RESUMO
BACKGROUND: The identification of markers that can facilitate the early diagnosis of silicosis has remained challenging. We evaluated the association of inflammatory markers with the presence of silicosis and lung function impairment in individuals exposed to silica. METHODS: Individuals exposed and not exposed to silica were assessed by occupational history, clinical findings, lung function, chest imaging findings, and inflammatory markers. RESULTS: Among 297 men evaluated, 51 were unexposed controls (G1), 149 were exposed to silica without silicosis (G2), and 97 were exposed to silica with silicosis (G3). Inflammatory marker levels were higher in G3 than in G2 and G1. Platelet/lymphocyte ratio (PLR), lactate dehydrogenase (LDH), soluble tumor necrosis factor II (sTNFRII), and macrophage inflammatory protein-4 (MIP-4) were associated with silicosis, and LDH, neutrophil/lymphocyte ratio (NLR), sTNFRII, monocyte chemoattractant protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and fibrinogen were negatively associated with lung function. CONCLUSION: Blood inflammatory markers are associated with silicosis and impaired lung function.
Assuntos
Dióxido de Silício , Silicose , Masculino , Humanos , Dióxido de Silício/toxicidade , Pulmão , Biomarcadores , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.
Assuntos
Pneumonia , Silicose , Animais , Camundongos , Dióxido de Silício/toxicidade , Camundongos Endogâmicos C57BL , Silicose/patologia , Pneumonia/induzido quimicamente , Pneumonia/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Pulmão/patologia , Sinapses/patologia , Peptídeos beta-Amiloides , Hipocampo/patologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , CitocinasRESUMO
OBJECTIVE: Silicosis is a pneumoconiosis characterized by fibrosis of the lung parenchyma caused by inhalation of silica particles. Genetic factors might play a role in the severity silicosis. We sought to evaluate the influence of polymorphisms in the ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1, and TNF genes on the severity of silicosis. METHODS: Nine polymorphisms were genotyped by PCR in a sample of 143 patients with silicosis in the state of Rio de Janeiro, Brazil. RESULTS: Fifty-seven patients (40%) were classified as having simple silicosis and 86 (60%) were classified as having complicated silicosis. The TT genotype of rs1800469 in the TGFB1 gene showed a protective effect for complicated silicosis (OR = 0.35; 95% CI, 0.14-0.92; p = 0.028) when compared with the other two genotypes (CC+CT). The polymorphic T allele of rs763110 in the FASLG gene (OR = 0.56; 95% CI, 0.31-0.99; p = 0.047), as well as a dominant model for the T allele (TT+CT: OR = 0.37; 95% CI, 0.15-0.96; p = 0.037), also showed a protective effect. When patients with simple silicosis despite having been exposed to silica for a longer time (> 44,229 hours) were compared with patients with complicated silicosis despite having been exposed to silica for a shorter time, the T allele of rs763110 in the FASLG gene (OR = 0.20; 95% CI, 0.08-0.48; p < 0.0001), as well as dominant and recessive models (OR = 0.06; 95% CI, 0.00-0.49; p = 0.01 and OR = 0.22; 95% CI, 0.06-0.77; p = 0.014, respectively), showed a protective effect against the severity of silicosis. CONCLUSIONS: It appears that rs1800469 polymorphisms in the TGFB1 gene and rs763110 polymorphisms in the FASLG gene are involved in the severity of silicosis. Given the lack of studies relating genetic polymorphisms to the severity of silicosis, these results should be replicated in other populations.
Assuntos
Dióxido de Silício , Silicose , Humanos , Dióxido de Silício/toxicidade , Dióxido de Silício/análise , Predisposição Genética para Doença , Brasil , Estudos de Casos e Controles , Silicose/genética , Polimorfismo Genético , Proteínas Ativadoras de GTPase/genéticaRESUMO
Silicon oxide (SiO2) nanostructures (SiO2NS) are increasingly being incorporated into an array of products, notably in the food, pharmaceutical, medical industries and in water treatment systems. Amorphous SiO2NS have low toxicity, however, due to their great versatility, superficial modifications can be made and these altered structures require toxicological investigation. In this study, SiO2NS were synthetized and amine-functionalized with the molecules (3-aminopropyl)triethoxysilane (APTMS) and 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane (AEAEAPTMS), named SiO2NS@1 and SiO2NS@3, respectively. The bare SiO2NS, SiO2NS@1 and SiO2NS@3 samples were characterized and the influence of the culture medium used in the toxicological assays was also evaluated. The effect of amine functionalization of SiO2NS was investigated through acute and chronic toxicity assays with Daphnia magna. Modifications to ultrastructures of the intestine and eggs of these organisms were observed in TEM and SEM analysis. The toxicity was influenced by the surface modifications and a possible Trojan horse effect was highlighted, particularly in the case of chronic exposure. Exposure to all NSs promoted alterations in the microvilli and mitochondria of the D. magna intestine and some damage to egg cells was also observed. The results demonstrate the importance of carrying out a full characterization of these materials, since surface modifications can enhance their toxic potential.
Assuntos
Daphnia/fisiologia , Nanoestruturas/toxicidade , Dióxido de Silício/toxicidade , Aminas , Animais , Bioensaio , Daphnia/efeitos dos fármacos , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Poluentes Químicos da Água/toxicidadeRESUMO
Inhalation is the main route of nanoparticles (NP) exposure during manufacturing. Although many mechanisms of toxicity have been described, the interaction of NP with relevant pneumocytes organelles is not widely understood. Considering that the physicochemical properties of NP influence their toxicological responses, the objective of this study was to evaluate whether exposure to different NP, crystalline Fe3O4 NP and amorphous SiO2 NP could alter pneumocytes organelles in alveolar epithelial cells. To achieve this goal, cell viability, ultrastructural changes, lysosomal damage, mitochondrial membrane potential (MMP), lipid droplets (LD) formation and cytokines production were evaluated by MTT, electron microscopy, lysotracker red staining, JC-1, Oil Red staining and Milliplex® assay respectively. Both NP were observed within lamellar bodies (LB), lysosomes, and cytoplasm causing morphological changes. Exposure to SiO2 NP at 6 h induced lysosomal activation, but not Fe3O4 NP. MMP decreased and LD increased at the highest concentrations after both NP exposure. Pro-inflammatory cytokines were released only after SiO2 NP exposure at 48 h. These results indicate that SiO2 NP have a greater impact than Fe3O4 NP on organelles responsible for energy, secretion, degradation and metabolism in pneumocytes leading to the development of respiratory disorders or the exacerbation of preexisting conditions. Therefore, the established biocompatibility for amorphous NP has to be reconsidered.
Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Óxido Ferroso-Férrico/toxicidade , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Células A549 , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Thymol, a monoterpene phenol, is used as a natural biocide. To circumvent its chemical instability, we propose use of thymol-loaded biogenic silica nanoparticles (BSiO2 #THY NPs); however, the toxicity of this system for aquatic organisms is unknown. Thus, the present study aimed to evaluate the toxicogenetic effects induced by thymol, BSiO2 NP, and BSiO2 #THY on Artemia salina and zebrafish (Danio rerio) early life stages. We also investigated the impact of BSiO2 aggregation in different exposure media (saline and freshwater). Based on the median lethal concentration at 48 h (LC5048h ), BSiO2 #THY (LC5048h = 1.06 mg/L) presented similar toxic potential as thymol (LC5048h = 1.03 mg/L) for A. salina, showing that BSiO2 had no influence on BSiO2 #THY toxicity. Because BSiO2 aggregated and sedimented faster in A. salina aqueous medium than in the other medium, this NP had lower interaction with this microcrustacean. Thus, BSiO2 #THY toxicity for A. salina is probably due to the intrinsic toxicity of thymol. For zebrafish early life stages, BSiO2 #THY (LC5096h = 13.13 mg/L) was more toxic than free thymol (LC5096h = 25.60 mg/L); however, BSiO2 NP has no toxicity for zebrafish early life stages. The lower aggregation of BSiO2 in the freshwater medium compared to the saline medium may have enhanced thymol's availability for this aquatic organism. Also, BSiO2 #THY significantly induced sublethal effects as thymol, and both were genotoxic for zebrafish. In conclusion, although BSiO2 #THY still needs improvements to ensure its safety for freshwater ecosystems, BSiO2 NP seems to be a safe nanocarrier for agriculture. Environ Toxicol Chem 2021;40:333-341. © 2020 SETAC.
Assuntos
Nanopartículas , Poluentes Químicos da Água , Animais , Ecossistema , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Timol/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-ZebraRESUMO
BACKGROUND: Silicosis is a lung disease of fibrotic nature resulting from the inhalation and deposition of dust containing crystalline silica. Subjects exposed to the same environmental factors may show distinct radiological manifestations, and since silicosis is known as a multifactorial disease, it is plausible that individual genetic susceptibility may play a role in the pathology. This review of the literature aims to provide an assessment of the present data on the genetic association studies in silicosis and describe the genes that potentially might influence silicosis susceptibility in silica-exposed individuals. METHODS: We accessed the database of PubMed for articles published in English about interindividual genetic susceptibility to silicosis using terms related to the subject matter. RESULTS: Following the evaluation process, 28 studies were included in this systematic review, including 23 original studies and 5 meta-analyses. CONCLUSIONS: Regardless of the advances in the knowledge of the importance of gene variations in silicosis, more studies need to be performed, in particular, special polygenic and genome-wide investigations.
Assuntos
Exposição por Inalação/efeitos adversos , Dióxido de Silício/toxicidade , Silicose/genética , Citocinas/imunologia , Predisposição Genética para Doença , Humanos , Silicose/imunologiaRESUMO
The Organisation for Economic Co-operation and Development has listed thirteen engineered nanomaterials (ENM) in order to investigate their toxicity on human health. Silicon dioxide (SiO2) and titanium dioxide (TiO2) are included on that list and we added indium tin oxide (ITO) nanoparticles (NPs) to our study, which is not listed on OECD suggested ENM to be investigated, however ITO NPs has a high potential of industrial production. We evaluate the physicochemical properties of SiO2 NPs (10-20 nm), TiO2 nanofibers (NFs; 3 µm length) and ITO NPs (<50 nm) and the impact of protein-corona formation on cell internalization. Then, we evaluated the toxicity of uncoated ENM on human lung epithelial cells exposed to 10 and 50 µg/cm2 for 24 h. TiO2 NFs showed the highest capability to adsorb proteins onto the particle surface followed by SiO2 NPs and ITO NPs after acellular incubation with fetal bovine serum. The protein adsorption had no impact on Alizarin Red S conjugation, intrinsic properties for reactive oxygen (ROS) formation or cell uptake for all types of ENM. Moreover, TiO2 NFs induced highest cell alterations in human lung epithelial cells exposed to 10 and 50 µg/cm2 while ITO NPs induced moderated cytotoxicity and SiO2 NPs caused even lower cytotoxicity under the same conditions. DNA, proteins and lipids were mainly affected by TiO2 NFs followed by SiO2 NPs with toxic effects in protein and lipids while limited variations were detected after exposure to ITO NPs on spectra analyzed by Fourier Transform Infrared Spectroscopy.
Assuntos
Nanoestruturas/química , Nanoestruturas/toxicidade , Coroa de Proteína/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Tamanho Celular , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Células Epiteliais/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Dióxido de Silício/química , Dióxido de Silício/metabolismo , Dióxido de Silício/toxicidade , Propriedades de Superfície , Titânio/química , Titânio/metabolismo , Titânio/toxicidade , Cicatrização/efeitos dos fármacosRESUMO
Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to be effective for controlling chronic lung inflammatory diseases. In this study, the effect of flunisolide on silica-induced lung pathological changes in mice was investigated. Swiss-Webster mice were injected intranasally with silica particles and further treated with flunisolide from day 21 to 27 post-silica challenge. Lung function was assessed by whole body invasive plethysmography. Granuloma formation was evaluated morphometrically, collagen deposition by Picrus sirius staining and quantitated by Sircol. Chemokines and cytokines were evaluated using enzyme-linked immunosorbent assay. The sensitivity of lung fibroblasts was also examined in in vitro assays. Silica challenge led to increased leukocyte numbers (mononuclear cells and neutrophils) as well as production of the chemokine KC/CXCL-1 and the cytokines TNF-α and TGF-ß in the bronchoalveolar lavage. These alterations paralleled to progressive granuloma formation, collagen deposition and impairment of lung function. Therapeutic administration of intranasal flunisolide inhibited granuloma and fibrotic responses, noted 28 days after silica challenge. The upregulation of MIP-1α/CCL-3 and MIP-2/CXCL-2 and the cytokines TNF-α and TGF-ß, as well as deposition of collagen and airway hyper-reactivity to methacholine were shown to be clearly sensitive to flunisolide, as compared to silica-challenge untreated mice. Additionally, flunisolide effectively suppressed the responses of proliferation and MCP-1/CCL-2 production from IL-13 stimulated lung fibroblasts from silica- or saline-challenged mice. In conclusion, we report that intranasal treatment with the corticosteroid flunisolide showed protective properties on pathological features triggered by silica particles in mice, suggesting that the compound may constitute a promising strategy for the treatment of silicosis.
Assuntos
Anti-Inflamatórios/administração & dosagem , Fluocinolona Acetonida/análogos & derivados , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pneumonia/patologia , Dióxido de Silício/toxicidade , Silicose/patologia , Administração Intranasal , Animais , Fibrose/induzido quimicamente , Fibrose/prevenção & controle , Fluocinolona Acetonida/administração & dosagem , Masculino , Camundongos , Pneumonia/induzido quimicamente , Pneumonia/prevenção & controle , Silicose/complicações , Silicose/prevenção & controleRESUMO
BACKGROUND: Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. RESULTS: The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 µg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 µg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. CONCLUSION: The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.