Publications by authors named "Tooba Ghazanfari"

98 Publications

Interpretation of Hematological, Biochemical, and Immunological Findings of COVID-19 Disease: Biomarkers Associated with Severity and Mortality.

Iran J Allergy Asthma Immunol 2021 Feb 11;20(1):46-66. Epub 2021 Feb 11.

Department of Biostatistics and Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spread rapidly all over the world in late 2019 and caused critical illness and death in some infected patients. This study aimed at examining several laboratory factors, especially inflammatory and immunological mediators, to identify severity and mortality associated biomarkers. Ninety-three hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) were classified based on disease severity. The levels of biochemical, hematological, immunological, and inflammatory mediators were assessed, and their association with severity and mortality were evaluated. Hospitalized patients were mostly men (77.4%) with an average (standard deviation) age of 59.14 (14.81) years. The mortality rate was significantly higher in critical patients (85.7%). Increased serum levels of blood sugar, urea, creatinine, uric acid, phosphorus, total bilirubin, serum glutamic-oxaloacetic transaminase, serum glutamic-oxaloacetic transaminase, lactic dehydrogenase, C-reactive protein, ferritin, and procalcitonin were significantly prevalent (p=0.002, p<0.001, p<0.001, p=0.014, p=0.047, p=0.003, p<0.001, p<0.001, p<0.001, p<0.001, P<0.001, and p<0.001, respectively) in COVID-19 patients. Decreased red blood cell, hemoglobin, and hematocrit were significantly prevalent among COVID-19 patients than healthy control subjects (p<0.001 for all). Troponin-I, interleukin-6, neutrophil/lymphocyte ratio (NLR), procalcitonin, and D-dimer showed a significant association with the mortality of patients with specificity and sensitivity more than 60%. Age, sex, underlying diseases, blood oxygen pressure, complete blood count along with C-reactive protein, lactic dehydrogenase, procalcitonin, D-dimer, and interleukin-6 evaluation help to predict the severity and required management for COVID-19 patients. Further investigations are highly recommended in a larger cohort study for validation of the present findings.
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http://dx.doi.org/10.18502/ijaai.v20i1.5412DOI Listing
February 2021

The Effects of Particulate Matter on C57BL/6 Peritoneal and Alveolar Macrophages.

Iran J Allergy Asthma Immunol 2020 Dec 19;19(6):647-659. Epub 2020 Dec 19.

Department of Immunology, Medicine Faculty, Shahid Beheshti University of Medical Science, Tehran, Iran.

The presence of ambient particulate matter (PM) poses more dangers to human health than that of other common air pollutants such as Carbon dioxide (Co2) and ozone.  Epidemiologic studies show a direct correlation between PM and the risk of respiratory and cardiovascular diseases. The immune system seems to play a critical role in the process of these diseases. The main goal of this study was to investigate the effect of Tehran particulate matter in two aerodynamic diameters (PM2.5 and PM10) on alveolar macrophages (AM) from C57/BL6 mice. To evaluate the inflammatory effects of PMs, cultured alveolar, and peritoneal macrophages were treated with PM2.5 and PM10 (concentrations of 5 µg/mL and 10 µg/mL). Tumor necrosis factor-alpha (TNF-α) and IL-10 (representatives of inflammatory and anti-inflammatory cytokines, respectively) were assessed in the culture supernatant by ELISA. Expression of arginase and inducible nitric oxide synthase (iNOS) genes was carried out by quantitative real-time PCR. Different functional types of cultured alveolar macrophages (M1, M2) were also determined in this study. Our results suggest that PM2.5 induces M1 inflammatory phenotype in comparison with PM10. We found Also, an increase in TNF-α and M1-related gene expression (iNOS), as well as a decrease in both IL-10 and M2 phenotype genes (Arginase). Moreover, a reduction in phagocytic capacity and increased apoptosis function of macrophage cells were detected. PM2.5 as a major component in hydrocarbons has a considerable effect on polarizing the alveolar macrophages to an inflammatory phenotype and eliciting lung inflammation in mice.
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http://dx.doi.org/10.18502/ijaai.v19i6.4934DOI Listing
December 2020

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.

Neurobiol Aging 2021 03 5;99:102.e1-102.e10. Epub 2020 Oct 5.

School of Biology, College of Science, University of Tehran, Tehran, Iran. Electronic address:

Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.021DOI Listing
March 2021

Indicated and non-indicated antibiotic administration during pregnancy and its effect on pregnancy outcomes: Role of inflammation.

Int Immunopharmacol 2020 Dec 14;89(Pt B):107081. Epub 2020 Oct 14.

Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran; Breastfeeding Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

The objective of this study was to compare the release of endotoxin and pro-inflammatory cytokines as well as pregnancy outcomes after antibiotic exposure in healthy and bacterial infected pregnant rats. Thirty female Wistar pregnant rats were divided into five groups. Group A considered as control and received intraperitoneal saline 0.9% on 17th day of gestation or DG) and groups B and C treated with 20 mg/kg/day intravenous ceftriaxone and ceftazidime, respectively (DG: 18-20). Groups D and E received intraperitoneal E. coli and LPS on 17th DG respectively. Also, groups F and G received the same treatment as group D but they treated with the exact antibiotics mentioned for groups B and C (same dose and duration). Pregnancy outcomes as well as maternal sera levels of endotoxin, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 were assessed using enzyme-linked immunosorbent assay. It was shown that group B had a higher IL-1β (P = 0.003) and TNF-α (P = 0.003) levels compared to the controls (CTC). Group C expressed a lower gestational duration (P = 0.007) as well as higher IL-6 (P = 0.025) and TNF-α (P < 0.001) levels CTC. Interestingly, both group B (P = 0.021) and C (P < 0.001) had a higher rate of endotoxin release CTC. Moreover, in group C, IL-6 (P < 0.0001 and r = -0.941) had a significant correlation with gestational duration. As the results showed, antibiotic administration in non-indication condition seems to be associated with significantly higher production of endotoxin and inflammatory cytokines which increase the risk of poor pregnancy outcomes.
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http://dx.doi.org/10.1016/j.intimp.2020.107081DOI Listing
December 2020

Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.

Eur Respir J 2020 12 24;56(6). Epub 2020 Dec 24.

Rheumatology Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

Introduction: There are no determined treatment agents for severe COVID-19. It is suggested that methylprednisolone, as an immunosuppressive treatment, can reduce the inflammation of the respiratory system in COVID-19 patients.

Methods: We conducted a single-blind, randomised controlled clinical trial involving severe hospitalised patients with confirmed COVID-19 at the early pulmonary phase of the illness in Iran. The patients were randomly allocated in a 1:1 ratio by the block randomisation method to receive standard care with methylprednisolone pulse (intravenous injection, 250 mg·day for 3 days) or standard care alone. The study end-point was the time of clinical improvement or death, whichever came first. Primary and safety analysis was done in the intention-to-treat (ITT) population.

Results: 68 eligible patients underwent randomisation (34 patients in each group) from April 20, 2020 to June 20, 2020. In the standard care group, six patients received corticosteroids by the attending physician before the treatment and were excluded from the overall analysis. The percentage of improved patients was higher in the methylprednisolone group than in the standard care group (94.1% 57.1%) and the mortality rate was significantly lower in the methylprednisolone group (5.9% 42.9%; p<0.001). We demonstrated that patients in the methylprednisolone group had a significantly increased survival time compared with patients in the standard care group (log-rank test: p<0.001; hazard ratio 0.293, 95% CI 0.154-0.556). Two patients (5.8%) in the methylprednisolone group and two patients (7.1%) in the standard care group showed severe adverse events between initiation of treatment and the end of the study.

Conclusions: Our results suggest that methylprednisolone pulse could be an efficient therapeutic agent for hospitalised severe COVID-19 patients at the pulmonary phase.
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http://dx.doi.org/10.1183/13993003.02808-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758541PMC
December 2020

Two dimensional proteomic analysis of serum shows immunological proteins exclusively expressed in sulfur mustard exposed patients with long term pulmonary complications.

Int Immunopharmacol 2020 Nov 24;88:106857. Epub 2020 Aug 24.

Immunoregulation Research Center, Shahed University, Tehran, Iran, Department of Immunology, Shahed University, Tehran, Iran, Department of Immunology, Shahed University, Tehran 3319118651, Iran. Electronic address:

Background: Despite more than 30 years after utilization of sulfur mustard or bis (2-chloroethyl) sulfide (SM) by Iraqi troops against Iranian military members and civilians, there are a lot of reported delayed complications for the exposed people. Nonetheless, the molecular mechanism of action from this chemical warfare agent is not recognized yet.

Material And Method: In this study, we employed two dimensional gel electrophoresis (2DE) technique to investigate the serum proteins from chemical exposed people compared to non-exposed individuals to provide an inside into molecular mechanism of this chemical agent. Each group was divided into two subgroups including individuals with, and without respiratory complications. For each group, 10 individuals were included after informed consent.

Result: The results showed protein spots, which were exclusively/mainly expressed in chemical exposed patients with complications, including T cell receptor alpha, and hematopoietic cell signal transducer. Also there were protein spots that were expressed only in all exposed groups (with and without complications). On the other hand, we could identify protein spots that were exclusively expressed/altered only in non-exposed group with complications including Pre T-cell antigen receptor, CD40 ligand, and multidrug and toxin extrusion proteins.

Conclusion: Our investigation could result in identification of proteins that are associated to chemical exposure, as well as those specific for respiratory complications irrespective of chemical exposure. These candidate proteins can be used as biomarker, as well as a base for understanding the molecular mechanism of this chemical agent.
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http://dx.doi.org/10.1016/j.intimp.2020.106857DOI Listing
November 2020

A review of Sulfur Mustard-induced pulmonary immunopathology: An Alveolar Macrophage Approach.

Toxicol Lett 2020 Oct 3;333:115-129. Epub 2020 Aug 3.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury, the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as well as its maintenance, resolution, and repair. Importantly, macrophages can serve as either pro-inflammatory or anti-inflammatory populations depending on the present conditions at any pathological stage. Different characteristics of macrophages, including their differentiation, phenotypic, and functional properties, as well as interactions with other cell populations determine the outcomes of lung diseases and the extent of long- or short-term pulmonary damage induced by SM. In this paper, we summarize the current state of knowledge regarding the role of alveolar macrophages and their mediators in the pathogenesis of SM in pulmonary injury. Investigating the specific cells and mechanisms involved in SM-lung injury may be useful in finding new target opportunities for treatment of this injury.
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http://dx.doi.org/10.1016/j.toxlet.2020.07.035DOI Listing
October 2020

Immunoinformatics design of multivalent chimeric vaccine for modulation of the immune system in Pseudomonas aeruginosa infection.

Infect Genet Evol 2020 11 16;85:104462. Epub 2020 Jul 16.

Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran.

Increasing in drug-resistant Pseudomonas aeruginosa and high mortality and morbidity rate have become a health challenge worldwide; therefore, developing the novel therapeutic strategies such as immunogenic vaccine candidate are required. Despite a substantial research effort, the future of immunization against P. aeruginosa due to failure in covering two separate stages of infection, and furthermore, inducing ineffective type of immune response, still remains controversial. In this study, immunoinformatics approach was utilized to design multivalent chimeric vaccine from both stages of infection containing Lectin, HIV TAT peptide, N-terminal fragment of exotoxin A and Epi8 of outer membrane protein F (OprF) with hydrophobic linkers which have a high density of B-cell, T Lymphocytes (HTL), T Lymphocytes (CTL), and IFN-γ epitopes. The physicochemical properties, antigenicity, and allergenicity for designed vaccine were analyzed. 3D model generation and refinement further validation of the final vaccine were followed by computational docking with molecular dynamics analyses that demonstrated high- affinity interaction between vaccine and TLR-4. Finally, designed vaccine was in silico cloned in pET22b. We have expected that the designed vaccine able to elucidate innate, humoral and cellular innate immune responses and control the interaction of P. aeruginosa with host and maybe overcome to P. aeruginosa vaccines drawback.
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http://dx.doi.org/10.1016/j.meegid.2020.104462DOI Listing
November 2020

Anti-inflammatory Effects of Matricaria chamomilla Extracts on BALB/c Mice Macrophages and Lymphocytes.

Iran J Allergy Asthma Immunol 2020 May 17;19(S1):63-73. Epub 2020 May 17.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Matricaria chamomilla (MC) was shown to have anti-inflammatory effects. Flavonoids are major groups of MC immunomodulators. The anti-inflammatory effects of apigenin as an MC flavonoid has already been demonstrated. In this study, we aimed to report the amount of this compound by liquid chromatography-mass spectrometry (LC-MS) and measuring the total phenol content (TPC) in both the MC aqueous and alcoholic extracts. We also investigated the MC aqueous and ethanolic extracts effect on BALB/c separated macrophages and lymphocytes cell viability and macrophage nitric oxide production. Interferon-γ and interleukin-10 secretion were also measured in lymphocytes. We found that the amount of apigenin was 0.078 and 0.25 mg/g per each of dry aqueous and alcoholic extracts, respectively. Also, the total phenol content was 2.99% in aqueous and 3.95% in alcoholic extracts. BALB/c separated macrophages cell viability significantly increased when treated with the MC aqueous extract but decreased when treated by the MC alcoholic extract in the presence of lipopolysaccharide. Also, the amount of nitric oxide production by macrophages and BALB/c separated lymphocytes cell viability in treatment with aqueous and alcoholic extracts significantly decreased. Interferon-γ increased, and interleukin-10 decreased in lymphocytes treated with the MC aqueous extract, which may suggest Th1 polarization. There was no significant change in the interferon-γ level in lymphocytes when treated with the MC alcoholic extract, but the level of IL-10 increased in these cells. Altogether, besides the anti-inflammatory effect of MC extracts, we found MC aqueous extract effects as disrupting Th1/Th2 balance to Th1 upregulation. Overall, the anti-inflammatory effect of the MC alcoholic extract was higher than the MC aqueous extract.
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http://dx.doi.org/10.18502/ijaai.v19i(s1.r1).2862DOI Listing
May 2020

Impairment of endothelial progenitor cells function in patient with mustard gas intoxication.

Inhal Toxicol 2020 02 20;32(3):131-140. Epub 2020 Apr 20.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Sulfur mustard (SM), also known as mustard gas, was first widely used in the Iraq-Iran. After SM exposure, the most prominent clinical signs are the development of extensive non-healing skin wounds and pulmonary signs, persisting over long time. Since the most frequent complications in SM-intoxicated patients are respiratory and dermatologic lesions, and with respect to the important role of endothelial progenitor cells (EPCs) in the pathophysiology of these lesion, we conducted this study to recognize the potential effects of SM on biological features of EPCs in patients exposed with this gas. In this study, 30 patients with the history of SM exposure during the Iran-Iraq war (1984-1988), 27 patients with pulmonary signs with no history of SM exposure and 20 healthy participants were included. Cell population and function of EPCs were assessed 4 years post-exposure. For this purpose, circulating EPCs (cEPCs) were harvested and cultivated, then the biological features of these cells, including migratory, proliferative, and tubulogenic activities were analyzed. We also measured serum antioxidants levels and mRNA levels of some proangiogenic factors in EPCs from SM-intoxicated patients. Our results showed lesser number of cEPCs in patients exposed with SM, which was associated with decreased proliferative, migratory, and tubulogenic activity of these cells. Also, we found the lesser serum activity of SOD, GPX and MDA in the SM group than in the healthy control group. SM exposure resulted in decreased proliferation and migration of EPCs, which was associated with decreased tubule formation and angiogenic factors.
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http://dx.doi.org/10.1080/08958378.2020.1755396DOI Listing
February 2020

Evaluation of the LTBP1 and Smad6 Genes Expression in Lung Tissue of Sulfur Mustard-exposed Individuals with Long-term Pulmonary Complications.

Iran J Allergy Asthma Immunol 2019 Oct 23;18(5):473-478. Epub 2019 Oct 23.

Department of Immunology, Shahed University, Tehran, Iran AND Immunoregulation Research Center, Shahed University, Tehran, Iran.

Sulfur mustard (SM) exposure injures different organs such as the lungs and leads to short and long term complications Transforming growth factor beta (TGF-β) has the main role in altering fibroblast activities linked to airways remodeling. Latency TGF beta binding proteins 1 (LTBP1 facilitates localization of TGF-β in the extracellular matrix. Mothers against decapentaplegic homolog 6 (Smad6) negatively regulates TGF-β signaling, thus establishing a main negative feedback loop. In this study, we investigated the expression of LTBP1 and Smad6 in the lung tissues of SM-exposed and control individuals. Lung formalin-fixed paraffin-embedded (FFPE) blocks of SM-exposed (20 samples) and control groups (20 samples) were collected from archival pathology department of several general hospitals. The total mRNA of lung FFPE tissues was extracted. Quality of the extracted mRNA was evaluated by an Agilent Bio analyzer and RNA was quantified using a Nano Drop. LTBP1 and Smad6 expression levels were evaluated by real-time PCR. LTBP1 expression levels did not change between the two groups (p=0.626), howeverSmad6 expression levels were significantly higher (2.6 fold) in SM-exposed individuals compared to the control group (p=0.001). Our results revealed that Smad6 may be involved in lung tissue remodeling process in SM-exposed patients. Smad6 regulates fibrotic alterations in lung tissue and its function as negative feedback mechanisms in TGF-β.
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http://dx.doi.org/10.18502/ijaai.v18i5.1895DOI Listing
October 2019

Delayed effects of sulfur mustard on autophagy suppression in chemically-injured lung tissue.

Int Immunopharmacol 2020 Mar 15;80:105896. Epub 2020 Jan 15.

Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.

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.
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http://dx.doi.org/10.1016/j.intimp.2019.105896DOI Listing
March 2020

Pharmacological and biochemical properties of (L.) Roscoe ex Sm. and its therapeutic efficacy on osteoarthritis of knee.

J Family Med Prim Care 2019 Dec 10;8(12):3798-3807. Epub 2019 Dec 10.

Department of Health and Social Medicine, Shahed University, Tehran, Iran.

Osteoarthritis (OA) as the most frequent form of knee arthritis is one of the most annoying complications amongst old peoples. There are different pharmacological and non-pharmacological remedies which could be applied for treatment of knee OA. It's while, significant side effects mostly in patients who are older are the dangerous limiting factors. Integrative, supplementary, traditional remedies have been applied from long time ago in treatment of such chronic diseases like OA. Various topical and oral remedies have been presented in treatment of OA worldwide. In spite of the fact there are multiple remedies for reduction symptoms of patients who suffer from disorders and related inabilities which could enhance their life quality. Remedies which have been applied for a long time for treatment of OA have newly discovered to induce injury to some patients. On the other side, additional knowledge about alternative and supplementary remedies is a main way for enhancing health of patients who suffer from OA disorders. Zingiber zerumbet (Z. zerumbeton) is a kind of herb of the ginger family and is a natural compound with various biomedical characteristics like anti-proliferative, anti-inflammatory, and antioxidant effect. However, Z. zerumbet could be applied for reduction of OA symptoms because of its circulatory stimulant and anti-inflammatory effects. Anyway, up to now there is not any methodical literature review for evaluating the Z. zerumbet clinical effectiveness productiveness in treatment of OA. The main aim of the current study is to review scientific resources around therapeutic effectiveness of Zingiber zerumbet in treatment of adverse symptoms of OA disorder.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_594_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924210PMC
December 2019

Alteration in serum levels of immunoglobulins in seriously eye-injured long-term following sulfur-mustard exposure.

Int Immunopharmacol 2020 Mar 29;80:105895. Epub 2019 Nov 29.

Department of Biostatistics and Social Medicine, Zanjan University of Medical Sciences, Zanjan 4515613191, Iran.

Introduction: Sulfur mustard (SM) is a potent toxic agent that cause local and systemic changes in the human body such as dysregulation of the immunological system. This gas affects different organs such as lungs, skin, eyes and the gastrointestinal tract.

Methods: 128 veterans with SM-induced eye injuries were examined and compared to 31 gender- and age-matched healthy controls. Serum levels of IgM, IgE, IgA, IgG, and IgG subclasses were measured using ELISA method.

Results: There was no significant difference in IgM level between two groups with abnormal and normal ocular conditions except for those having bulbar conjunctiva-limbal ischemia and bulbar conjunctiva-hyperemia abnormalities. There were not significant difference in IgA, IgE, and IgG levels between two groups with and without ocular problem also between study groups. IgG1 level in some ocular abnormalities were significantly lower than the healthy control groups. IgG2 level in SM-exposed participants with stromal abnormality was higher in the SM-exposed groups without this problem. IgG2 levels in the exposed group with some ocular problems were significantly increased compared with control. IgG3 level in all patients did not reveal any significant changes compared with the controls except the fundus abnormality. IgG4 level was not significantly different between two groups with normal and abnormal ocular conditions. Nonetheless, IgG4 level in the exposed participants with some ocular abnormalities significantly increased compared with the controls.

Conclusion: The results showed SM exposure could alter immunoglobulins level compared with healthy controls and the changes of IgG2 and IgG1 levels were associated with some ocular problems.
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http://dx.doi.org/10.1016/j.intimp.2019.105895DOI Listing
March 2020

The immunomodulatory effects of mesenchymal stem cells on long term pulmonary complications in an animal model exposed to a sulfur mustard analog.

Int Immunopharmacol 2020 Mar 22;80:105879. Epub 2019 Nov 22.

Immunoregulation Research Center, Shahed University, Tehran, Iran; Department of Immunology, Shahed University, Tehran, Iran. Electronic address:

Introduction: Sulfur Mustard (SM) is one of the most lethal chemicals with major complications manifested in the lungs. Although the pathogenesis behind SM-induced lung injury still remains poorly understood, prolonged activation and the imbalance of two major macrophage populations (M1 and M2) have been suggested to be involved. Here, we tried to investigate the effectiveness of adipose-derived mesenchymal stem cells (AD-MSC) on long-term lesions induced by CEES, an SM analog. The modulation of pulmonary immune cells and alveolar macrophage phenotype alteration was studied in the animal model used.

Methods: Histopathological changes were investigated in the lungs and analysis of surface markers of alveolar macrophages as well as their cytokine expression in the BAL fluid was carried out by flow cytometry and ELISA, respectively.

Results: Treatment of mice with AD-MSC after intraperitoneal administration of CEES (10 mg/kg) reduces progressive histopathologic changes in the lung. Flow cytometric analysis of isolated alveolar macrophages in the bronchoalveolar lavage showed that the accumulation of both M1 and M2 macrophages in response to CEES was reduced by MSC administration. AD-MSCs caused a marked reduction in the CD86- and CD206-expressing macrophages compared to the untreated groups. The modulating effect of AD-MSCs in the M1-subset was much more significant compared to M2. These findings suggest that AD-MSCs understand their environment and restore the balance in disorders associated with Th1 or Th2 imbalance. Our results indicate that MSCs may represent an effective approach to repair lung injury induced by mustards.
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http://dx.doi.org/10.1016/j.intimp.2019.105879DOI Listing
March 2020

SP-A and TLR4 localization in lung tissue of SM-exposed patients.

Int Immunopharmacol 2020 Mar 11;80:105936. Epub 2019 Nov 11.

Immunoregulation Research Center, Shahed University, Tehran, Iran; Department of Immunology, Shahed University, Tehran, Iran. Electronic address:

Introduction: Long-term pulmonary complications are one of the major long-term consequences of sulfur mustard (SM) exposure. Toll-like receptor 4 (TLR4) involves in the pathogenesis of several pulmonary disorders. Surfactant protein-A (SP-A) regulates LPS-induced TLR4 localization and activation responses. However, the intensity and significance of TLR4 and SP-A expression by lung cells in SM-exposed patients is not clear.

Methods: The gene expression of TLR4 (through real-time PCR) and TLR4 and SP-A positive cells and alveolar type II cells, as SP-A producers, (using IHC) were assessed in formalin fixed paraffin embedded (FFPE) specimens from SM-exposed (n = 17), and non-SM exposed individuals (n = 12).

Results: TLR4 gene expression did not change between study groups. However, its cell surface presentation was significantly reduced in SM-exposed patients and particularly in which with constrictive bronchiolitis compared with the control group (P < 0.001 and P = 0.002, respectively). Frequency of alveolar type II cells was lower in the case group rather than the control group while the number of SP-A positive cells did not alter.

Conclusions: These findings suggest that reduced TLR4 cell surface presentation may have anti-inflammatory function and SP-A may have a critical role in regulation of inflammatory responses in SM-exposed patients. Further investigation on other possible mechanisms involved in TLR4 internalization maybe help to illustrate the modulatory or inflammatory activity of TLR4 in these patients.
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http://dx.doi.org/10.1016/j.intimp.2019.105936DOI Listing
March 2020

Alteration in inflammatory mediators in seriously eye-injured war veterans, long-term after sulfur mustard exposure.

Int Immunopharmacol 2020 Mar 1;80:105897. Epub 2019 Nov 1.

Immunoregulation Research Center, Shahed University, Tehran 3319118651, Iran; Department of Immunology, Shahed University, Tehran 3319118651, Iran. Electronic address:

Background: Sulfur mustard (SM) exposure produces extensive systemic and ocular adverse effects on the victims. One of the most important effects is immunological insults that can lead to other organ damages, including the eyes.

Methods: In this descriptive study, 128 SM-exposed veterans with severe eye injury were compared with 31 healthy controls. Tear levels of tumor necrosis factor (TNF)-α and serum concentrations of interleukin (IL)-1α, IL-1β, IL1Ra, IL-6, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and Fas Ligand (FasL) were compared between the two groups.

Results: Meibomian gland dysfunction (MGD); tear breakup time (TBUT < 10″); and conjunctival, limbal, and corneal abnormalities were more frequent among the cases (MS-exposed veterans) than the controls. Ocular involvement was mild in 14.8%, moderate in 24.2%, and severe in 60.9% of the cases. Serum levels of IL-1α and FasL were significantly higher among the cases than among the controls (P < 0.001 and P = 0.037, respectively). Also, a significant decrease was observed in serum and tear levels of TNF-α in the cases as compared with controls (P < 0.001, P < 0.001, respectively). Serum levels of FasL were significantly higher in cases with severe ocular involvement than in the controls (P = 0.03). Nonetheless, serum levels of IL-1β, IL-1Ra, IL-1α/IL-1Ra, and IL-6 were not significantly different between the two groups.

Conclusion: Serum levels of IL-1α and FasL may cause different ocular surface abnormalities in SM-exposed patients. Lower tear TNF-α concentration may be due to lower serum levels of this cytokine in these patients.
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http://dx.doi.org/10.1016/j.intimp.2019.105897DOI Listing
March 2020

Tear and serum MMP-9 and serum TIMPs levels in the severe sulfur mustard eye injured exposed patients.

Int Immunopharmacol 2019 Dec 31;77:105812. Epub 2019 Oct 31.

Department of Immunology, Shahed University, Tehran, Iran; Immunoregulation Research Center, Shahed University, Tehran, Iran. Electronic address:

Introduction: Sulfur mustard (SM) intoxication produces local and systemic changes in the human body. In this study, the relationship between tear and serum matrix metalloproteinase (MMP)-9 and serum tissue inhibitors of metalloproteinases (TIMPs) are assessed in serious eye-injured SM-exposed casualties.

Methods: A group of 128 SM-exposed patients with serious ocular injuries in three subgroups (19 mild, 31 moderate, and 78 severe cases) is compared with 31 healthy controls. Tear and ocular status and serum MMPs and MMP-9/TIMPs complex levels were evaluated using enzyme-linked immunosorbent assay (ELISA).

Results: Serum level of MMP-9 was significantly higher in the SM-exposed group compared to the control group (P = 0.009). Mean serum MMP-9 level in the SM-exposed group with ocular abnormalities was significantly higher than that in the SM-exposed group without ocular abnormalities. SM-exposed people with corneal calcification had significantly higher serum MMP-9/TIMP-1 level compared to the SM-exposed ones without this problem (P = 0.045). The SM-exposed group with severe ocular injuries had significantly higher MMP-9/TIMP-1 than the controls (P = 0.046). The SM-exposed group had significantly lower levels of MMP-9/TIMP-4 complex than the controls (P < 0.001). The SM-exposed group with tear meniscus and fundus abnormality had significantly higher MMP-9/TIMP-4 levels than the SM-exposed group without these problems (P = 0.009 and P = 0.020).

Conclusion: Serum MMP-9 level had increased in SM-exposed groups with ocular problems, while TIMP-1 and TIMP-2 levels had remained unchanged. Serum TIMP-4 drastically decreased in SM-exposed group, which clearly explains the severity of the systemic and ocular damages.
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http://dx.doi.org/10.1016/j.intimp.2019.105812DOI Listing
December 2019

Tear and serum interleukin-8 and serum CX3CL1, CCL2 and CCL5 in sulfur mustard eye-exposed patients.

Int Immunopharmacol 2019 Dec 24;77:105844. Epub 2019 Oct 24.

Department of Immunology, School of Medical Sciences, Tarbiat Modares University, 14115111 Tehran, Iran. Electronic address:

Background: The serum and tear levels of four inflammatory chemokines were evaluated in sulfur mustard (SM)-exposed with serious ocular problems.

Materials And Methods: In this study, 128 SM-exposed patients and 31 healthy control participants participated. Tear and serum levels of chemokines were assessed by ELISA method.

Results: There was no significant difference in the serum level of IL-8/CXCL8, CX3CL1/fractalkine, CCL2/MCP-1, and CCL5/RANTES between all SM-exposed subjects and control groups. The tear level of IL-8 in the SM-exposed group was lower than the control group, but the difference was not significant. In the SM-exposed group with the abnormalities in tear breakup time (TBUT) test, fundus and pannus formation were significantly higher than SM-exposed patients without these problems. CX3CL1 levels have significantly increased in SM-exposed group with blepharitis, pterygium, and conjunctival pigmentation as compared with the control group. Besides, significantly higher levels of CX3CL1 were observed in SM-exposed group with or without bulbar conjunctival hyperemia and abnormal vessels a well as with fundus abnormality compared to the control group. Only, SM-exposed group with subconjunctival fibrosis had significantly lower levels of CCL5 than SM-exposed group without this problem.

Conclusion: The higher level of CX3CL1 and consistent levels of IL-8/CXCL8, MCP-1/CCL2, and RANTES/CCL5 in SM-exposed individuals may indicate an anti-inflammatory response against the destructive effects of SM gas. High tear level of IL-8/CXCL8 reflects the severity of ocular surface abnormalities, yet significantly low tear level found in mild SM-exposed subgroup compared with the control group. The lower levels of CX3CL1 and RANTES/CCL5 may represent the different pathophysiology which requires further studies.
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http://dx.doi.org/10.1016/j.intimp.2019.105844DOI Listing
December 2019

Serum and sputum levels of IL-17, IL-21, TNFα and mRNA expression of IL-17 in sulfur mustard lung tissue with long term pulmonary complications (28 years after sulfur mustard exposure).

Int Immunopharmacol 2019 Nov 17;76:105828. Epub 2019 Oct 17.

Immunoregulation Research Center, Shahed University, Tehran, Iran. Electronic address:

Background: Iranian veterans who had exposed to Sulfur Mustard (SM) suffer from long term complications such as Chronic Obstructive Pulmonary Disease (COPD) and bronchiolitis obliterate (BO). Th17 cells product IL-17A, IL-17F, IL-21, and IL-22. They have important roles in chronic inflammatory diseases. Also, TNFα has a major part in pathobiological processes of COPD. In this study, we evaluate the serum and sputum levels of IL-17, IL-21, TNF-α, and mRNA expression of IL-17 in the lung tissue of the patients 28 years after SM exposure.

Material And Method: The cytokine levels of IL-17, IL-21 and TNFα were measured by ELISA method in serum and sputum of 455 SM-exposed and 123 unexposed people participated in Sardasht-Iran Cohort Study (SICS) of chemical victims. The mRNA expression of IL-17 was evaluated with qRT-PCR in lung biopsies (SM-exposed =52, control =33). Analyses of all data were accomplished with the SPSS software with P value ≤05.

Result: The results show the sputum level of IL-17 in the exposed group decreased significantly compared to control group (P = 0.007) and Veterans and Martyrs Affair Foundation (VMAF) assessment was significantly lower in abnormal/exposed than normal/exposed group (P = 0.042). There were no significant differences between control and exposed groups in serum level of IL-17; also serum and sputum levels of IL-21, TNF-α, and IL-17 mRNA expression.

Conclusion: Conclusively, The IL-17 level decreased in the exposed group. This decline could cause by mutation on transcription factors like Signal transducer and activator of transcription 3 gene (STAT3) or CCL20 as a chemokine.
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http://dx.doi.org/10.1016/j.intimp.2019.105828DOI Listing
November 2019

Angiogenesis modulatory factors in subjects with chronic ocular complications of Sulfur Mustard exposure: A case-control study.

Int Immunopharmacol 2019 Nov 16;76:105843. Epub 2019 Oct 16.

Immunoregulation Research Center, Shahed University, Tehran 3319118651, Iran. Electronic address:

Background: Chronic ocular complications of Sulfur Mustard (SM) exposure leads to severe ocular morbidity during time. The aim of this study was to compare serum levels of Interleukin 17 (IL-17), IL-12, vascular endothelial growth factor (VEGF)-C, VEGF-D and nitric oxide (NO) in SM-exposed patients versus the control group and to measure tear concentration of VEGF-C only in the SM-exposed group.

Methods: In this prospective case control, 128 SM-exposed patients and 31 healthy control subjects were included. In the case group ocular manifestations were classified to three subgroups of mild (19 cases), moderate (31 cases) and severe (78 cases) forms of disease. Serum levels of IL-17, IL-12, NO, VEGF-C and VEGF-D, in all subjects and tear concentration of VEGF-C in SM-exposed group was evaluated.

Results: All subjects were male and mean ± standard deviation (SD) of age in the case and control groups were 44.9 ± 8.8 and 40.9 ± 10.1 years, respectively. Except for significantly lower serum level of IL-17 (p < 0.001) and NO (p = 0.003), other values were not significantly different. The tear concentration of VEGF-C and serum level of IL-12 were not different between subgroups in the SM-exposed group, yet were significantly lower among those with abnormally dilated and tortuous conjunctival vessels and corneal pannus, respectively (p = 0.01, p = 0.015).

Conclusions: Exposure to SM significantly reduced serum level of IL-17 and NO in the delayed phase, yet did not influence VEGF-C; VEGF-D or IL-12.
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http://dx.doi.org/10.1016/j.intimp.2019.105843DOI Listing
November 2019

Serum Concentration of Thyroid Hormones Long-Term after Sulfur Mustard Exposure.

Iran J Public Health 2019 May;48(5):949-955

Endocrine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Despite several reports on the clinical manifestations of sulfur mustard (SM) intoxication, there is no study on serum concentrations of thyroid hormones long-term after SM exposure. In this study, the changes in thyroid functioning parameters 20 yr after SM exposure were evaluated.

Methods: This study is a part of a larger historical cohort study conducted in 2007 following 20 years of the exposure to SM, called Sardasht-Iran cohort study (SICS). We (SICS) comprised an SM-exposed group from Sardasht City, West Azerbaijan Province, Iran (n=169 as hospitalized group and n=203 as non-hospitalized exposed group); and control participants were selected from Rabat, a town near Sardasht (n=126). Peripheral blood samples were taken in fasting state and then the sera were separated. T4, T3, TSH, antithyroglobulin (anti-Tg), and antithyroid peroxidase (anti-TPO) concentrations in the sera were measured by the ELISA method.

Results: The mean of T3 concentration was significantly higher in the exposed than control group (0.88 ± 0.26 nmol/L vs 0.8 ± 0.25 nmol/L, <0.001). The levels of TSH, T4, and T3up were not significantly different between the exposed and control groups. Thyroglobulin level was significantly higher in the exposed non-hospitalized group (56.07 ± 140.22 μg/L vs 17.66 ± 41.49 μg/L, =0.004), but the level of anti-Tg and anti-TPO showed no significant differences between the two groups.

Conclusion: More studies are needed on the alterations in thyroid hormones, their gene expressions, and mechanisms involved in SM exposure to clarify the causes of these alterations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717423PMC
May 2019

Expression of miR-15b-5p, miR-21-5p, and SMAD7 in Lung Tissue of Sulfur Mustard-exposed Individuals with Long-term Pulmonary Complications.

Iran J Allergy Asthma Immunol 2019 Jun 8;18(3):332-339. Epub 2019 Jun 8.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

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.
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http://dx.doi.org/10.18502/ijaai.v18i3.1126DOI Listing
June 2019

Peripheral blood mononuclear cellular viability and its correlation with long-term pulmonary complications after sulfur mustard exposure.

Int Immunopharmacol 2019 Nov 4;76:105814. Epub 2019 Sep 4.

Immunoregulation Research Center, Shahed University, Tehran, Iran. Electronic address:

Introduction: Sulfur mustard (SM) as a chemical warfare agent has short- and long-term complications on its victims. Complications of exposure to SM depend on the level of contamination. Long-term pulmonary complications are the most serious problems. Recent evidence has shown that absorbed SM can be conducted to other tissues by the bloodstream. In this study, we evaluated the long-term effects of SM on the vital activity of peripheral blood mononuclear cells (PBMCs) in SM-exposed patients with long-term pulmonary complications.

Materials And Methods: Our study samples were 110 patients with long-term pulmonary complications in the SM-exposed group and 109 unexposed individuals in the control group. After clinical examination and pulmonary function tests, the severity of pulmonary complications was classified. Also, the participants' peripheral blood was taken into EDTA-treated Vacutainer tubes. Then, the complete blood count (CBC) was calculated, and PBMCs was purified from whole blood using Ficol-Paque gradient method, finally, the vital activity was assessed by MTT assay.

Result: The vital activity of PBMCs in the SM-exposed group with the mitogen was significantly lower than that in the control group (P = 0.016). Whereas, there was no significant difference in the viability of PBMCs without the mitogen between two groups. Furthermore, hematologic findings indicated that the SM-exposed group had a significant increase in the total count of WBC, neutrophil, MCV, and HCT values but the lymphocyte count and MCHC value were significantly lower than those in the control group.

Conclusion: Exposure to SM even after a long time, can affect hematologic parameters and vital activity of PBMCs.
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http://dx.doi.org/10.1016/j.intimp.2019.105814DOI Listing
November 2019

Alteration in serum levels of ICAM-1 and P-, E- and L-selectins in seriously eye-injured long-term following sulfur-mustard exposure.

Int Immunopharmacol 2019 Nov 31;76:105820. Epub 2019 Aug 31.

Immunoregulation Research Center, Shahed University, Tehran, Iran; Department of Immunology, Shahed University, Tehran, Iran. Electronic address:

Introduction: In this study, the serum levels of soluble intercellular adhesion molecule 1 (ICAM-1), P-, E-, and L-selectins were investigated in seriously eye-injured patients exposed to sulfur mustard (SM).

Material And Methods: A total of 128 individuals with SM-induced serious eye injuries and 31 healthy male controls were included in this study. The serum concentration of soluble forms of adhesion molecules was measured by enzyme-linked immunosorbent assay (ELISA) method.

Result: The serum level of soluble ICAM-1 was significantly higher in the SM-exposed individuals with an abnormality in tear meniscus height, corneal verticillata, and pannus compared with SM-exposed individuals without these abnormalities. There were no significant differences in the level of all three measured selectins between the SM-exposed group and the control groups. SM-exposed individuals with corneal defect had a significantly higher level of soluble E-selectin than SM-exposed individuals without this abnormality. The serum level of soluble P-selectin in the SM-exposed group with limbal abnormality was significantly lower than that in the SM-exposed without this abnormality; also it was significantly higher in SM-exposed group with fundus abnormality compared to that in the control group or SM-exposed group without this abnormality.

Conclusion: The changes in the levels of selectins and ICAM-1 in the SM-exposed group with various ocular abnormalities is a defense mechanism against the toxicity of SM. Further analysis is required to understand the molecular mechanisms of the relationship between adhesion molecules with ocular complications in SM-exposed individuals.
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http://dx.doi.org/10.1016/j.intimp.2019.105820DOI Listing
November 2019

Circulating mesenchymal stem cells in sulfur mustard-exposed patients with long-term pulmonary complications.

Toxicol Lett 2019 Sep 13;312:188-194. Epub 2019 May 13.

Department of Biostatistics and Social Medicine, Zanjan University of Medical Sciences, Zanjan, Islamic Republic of Iran.

Sulfur mustard (SM) is a toxic agent that causes acute and long-term pulmonary complications. Recent evidence has shown the impact of SM on mesenchymal stem cells (MSCs). These cells have a critical role in repairing the damaged tissues. In this study, we evaluated the mobilization of MSCs in SM-exposed patients with long-term pulmonary complications. Fifty-nine SM-injured patients with prolonged pulmonary complications and 20 healthy individuals were included. Patients were classified based on taking drugs, having comorbidities, and severity of respiratory consequence. MSCs with phenotype of CD45-CD44CD29CD105 were evaluated in peripheral blood using flow cytometry. Circulating MSCs were lower in SM-exposed patients compared to the control group (0.93 vs. 2.72 respectively, P = 0.005). No significant difference was observed in the MSC count between patients taking corticosteroids or antibiotics and those patients not taking them. Comorbidities like liver and kidney diseases had changed the count of MSCs in SM-exposed subjects. In addition, the frequency of MSCs did not show any association with the severity of long-term pulmonary complications. In conclusion, SM-exposure causes a decline in the frequency of circulating MSCs in survivors. The lower number of the peripheral MSC population in SM-exposed patients was not affected by taking corticosteroids or antibiotics, but comorbidities are probably involved in MSC frequency. The decreases observed in the number of circulating MSCs was not associated with the severity of the pulmonary complications; however, further studies in mustard lung models are required to demonstrate the therapeutic or pathologic role of MSCs in SM injuries.
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http://dx.doi.org/10.1016/j.toxlet.2019.05.015DOI Listing
September 2019

Time course study of oxidative stress in sulfur mustard analog 2‑chloroethyl ethyl sulfide-induced toxicity.

Int Immunopharmacol 2019 Aug 10;73:81-93. Epub 2019 May 10.

Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. Electronic address:

Oxidative stress is the major mechanism impairing cell homeostasis, inducing cell death and tissue damage in sulfur mustard (SM)-exposed individuals. The aim of the present study was to evaluate time course changes of oxidative stress in the mice exposed with 2‑chloroethyl ethyl sulfide (CEES) as SM analog. For this purpose, male BALB/c mice were divided into control groups and experimental groups that received CEES (10 mg/kg) through intraperitoneal injection. In both groups, animals were euthanized at three periods: short (12, 24 h and 1 week), medium (1, 2 and 3 months) and long-term (5 and 6 months) after CEES exposure. Oxidative stress indices and the antioxidant defense systems were evaluated in lung and liver tissues. The time course findings in both tissues showed a significant increase in oxidative damage markers such as malondialdehyde (lung P < 0.001, liver P < 0.001), protein carbonyl (lung P < 0.0001), and 8-hydroxy-deoxyguanosine (lung P < 0.0001, Liver P < 0.0001) and also a significant reduction in the antioxidant defense system including reduced glutathione level (lung P < 0.001, Liver P < 0.001,), activities of catalase (lung P < 0.01 and liver P < 0.05), superoxide dismutase (lung P < 0.05), glutathione S‑transferase (lung P < 0.05, liver P < 0.01), glutathione peroxidase (lung, P < 0.05, Liver P < 0.05) and glutathione reductase (lung P < 0.001, liver P < 0.01) in the long-term. However, these changes occur with less intensity in the short-term and return to the normal status in the medium-term. Moreover, there was a positive time course correlation between oxidative damage indices and the percent of histopathological damage in both tissues (P < 0.05). This correlation finding confirms and supports the fact that time course oxidative-antioxidant imbalance plays an important role in the development of SM-induced acute and delayed injuries.
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http://dx.doi.org/10.1016/j.intimp.2019.04.055DOI Listing
August 2019

Altered levels of GST activity, Vit C, TPX and Cu in individuals with long-term sulfur mustard-induced lung complications.

Inhal Toxicol 2018 Nov - Dec;30(13-14):483-491. Epub 2019 Mar 8.

d Immunoregulation Research Center , Shahed University , Tehran , Iran.

Context: Sulfur mustard (SM) as a cytotoxic and blistering agent can alkylate a variety of cellular components, causing the incidence of ongoing oxidative stress.

Objective: The present study was conducted to assess oxidative stress index (OSI) in SM-exposed veterans with long-term pulmonary complications.

Methods: Participants consisted of 289 SM-exposed individuals with pulmonary complications (classified into three groups: mild, moderate and severe) and 66 healthy individuals as the control group. Enzymatic and non-enzymatic antioxidant and also trace elements were measured in the study groups. Moreover, some of oxidative stress indicators consist of malondialdehyde (MDA), protein carbonyl (CO), total antioxidant (TA) and total peroxide (TPX) were measured and then OSI was calculated.

Results: Glutathione-S-transferase (GST) activity and vitamin C (Vit C) were significantly decreased in SM-exposed patients as compared with controls. Besides, Cu level and Cu/Zn ratio in SM-exposed veterans showed a significant correlation with the severity of the diseases. Serum TPX was significantly increased in SM-exposed individuals, as a result of which the OSI was slightly higher in them than controls. This can be considered as an indicative for oxidative stress in SM-exposed patients.

Conclusion: This study suggests a particular role for TPX, Cu, Vit C and GST in SM-induced pulmonary complications. Therefore, a special attention should be paid to these factors in designing therapeutic protocols, which can reduce the progression risk of the disease.
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http://dx.doi.org/10.1080/08958378.2018.1545809DOI Listing
September 2019

Association of Sulfur Mustard-Induced Ocular Problems with Serum and Blood Biochemical Parameters Changes.

Iran J Pathol 2018 17;13(2):157-166. Epub 2018 Jul 17.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Background & Objective: Many biochemical features of sulfur mustard (SM) intoxication have remained unknown. So far, the direct association between biochemical parameter changes and ocular problems in patients exposed to SM is not evaluated. The current study aimed at evaluating the associations between the ocular findings in patients with SM intoxication and the changes of serum and blood biochemical parameters.

Methods: In the current study, 372 patients exposed to SM and 128 matched controls were compared concerning the association between their ocular problems and biochemical parameters. Ocular problems include photophobia, ocular surface discomfort (OSD), etc. Biochemical parameters include uric acid, creatinine (Cr), hematocrit (HCT), total, direct and indirect bilirubin, high-density lipoproteins (HDL), alanine aminotransferase (ALT), calcium (Ca), fasting blood sugar (FBS), mean corpuscular hemoglobin concentration (MCHC), etc.

Results: The SM-exposed group with photophobia, OSD, tearing, blurred vision, abnormal tear status, and slit-lamp findings had significantly higher mean serum and blood levels of uric acid, Cr, HCT, and total and indirect bilirubin than the controls. The SM-exposed group with photophobia, tearing, ocular pain, blurred vision, bulbar conjunctival and limbal abnormalities had significantly higher mean serum and blood levels of HDL, ALT, Ca, FBS, MCHC, and HDL, indirect and total bilirubin, compared to the control group.

Conclusion: The association of photophobia with uric acid, OSD and tearing with Cr, photophobia with HDL, ocular pain with Ca, and blurred vision with FBS may be explained for their known ocular effects in the SM-exposed subjects. SM-induced biochemical changes may intensify the ocular problems induced by the direct effects of SM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339492PMC
July 2018

Sulfur Mustard-induced Changes in Blood Urea Nitrogen, Uric Acid and Creatinine Levels of Civilian Victims, and Their Correlation with Spirometric Values.

Iran J Public Health 2018 Nov;47(11):1725-1733

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Background: The aim of this study was assessment of the chronic effects of sulfur mustard (SM) among victims.

Methods: In this cohort study, 355 SM-exposed subjects from Sardasht, and 123 controls from Rabat, both from West Azerbaijan Province, Iran were included. The spirometric evaluation and the global initiative for chronic obstructive lung disease (GOLD) classification were applied for all. Serum levels of urea, creatinine (Cr), and uric acid (UA) and glomerular filtration rate (GFR) were assessed. Data analysis was conducted using IBM SPSS.

Results: All were male, with a mean age of 43.7±10.7 and 41.6±9.9 years in case and control groups, respectively. The case group had significantly higher values of Cr (<0.001) and UA (=0.018) than the control group. This was also the case in the Cr level (<0.001) in subjects without pulmonary dysfunction, between both groups. There was significant difference in the GFR (=0.047) between both groups and between subgroups with pulmonary dysfunction in the case and control groups (=0.045), as well as between SM-exposed subjects with and without pulmonary dysfunction (=0.009). Serum Cr, UA, sUA/Cr ratio, and BUN as well as the GFR did not have any significant correlation with forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio.

Conclusion: Despite significantly high levels of Cr and UA in the case group, no significant correlation was found between serum Cr, UA, sUA/Cr ratio, BUN, and GFR with spirometric values. Further studies are required to reveal the underlying molecular and clinical significance of these findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294863PMC
November 2018