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Context: Mustard gas (e.g. sulfur mustard (SM)) has been used as a chemical agent in several battles and is still a potential worldwide menace. Besides local absorption, particularly in the skin, eyes and lungs, systemic spread of the agent also has detrimental effects on gonads, bone marrow and nervous system. Moreover, chronic exposure of SM to respiratory system causes death. Inducing oxidative stress, and disturbing DNA and tissue repair systems, inflammation and cell death signaling pathways have been introduced as molecular mechanisms of the injury., Methods: In this systematic review, more than 1200 (2000-2014) articles focusing on gross or molecular pathological reports in the acute phase of the respiratory injury after SM exposure were reviewed, followed by two different layers of gross and molecular pathological data (clinic and laboratory) integrated together in a spatio-temporal order. Role of epithelial, neutrophil and macrophage cells and three signaling pathways of inflammation, oxidative stress and cell death are covered in details., Results and Conclusion: Our results propose a critical role of interleukin-17 producing cells in acute and chronic inflammatory responses.

Human airway is generally destructed by inhaled factors and is the barrier to the external environment and has a crucial role in protection of the internal homeostasis of the lung. Sulfur mustard (SM) is a chemical warfare that capable of producing severe chemical injuries primarily in the lungs. Trefoil factor family (TFFs) plays major roles in epithelial repair and homeostasis, particularly in the lung. This study attempted to verify the role of TFFs in airway that induced by sulfur mustard. Fifteen patients exposed to SM and 10 non-exposed subjects were enrolled in this study. Bronchoscopy was carried out and endobronchial biopsy specimens were taken. The TFFs gene expressions were evaluated by RT-PCR. The results revealed that the TFF1 was overexpressed in exposed subjects in comparison to non-exposed subjects. In conclusion, TFF1 displays a distinct protein expression pattern in the developing of airway remodeling due to SM inhalation and plays an important role in maintaining the airway epithelium function.

Sulfur mustard (SM) is a blister-forming agent and can cause damages in various momentous human organs. Previous studies have demonstrated that chemical and mechanical injuries of epithelial cells cause to give rise the secretion of TGF-β1 and TGF-β2. These cytokines play a key role in respiratory remodeling due to SM. In this study, we investigated the impact of SM on the expression level of TGF-β isoforms and their receptors in vitro using reverse transcriptase polymerase chain reaction and western blotting. Our finding revealed the significant increase at concentrations of 25 μl/ml SM for 30 min and 60 min and also 100 μl/ml for 60 min for TGF-β1, 25, 50 and 100 μl/ml SM for 30 min for TGF-βr1 and after exposing with 100 μl/ml SM for both 30 and 60 min for TGF-β2 (p < 0.05). Data from western blotting showed the increase of TGF-β1 expression at the level of protein as the same pattern as the mRNA level. In vitro short-time exposure of fibroblast to SM can induce the expression of TGF-β1, TGF-β2 and TGF-βR1 denoting that over-expression of TGF-β isoforms and their receptors leads to differentiation and collagen production, causing in airway remodeling and fibrosis.

Sulfur mustard (SM) is a potent alkylating agent which reacts with nucleophilic groups on DNA, RNA and proteins. It is capable of inducing cellular toxicity and oxidative stress via production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The accumulation of high amounts of the reactive species causes harmful effects such as DNA damage, lipid peroxidation, protein oxidation, inflammation and apoptosis. Although SM (also known as mustard gas) and its derivatives are rapidly removed from the body, long-term damages are much more serious than the short-term effects and may be correlated with the subsequent changes occurred on the genome. In order to defend against oxidative properties of this toxic molecule, cells trigger several anti-oxidant pathways through up-regulating the corresponding genes. Enzymes like heme oxygenase-1, superoxide dismutase and glutathione-S-transferase are the examples of such genes. These enzymes produce anti-oxidant substances that are able to scavenge the reactive species, alleviate their noxious effects and protect the cells. Following SM gas exposure, gene transcription (mRNA levels) of these enzymes are ramped up to help detoxify the cells. Yet, some studies have reported that the up-regulated transcription does not necessarily translate into higher protein expression levels. The exact reason why this phenomenon happens is not clear. Creation of mutations in the genome sequence may lead to protein structure changes. Phosphorylation or other post-translational alterations of proteins upon SM exposure are also considered as possible causes. In addition, alterations in some microRNAs responsible for regulating post-translation events may inhibit the expression of the anti-oxidant proteins in the poisoned cells at translational level.

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.

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.

Context: Sulfur mustard (SM) is known as an effective chemical agent and was used in the 1980s during the Iran-Iraq war against Iranians. At the present time, there are more than 40,000 people suffering from pulmonary lesions due to mustard gas in Iran. Though much is known about the gross pathology of SM damage, the molecular and cellular basis for this pathology is not well understood., Objective: One of the most important protein groups involved in inflammatory responses is nuclear factor κB protein (NF-κB1) family. They belong to the category of DNA-binding protein factors necessary for transcription of many proinflammatory molecules. In our research, we examined the role of NF-κB1/RelA in the pathophysiology of the lung., Materials and Methods: We investigated 10 normal individuals and 20 SM induced patients. Expression of NF-κB1/RelA in controls and the SM exposed samples was measured by real-time polymerase chain reaction and localization of NF-κB1 protein was detected by immunohistochemistry staining., Results: Our results revealed that expression levels of NF-κB1 and RelA were upregulated 0.64-6.50 fold and 0.83-8.34 fold, respectively, in the SM exposed patients in comparison with control samples., Discussion and Conclusion: As far as we know, this is the first finding of induction of NF-κB in patients exposed to SM. NF-κB1/RelA may play a major role in inflammation induced by mustard gas or even in cell survival in the bronchial wall of affected patients.

Airway remodelling is characterized by the thickening and reorganization of the airways seen in mustard lung patients. Mustard lung is the general description for the chronic obstructive pulmonary disease induced by sulfur mustard(SM). Pulmonary disease was diagnosed as the most important disorder in individuals that had been exposed to sulfur mustard. Sulfur mustard is a chemical warfare agent developed during Wars. Iraqi forces frequently used it against Iranian during Iran -Iraq in the 1980-1988. Peribronchial fibrosis result from airway remodeling that include excess of collagen of extracellular matrix deposition in the airway wall. Some of Smads families in association with TGF-β are involved in airway remodeling due to lung fibrosis. In the present study we compared the mRNA expression of Smad2, Smad3, and Smad4 and Smad7 genes in airway wall biopsies of chemical-injured patients with non-injured patients as control. We used airway wall biopsies of ten unexposed patients and fifteen SM-induced patients. Smads expression was evaluated by RT-PCR followed by bands densitometry. Expression levels of Smad3 and Smad4 in SM exposed patients were upregulated but Smad2 and Smad7 was not significantly altered. Our results revealed that Smad3, and 4 may be involved in airway remodeling process in SM induced patients by activation of TGF-β. Smad pathway is the most represented signaling mechanism for airway remodeling and peribronchial fibrosis. The complex of Smads in the nucleus affects a series of genes that results in peribronchial fibrosis in SM-induced patients.

Background: Sulfur mustard (SM) is a blister-forming agent that has been used as a chemical weapon. Sulfur mustard can cause damage in various organs, especially the skin, respiratory system, and eyes. Generally, the multiple complications of mustard gas result from its alkalizing potency; it reacts with cellular components like DNA, RNA, proteins, and lipid membranes.TGF-β is a multi-functional cytokine with multiple biological effects ranging from cell differentiation and growth inhibition to extracellular matrix stimulation, immunosuppression, and immunomodulation. TGF-β has 3 isoforms (TGF-β 1, 2, 3) and its signaling is mediated by its receptors: R1, R2 and intracellular Smads molecules.TGF-β has been shown to have anti-inflammatory effects. TGF-βs and their receptors also have an important role in modulation of skin inflammation, proliferation of epidermal cells, and wound healing, and they have been implicated in different types of skin inflammatory disorders., Methods: Seventeen exposed SM individuals (48.47 ± 9.3 years), 17 chronic dermatitis patients (46.52 ± 14.6 years), and 5 normal controls (44.00 ± 14.6 years) were enrolled in this study.Evaluation of TGF-βs and their receptors expressions was performed by semiquantitative RT-PCR. Only TGF1 was analyzed immunohistochemically., Results: Our results showed significant decreases in the expression percentages of TGF-β 1, 2 and R1, R2 in chemical victims in comparison with chronic dermatitis and normal subjects and significant decreases in the intensity of R1 and R2 expressions in chemical victims in comparison with chronic dermatitis and normal controls. (P value < 0.05), Conclusions: TGF-βs and their receptors appear to have a noticeable role in chronic inflammatory skin lesions caused by sulfur mustard.