Correlation between MMP-9 and MMP-9/ TIMPs Complex with Pulmonary Function in Sulfur Mustard Exposed Civilians: Sardasht-Iran Cohort Study.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteinases and have the vigorous capacity to degrade all parts of the extracellular matrix. MMP enzymes strongly participate in physiological processes such as normal tissue remodeling and wound healing and in pathology of pulmonary diseases. They are released in response to environmental stimuli such as toxins and regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Sulfur mustard (SM) is a chemical toxic which can cause severe permanent damages to lung tissues. The aim of this study was assessing the possible role of MMP-9 and TIMPs in SM-induced lung symptoms and signs in exposed patients 20 years after exposure. METHODS: Totally, 372 male volunteers with a history of SM- exposure and 128 age- and sex-matched unexposed controls participated and were divided into three groups: normal, mild and moderate-severe. All participants underwent clinical evaluation and pulmonary function tests and serum concentrations of MMP-9 and its inhibitors were measured using the ELISA technique. RESULTS: Serum level of MMP-9 was increased in the SM exposed group who had moderate-severe pulmonary complications compared with the SM exposed with normal lung (2.321 ± 2.836 vs. 1.546 ± 2.176, P = 0.001) while only the MMP-9/TIMP-4 complex was elevated in the SM exposed with normal lung individuals compared to its corresponding control group (85 ± 265 vs. 82 ± 222, P = 0.025). Although MMP-9 and its inhibitors did not show any correlation with spirometry findings, elevated circulating MMP-9 was detected in SM exposed patients with chronic chough and hemoptysis (P = 0.013 and P = 0.013 respectively). CONCLUSION: High level of tissue disruption and remodeling mediators could influence lung structure in long-term after SM-exposure. The correlation of clinical evaluation with these factors efficiently helps us to identify important effectors.

Association between Acne and Serum Pro-inflammatory Cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) in Mustard Gas-Exposed Patients: Sardasht-Iran Cohort Study.

BACKGROUND: Acne vulgaris is a very common chronic inflammatory disorder, yet its pathogenesis is not clearly understood. As part of the SICS, this study was conducted to evaluate the association between the incidence of acne vulgaris in SM-exposed subjects (20 years after the exposure) and serum levels of proinflammatory cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) in an attempt to better understand the pathogenesis of long-term skin disorders of these individuals. METHODS: Serum concentrations of cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) were measured using sandwich ELISA technique. RESULTS: The median of serum levels of IL-1ß, IL-8 and RANTES were significantly higher in the exposed patients with acne than those without acne (P = 0.05, 0.03 and 0.001 respectively). There was no significant difference in serum levels of IL-1α, IL-1Ra and IL-6 between the exposed subgroups. CONCLUSION: We found a positive association between serum levels of pro-inflammatory cytokines (IL-1ß, IL-8, IL-12 and RANTES) and acne among SM-exposed population.

A clinicopathological approach to sulfur mustard-induced organ complications: a major review.

CONTEXT: Sulfur mustard (SM), with an old manufacturing history still remains as potential threat due to easy production and extensive effects. OBJECTIVES: Increasing studies on SM indicates the interest of researchers to this subject. Almost all human body organs are at risk for complications of SM. This study offers organ-by-organ information on the effects of SM in animals and humans. METHODS: The data sources were literature reviews since 1919 as well as our studies during the Iraq-Iran war. The search items were SM and its all other nomenclatures in relation to, in vivo, in vitro, humans, animals, eye, ocular, ophthalmic, lungs, pulmonary, skin, cutaneous, organs and systemic. Amongst more than 1890 SM-related articles, 257 more relevant clinicopathologic papers were selected for this review. RESULTS: SM induces a vast range of damages in nearly all organs. Acute SM intoxication warrants immediate approach. Among chronic lesions, delayed keratitis and blindness, bronchiolitis obliterans and respiratory distress, skin pruritus, dryness and cancers are the most commonly observed clinical sequelae. CONCLUSION: Ocular involvements in a number of patients progress toward a severe, rapid onset form of keratitis. Progressive deterioration of respiratory tract leads to "mustard lung". Skin problems continue as chronic frustrating pruritus on old scars with susceptibility to skin cancers. Due to the multiple acute and chronic morbidities created by SM exposure, uses of multiple drugs by several routes of administrations are warranted.

Chemokines, MMP-9 and PMN elastase in spontaneous sputum of sulfur mustard exposed civilians: Sardasht-Iran Cohort Study.

Chemokines play an important role in acute and chronic pulmonary diseases. The aim of this study was to evaluate the levels of chemokines, MMP-9, and PMN elastase in spontaneous sputum and serum of patients 20 years after SM exposure. In context of Sardasht-Iran Cohort Study (SICS) 40 male volunteers with a history of SM exposure in June 1987 and complain of excessive sputum were recruited. The volunteers were clinically examined and their history was collected by internists. Sputum and serum levels of IL-8, fractalkine, MCP-1, RANTES, MMP-9, and PMN elastase were measured using ELISA kits (R&D System). Spirometries were performed on all the participants. Sputum level of fractalkine was significantly lower in the hospitalized group (N=16, Median=1.05; IQR=0.41-2.62) than non-hospitalized group (N=18, 4.031; IQR=0.947-8.203) (p=0.042). However, serum levels of fractalkine were higher in the hospitalized group (Mean±SD=2.08±5.09) than in the non-hospitalized (Mean±SD=0.53±0.87) group (T-test, p=0.03). Serum levels of PMN-elastase were also higher in the hospitalized group (Mean±SD; 64,794.43±26,820.08) than in the non-hospitalized group (Mean±SD=44,049.33±17,675.85) (p=0.017). There was no relationship between the cytokines and the studied factors in sputum and the GOLD classification, but the serum levels of fractalkine and MMP-9 were significantly higher in the more severe (grades 3-4) group. There was no significant correlation between sputum and serum levels of measured inflammatory mediators and pulmonary complications in the patients who were exposed to SM 20 years earlier. Pathophysiologic process involved in SM induced pulmonary problems might be different from those in other chronic pulmonary diseases such as COPD and asthma.

Long term impact of sulfur mustard exposure on peripheral blood mononuclear subpopulations--Sardasht-Iran Cohort Study (SICS).

The most important long-term morbidity problem of sulfur mustard (SM) toxicity is pulmonary complications but the pathogenesis of these complications is not clearly understood. This study evaluates the peripheral blood mononuclear sub-sets and their correlation with pulmonary function in SM exposed civilian cases 20 years post-exposure as gathered in the context of the Sardasht-Iran Cohort Study (SICS). Samples were randomly selected from two groups, SM-exposed (n=372) and control (n=128), with the same ethnicity, culture, and demography. Three color flow cytometry was applied for peripheral blood mononuclear sub-population determination. Results indicated a significant decrease in CD45+/CD3+, CD45+/CD3+/CD4+, and an increase in CD3+/CD16+56+ percentages. It was also found that absolute count of NK cells was highly increased in peripheral blood of exposed cases. There was a significant increase in NK cell count of SM exposed group with pulmonary problems as compared to the same group without pulmonary problems (p-value<0.04) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The findings showed a significant negative correlation between absolute numbers of T lymphocyte and FVC % and positive correlation with FEV1/FVC%. The results also demonstrated that absolute numbers of monocytes had a negative correlation with FVC %. We propose that NK and T cells are probably involved in the pathogenesis or immune reactions to the delayed pulmonary complications induced by SM. This hypothesis should be tested in a more severe pulmonary complicated group.

Metastatic breast carcinoma initially diagnosed as pulpal/periapical disease: a case report.

INTRODUCTION: Metastatic tumors to oral cavity and jaws are rare, and mandible is the most commonly involved location. Because the most common jaw symptom is pain, these lesions could be misdiagnosed as pathologic entities with dental origin. In this article a case of metastatic breast carcinoma initially diagnosed as pulpal/periapical disease is presented and discussed. METHODS: A 40-year-old female patient was referred to our department with vague pain in right mandibular area. Clinical and radiographic examinations were performed, leading to the initial diagnosis. Patient's medical history was reevaluated, and an incisional biopsy was performed to confirm the final diagnosis. RESULTS: Regarding the initial signs and symptoms, a pulpal/periapical inflammatory process was considered in the differential diagnosis. Because lip paresthesia was also noted, a more aggressive process was suspected. Patient's medical records and histopathologic slides were requested and reviewed carefully. The diagnosis of metastatic breast carcinoma was confirmed by comparing the histopathologic findings of the jaw lesion with previous slides of the breast. CONCLUSIONS: Despite their rarity, metastatic tumors should be considered in the differential diagnosis of inflammatory and reactive lesions of the jaws. These lesions might be diagnosed first by the patient's dentist or by the maxillofacial surgeon. This case emphasized the importance of a complete and careful work-up with particular attention to detailed medical history as well as careful clinical and radiographic inspection for unusual signs and symptoms.

Serum levels of GM-CSF 20 years after sulfur mustard exposure: Sardasht-Iran Cohort Study.

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.

Alterations in the serum levels of soluble L, P and E-selectin 20 years after sulfur mustard exposure: Sardasht-Iran Cohort Study.

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.

Sardasht-Iran cohort study of chemical warfare victims: design and methods.

BACKGROUND: Insights into long-term clinical consequences of sulfur mustard have emerged from some investigations but less is known about the basic and molecular mechanisms of these complications. Sardasht-Iran Cohort Study is a comprehensive historical cohort study on Sardasht chemical victims' population which was designed to find out the long-term complications of sulfur mustard exposure and the basic mechanisms underlying clinical manifestations. This paper describes the design and methodology of Sardasht-Iran Cohort Study. METHODS: In Sardasht-Iran Cohort Study, 500 individuals including 372 subjects from Sardasht, as the exposed group, and 128 subjects from Rabat, as the unexposed age-matched control group were evaluated. The exposed group was divided into two groups based on the severity of clinical complications at the time of exposure. Different samples including blood, sputum, saliva, tear, urine, and semen were collected for immunologic, hematologic, biochemical, and other laboratory analysis. Data were gathered from medical records, clinical examinations, laboratory tests, and questionnaires for psychological and lifestyle situations. CONCLUSION: The important distinctions setting this study apart from the previous ones are discussed. The Sardasht-Iran Cohort Study provides important information on various aspects of long-term consequences of sulfur mustard exposure. This database will provide a better position to suggest guidelines for the diagnosis, treatment, and prevention of delayed complications in the patients exposed to sulfur mustard.

Long-term ocular complications of sulfur mustard in the civilian victims of Sardasht, Iran.

Eyes are very sensitive to sulfur mustard (SM) gas because they have wet surfaces. The severity of ocular damage is related to the dose and duration of exposure to SM, and recovery may take up to several years after the exposure. We conducted a large cohort study to evaluate the ocular signs and symptoms of 367 chemical war victims in Sardasht City, Iran, 20 years after their exposure to mustard gas. The results of these chemical war victims (i.e., the cases) were compared with the results for 128 unaffected civilians (i.e., the controls). Photophobia was the most significant symptom in the cases (36.8%) (compared with 20.3% in the controls) (p < or = .001). Ocular surface discomfort (burning, itching, and redness) was the second most significant symptom in the cases (29.2%) (compared with 19.5% in the controls) (p = .034). Other symptoms such as foreign-body sensation, tearing, pain, blurring of vision, and dry eye sensation were not significantly different between the 2 groups. In the slit-lamp findings, bulbar conjunctival abnormality was the most significant sign in the cases (9.3%) (compared with 1.6% in the controls) (p = .004). Limbal tissue changes were the second most significant sign in the cases (3.0%) (compared with 0.0% in the controls) (p = .048). Other slit-lamp findings related to tearing and abnormalities in the lids and cornea were not significantly different between the 2 groups. Our findings in the present study showed that photophobia and ocular surface discomfort (burning, itching, and redness) were the most significant symptoms. In addition, bulbar conjunctival abnormalities and limbal tissue changes were the most significant signs among the sulfur mustard chemical war victims.