique. In both the control and exposed groups mitogen-induced IL-10 production was significantly elevated with severity of PA intensity (p<0.05). In the control subjects with moderate PA intensity, the mitogen-induced IL-10 production was higher than the corresponding in the exposed group (p<0.05). In the exposed group, mitogen-induced IL-10 production had significant positive correlation with total PA, total transport PA, total recreational PA and total moderate intensity work (p<0.05). The positive relationship between high PA and the levels of anti-inflammatory cytokine IL-10 indicates a need to encourage a more active lifestyle among the SM exposed subjects who have various inflammatory complications.

The serum levels of four important and well characterized inflammatory chemokines including MCP-1/CCL2, RANTES/CCL5, IL-8/CXCL8 and Fractalkine/CX3CL1 were evaluated in sulfur mustard (SM) exposed Iranian population 20 years after exposure. In this historical cohort study 372 SM exposed participants from Sardasht, and 128 unexposed participants as controls were studied. The serum concentrations of chemokines were measured by a sandwich ELISA technique. The serum concentrations in the exposed comparing to the control group were 201.86 vs 180.60 pg/ml (p=0.002), for MCP-1/CCL2, 1182.6 vs 1393.1pg/ml (p=0.021) for RANTES/CCL5, 12.61 vs 15 pg/ml (p=0.002) for IL-8/CXCL8 and 0.696 vs 0.0648 (p=0.413) for Fractalkine/CX3CL1. In conclusion, elevated levels of MCP-1/CCL2 may suggest an anti inflammatory response and decreased levels of IL-8/CXCL8 and RANTES/CCL5 may represent a different pathophysiology and diverse molecular mechanisms involved in long term clinical manifestations of SM exposure. However, further prospect into their role in the pathogenesis of SM remains to be done.

Mustard gas, even in low doses, has the ability to inflict damage in multiple organs especially the skin, eyes, as well as the respiratory tract. This damage may cause many complications which persist during the lifespan of exposed subjects. Pro-inflammatory cytokines including TNF, IL-1alpha, IL-1beta and IL-1Ra cause systemic inflammatory reactions and numerous changes including altered cell signaling and migration, changes in cytokine production and fever. The aim of this study was to determine the serum levels of these cytokines in subjects who were exposed to mustard gas 20 years ago in comparison with an unexposed control group. In this historical cohort study 368 sulfur mustard (SM) exposed participants from Sardasht and 126 age-matched unexposed volunteers from Rabat (a nearby town) as controls were chosen by a random systematic sampling. The serum concentrations of IL-1alpha, IL-1beta, IL-1Ra and TNF were measured by a sandwich ELISA technique. Median of the serum levels of cytokines TNF, IL-1alpha, IL-1beta and IL-1Ra in the control group was 23.79, 1.89, 1.91 and 32.9 pg/ml respectively, while in the SM-exposed participants these values were 11.11, 0.81, 1.73 and 26.7 pg/ml respectively. The serum pro-inflammatory cytokine levels were significantly lower in the exposed group than in controls (p<0.01). There was also significant positive correlation between concentration of all of mentioned cytokines, the strongest being between IL-1beta and TNF (r=0.809 in the control group). The observed down-regulation of pro-inflammatory cytokines should be considered in interpretation of diagnosis and therapeutic measures taken to improve clinical complications.

The selectins (L, P and E) are carbohydrate-binding membrane glycoproteins acting as adhesion molecules involved in the development of different inflammatory reactions. Various eye, skin and lung diseases are associated with induction of soluble selectins. In this study serum levels of soluble forms of selectins (sL-selectin, sP-selectin and sE-selectin) were evaluated in the sulfur mustard (SM) exposed and the control groups using ELISA method. sL-selectin was significantly lower in the SM exposed group compared to the control group (1131.5+/-16.3 and 1205.7+/-26.9 pg/ml respectively; p=0.021). The serum levels of sP-Selectin was significantly reduced in the SM exposed group in comparison to the control group (149.35+/-2.61 and 170.25+/-5.16 pg/ml respectively; p<0.001). sE-selectin was significantly increased in sera of the exposed group compared to the control group (29.64+/-0.902 and 24.61+/-1.26 pg/ml respectively; p=0.003). sL-selectin positively correlated with the percentage of polymorphonuclear cells and negatively with the percentage of lymphocytes. There was a significant correlation between the count of platelets and sP-selectin in both the control and exposed groups. The change in the pattern of selectins in the SM exposed group in comparison to the control group may indicate suppressed acute inflammatory condition in which new remodeling of cytokine expression play a more crucial role in the immune-regulation.

Background: Exposure to mustard gas frequently results in long-term respiratory complications. However the factors which drive the development and progression of these complications remain unclear. The Renin Angiotensin System (RAS) has been implicated in lung inflammatory and fibrotic responses. Genetic variation within the gene coding for the Angiotensin Converting Enzyme (ACE), specifically the Insertion/Deletion polymorphism (I/D), is associated with variable levels of ACE and with the severity of several acute and chronic respiratory diseases. We hypothesized that the ACE genotype might influence the severity of late respiratory complications of mustard gas exposure., Methods: 208 Kurdish patients who had suffered high exposure to mustard gas, as defined by cutaneous lesions at initial assessment, in Sardasht, Iran on June 29 1987, underwent clinical examination, spirometric evaluation and ACE Insertion/Deletion genotyping in September 2005., Results: ACE genotype was determined in 207 subjects. As a continuous variable, FEV1 % predicted tended to be higher in association with the D allele 68.03 +/- 20.5%, 69.4 +/- 21.4% and 74.8 +/- 20.1% for II, ID and DD genotypes respectively. Median FEV1 % predicted was 73 and this was taken as a cut off between groups defined as having better or worse lung function. The ACE DD genotype was overrepresented in the better spirometry group (Chi2 4.9 p = 0.03). Increasing age at the time of exposure was associated with reduced FEV1 %predicted (p = 0.001), whereas gender was not (p = 0.43)., Conclusion: The ACE D allele is associated with higher FEV1 % predicted when assessed 18 years after high exposure to mustard gas.

Background and Objectives: Increased airway responsiveness to beta-agonists is noted in asthmatics and smokers. The lung may be exposed to chemical warfare agents such as mustard gas and pulmonary complications of exposure range from no effect to severe bronchial stenosis. There is little understanding of airway hyperresponsiveness to beta-agonist drugs in chemical war victims and this study examined airway responsiveness to salbutamol in victims of chemical warfare., Methods: The threshold concentrations of inhaled salbutamol required for a 20% change in FEV(1) as PC(20), or a 35% change in specific airway conductance (sGaw) as PC(35) were measured in 22 persons exposed to chemical warfare and 15 normal control subjects., Results: In 11 of the 22 subjects PC(20) salbutamol could be measured and in 15 of the 22 subjects PC(35) salbutamol could be measured. This group of patients was the responder group (PC(20) = 10.79 and PC(35) = 8.55 mg/L) and in them the concentration of salbutamol needed for a response was significantly lower than that required in normal controls (PC(20) = 237.68 and PC(35) = 88.72 mg/L, P < 0.001). There was a significant correlation between FEV(1) and PC(20) salbutamol (r = 0.815, P < 0.001)., Conclusions: These results showed increased airway responsiveness to salbutamol in most subjects exposed to chemical warfare; this was correlated with airway calibre.

Exposure to chemical agents, both deliberate and accidental, over the past 100 years has resulted in the deaths of thousands and a significant number of casualties requiring hospitalization. The respiratory system is an important portal of entry into the human body for many of these agents, and pulmonary symptoms are a hallmark of many chemical exposures. The 4 major chemical warfare agents are: lung-damaging, blood, blister, and nerve compounds. The review will cover historical exposures, signs and symptoms, treatment, and long-term consequences. There are numerous examples of deliberate (as well as accidental) exposure to harmful chemicals, and each incident requires the provider to understand the signs and symptoms of the particular chemical so that the correct treatment is provided. The respiratory implications of these agents appear to be dose and timing dependent, with full recovery often seen if supportive measures and appropriate antidotes are administered in a timely fashion.

Considering the undefinite nature of lung pathology in patients exposed to sulfur mustard (SM) many years after exposure, we conducted this study to document and quantify lung disease in this setting. In a cross sectional study, we selected 23 patients exposed to SM gas approximately 14 years ago during the Iran-Iraq war (1980-1988). We studied their clinical history, physical examination, pulmonary function test (PFT), high-resolution computed tomography scan (HRCT) of the chest, bronchoscopy, and bronchoalveolar lavage (BAL) sampling, and transbronchial lung biopsies. Other potential causes of lung disease, including smoking of cigarettes, were excluded. All 23 patients were symptomatic with cough, dyspnea, and/or felt tight in the chest. All of them had significant air trapping in HRCT and a marked increase of residual volume in PFT. The most common inflammatory cell in BAL fluid was neutrophil (88%). Of the 23 cases, there was sufficient tissue for detailed evaluation in 22. Histologically, 11 cases showed airway epithelial injury, and nine of the 14 lung biopsies with alveoli had histopathological changes diagnosable as organizing pneumonia (OP) or bronchiolitis obliterans OP (BOOP). Two out of 14 cases showed changes suggestive of OP. Inhalation of SM can lead to persistant and clinically significant lung disease, including bronchial mucosal injury and OP, many years after exposure.

It is well documented that inhalation of sulfur mustard causes injury of the respiratory system. While all of the reports and surveys thoroughly document long-term pulmonary effects after significant exposure to mustard, there is no direct evidence that addresses the issue of long-term respiratory effects in individuals who were exposed to very low level of mustard and suffered no acute respiratory tract injury. Our subjects were selected among all those who were in chemically contaminated areas with chemical warfare agents (CWA) and had been registered for an annual checkup. Subclinical exposure's definition is the absence of any acute symptoms at the time of exposure. We used standard respiratory questionnaires, and chest HRCT examinations and a pulmonary function test were done. Based on exclusion criteria from total of 200 patients claiming respiratory problems, just 77 veterans entered the study. After performing HRCT for all our patients there were 13 (38.23%) veterans with no observable defect, 13 (38%) of them had just significant air trapping in their HRCTs. All the others had at least air trapping (AT), which added to other defects. Septal wall thickening was seen in five veterans (14.7%) and bronchiectasis was seen in three (8.8%) cases. This study suggest that exposure to CWA was responsible for the occurrence of the bronchiolitis obliterans syndrome observed in our patients. There are many civilian and military people who have been present in contaminated area without signs and symptoms at the time of exposure, and early detection of such a population could be lifesaving.

The respiratory system plays a major role in the pathogenesis of nerve agent toxicity. It is the major route of entry and absorption of nerve agent vapor, and respiratory failure is the most common cause of death follow-ing exposure. Respiratory symptoms are mediated by chemical irritation,muscarinic and nicotinic receptor overstimulation, and central nervous system effects. Recent attacks have demonstrated that most patients with an isolated vapor exposure developed respiratory symptoms almost immediately. Most patients had only mild and transient respiratory effects, and those that did develop significant respiratory compromise did so rapidly. These observations have significant ramifications on triage of patients in a mass-casualty situation, because patients with mild-to-moderate exposure to nerve agent vapor alone do not require decontamination and are less likely to develop progressive symptoms following initial antidote therapy. Limited data do not demonstrate significant long-term respiratory effects following nerve agent exposure and treatment. Provisions for effective respiratory protection against nerve agents is a vital consideration in any emergency preparedness or health care response plan against a chemical attack.

Terrorism poses a clear and present danger to civilian populations. Although terrorist cells may gain access to traditional chemical weapons,there are literally thousands of other industrial chemicals to choose from. Common chemicals used on a daily basis in an industrialized society can be readily obtained from the local shopping center, rail yard. or from nearby industrial parks. and terrorists may choose to use these agents in an attack. The medical implications of a major incident involving the accidental or intentional release of a dangerous chemical are significant, and all healthcare facilities should have a plan in place to manage the casualties of such an event. This plan should include event recognition, crowd control, primary triage, emergency treatment, decontamination of injured and uninjured patients, and secondary triage. Emergency health care providers should be prepared to respond to classic chemical agents such as mustard,chlorine, and phosgene and must also work carefully with law enforcement and public health agencies to keep abreast of new threats. The ability to recognize an event promptly, triage patients, decontaminate casualties,administer antidotes when available, and provide best supportive care will minimize the adverse outcomes.