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1.
PLoS One ; 15(3): e0230719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218599

RESUMO

INTRODUCTION: Epidemiologically, cigarette smoking is a well-known risk factor for the pathogenesis of rheumatoid arthritis (RA). However, there has been few plausible explanations why cigarette smoking aggravated RA. We investigated the causal effect of smoking in experimental model of arthritis development. METHODS: During induction of experimental arthritis with collagen challenge, mice were exposed to a smoking environment with 3R4F cigarettes. Generated smoke was delivered to mice through a nose-only exposure chamber (ISO standard 3308). Human cartilage pellet was challenged by cigarette smoke extract to identify citrullinating potential in vitro. RESULTS: Cigarette smoke exacerbated arthritis in a collagen-induced arthritis (CIA) model. Exposure to smoke accelerated the onset of arthritis by 2 weeks compared to the conventional model without smoke. Citrullination of lung tissue as well as tarsal joints were revealed in smoke-aggravated CIA mice. Interestingly, tracheal cartilage was a core organ regarding intensity and area size of citrullination. The trachea might be an interesting organ in viewpoint of sharing cartilage with joint and direct smoke exposure. Anti-CCP antibodies were barely detected in the serum of CIA mice, they were significantly elevated in cigarette smoke group. Citrullinated antigens were increased in the serum of smoke-exposed mice. Lastly, a cigarette smoke extract enhanced human cartilage citrullination in vitro. CONCLUSIONS: Missing link of arthritic mechanism between smoke and RA could be partially explained by tracheal citrullination. To control tracheal cartilage citrullination may be beneficial for preventing arthritis development or aggravation if cigarette smoke is becoming a risk factor to pre-arthritic individual.

2.
Arch Toxicol ; 94(3): 887-909, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32080758

RESUMO

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol-alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol-alveoli. Bronchiol-alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using 1H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.

3.
Food Chem Toxicol ; 135: 110930, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678261

RESUMO

Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 µg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.


Assuntos
Fumar Cigarros/efeitos adversos , Inflamação/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Deficiência de Colina , Citocinas/metabolismo , Dieta Hiperlipídica , Progressão da Doença , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Macrófagos/efeitos dos fármacos , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/patologia , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/metabolismo , Fatores de Tempo
4.
J Chromatogr Sci ; 58(3): 187-194, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31885052

RESUMO

When assessing the inhalation toxicity of diverse inhalable substances, a first step is accurate quantitative analysis. In this study, we developed a method for the quantitative analysis of methylisothiazolinone (MIT) and methylchloroisothiazolinone (CMIT), main components in humidifier disinfectants. A simple thermal desorption (TD) method was used to analyze the CMIT/MIT. Using this method, sample loss during aerosolization was minimized compared with other more complicated pretreatment methods, like solvent absorption and extraction (SV). The results of the TD and SV methods were compared to determine the optimal analytical system for CMIT/MIT analysis. In both methods, the concentration of MIT increased systematically with increasing the CMIT/MIT aerosol concentration (R2 > 0.98). The MIT contents in the aerosol given by the two analytical methods were somewhat similar (MIT content = 1.52% (sample solution), 1.43% (TD) and 1.18% (SV)). In contrast, the measured CMIT content in the aerosol was different depending on the type of pretreatment used. The CMIT content was 2.90% for the TD method, while that for the solvent method recorded 0.75% (CMIT content of the sample solution = 4.66%). We confirmed that the sample loss of the CMIT with high reactivity occurred in the complicated sampling and pretreatment steps of the SV method.

5.
Environ Toxicol ; 35(1): 27-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31498972

RESUMO

In 2011, a link between humidifier disinfectants and patients with idiopathic pulmonary fibrosis was identified in Korea, and Kathon was suggested as one of the causative agents. In this study, Kathon induced apoptotic cell death along with membrane damage at 24 h post-exposure. Additionally, on day 14 after a single instillation with Kathon, the total number of pulmonary cells and the levels of TNF-α, IL-5, IL-13, MIP-1α, and MCP-1α clearly increased in the lung of mice. The proportion of natural killer cells and eosinophils were significantly elevated in the spleen and the bloodstream, respectively, and the level of immunoglobulin (Ig) A, but not IgG, IgM, and IgE, dose-dependently increased. Therefore, we suggest that inhaled Kathon may induce eosinophilia-mediated disease in the lung by disrupting homeostasis of pulmonary surfactants. Considering that eosinophilia is closely related to cancer and fibrosis, further studies are needed to understand the relationship between them.


Assuntos
Desinfetantes/toxicidade , Eosinofilia/induzido quimicamente , Pulmão/efeitos dos fármacos , Surfactantes Pulmonares/metabolismo , Tiazóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/imunologia , Eosinofilia/sangue , Eosinofilia/imunologia , Eosinófilos/citologia , Humanos , Imunoglobulina A/sangue , Exposição por Inalação/efeitos adversos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
6.
BMC Pulm Med ; 19(1): 241, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823765

RESUMO

BACKGROUND: The respiratory system is exposed to various allergens via inhaled and intranasal routes. Murine models of allergic lung disease have been developed to clarify the mechanisms underlying inflammatory responses and evaluate the efficacy of novel therapeutics. However, there have been no comparative studies on differences in allergic phenotypes following inhaled vs. intranasal allergen challenge. In this study, we compared the asthmatic features of mice challenged via different routes following allergen sensitization and investigated the underlying mechanisms. METHODS: To establish ovalbumin (OVA)-induced allergic asthma models, BALB/c mice were sensitized to 20 µg OVA with 1 mg aluminum hydroxide by the intraperitoneal route and then challenged by inhalation or intranasal administration with 5% OVA for 3 consecutive days. Cellular changes and immunoglobulin (Ig) E levels in bronchoalveolar lavage fluid (BALF) and serum, respectively, were assessed. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) staining. Levels of T helper (Th)2 cytokines including interleukin (IL)-4, -5, and -13 in BALF and epithelial cytokines including IL-25 and -33 in BALF and lung tissues were measured by enzyme-linked immunosorbent assay and western blotting. Airway hyperresponsiveness (AHR) was evaluated by assessing airway resistance (Rrs) and elastance (E) via an invasive method. RESULTS: OVA-sensitized and challenged mice showed typical asthma features such as airway inflammation, elevated IgE level, and AHR regardless of the challenge route. However, H&E staining showed that inflammation of pulmonary vessels, alveolar ducts, and alveoli were enhanced by inhaled as compared to intranasal OVA challenge. PAS staining showed that intranasal OVA challenge induced severe mucus production accompanied by inflammation in bronchial regions. In addition, Th2 cytokine levels in BALF and AHR in lung were increased to a greater extent by inhalation than by intranasal administration of OVA. Epithelial cytokine expression, especially IL-25, was increased in the lungs of mice in the inhaled OVA challenge group. CONCLUSION: OVA-sensitized mice exhibit different pathophysiological patterns of asthma including expression of epithelial cell-derived cytokines depending on the OVA challenge route. Thus, some heterogeneous phenotypes of human asthma can be replicated by varying the mode of delivery after OVA sensitization.

7.
J Immunol Res ; 2019: 8315845, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781683

RESUMO

Inhalation of diesel exhaust particulate (DEP) causes oxidative stress-induced lung inflammation. This study investigated the protective effects of TF-343, an antioxidant and anti-inflammatory agent, in mouse and cellular models of DEP-induced lung inflammation as well as the underlying molecular mechanisms. Mice were intratracheally instilled with DEP or vehicle (0.05% Tween 80 in saline). TF-343 was orally administered for 3 weeks. Cell counts and histological analysis of lung tissue showed that DEP exposure increased the infiltration of neutrophils and macrophages in the peribronchial/perivascular/interstitial regions, with macrophages harboring black pigments observed in alveoli. TF-343 pretreatment reduced lung inflammation caused by DEP exposure. In an in vitro study using alveolar macrophages (AMs), DEP exposure reduced cell viability and increased the levels of intracellular reactive oxygen species and inflammatory genes (IL-1ß, inhibitor of nuclear factor- (NF-) κB (IκB), and Toll-like receptor 4), effects that were reduced by TF-343. A western blot analysis showed that the IκB degradation-induced increase in NF-κB nuclear localization caused by DEP was reversed by TF-343. In conclusion, TF-343 reduces DEP-induced lung inflammation by suppressing NF-κB signaling and may protect against adverse respiratory effects caused by DEP exposure.

8.
Regul Toxicol Pharmacol ; 108: 104440, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31398363

RESUMO

Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120 mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120 mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40 mg/kg/day.


Assuntos
Anti-Infecciosos/toxicidade , Guanidinas/toxicidade , Troca Materno-Fetal , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Gravidez , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos
9.
Metabolomics ; 15(8): 111, 2019 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-31422500

RESUMO

INTRODUCTION: Polyhexamethylene guanidine phosphate (PHMG) has been used as a disinfectant and biocide, and was known to be harmless and non-toxic. However, in 2011, PHMG used as a humidifier disinfectant was reported to be associated with lung diseases, such as, fibrosis in the toxicant studies on pulmonary fibrosis by PHMG. However, no metabolomics study has been performed in PHMG-induced mouse models of pulmonary fibrosis. OBJECTIVES: We performed a metabolomic study to understand the biochemical events that occur in bleomycin (BLM)- and PHMG-induced mouse models of pulmonary fibrosis using gas chromatography-mass spectrometry (GC-MS), LC-tandem MS, and GC-tandem MS. RESULTS: The levels of 61 metabolites of 30 amino acids, 13 organic acids, 12 fatty acids, 5 polyamines, and oxidized glutathione were determined in the pulmonary tissues of mice with BLM- and PHMG-induced pulmonary fibrosis and in normal controls. Principal component analysis and partial least squares discriminant analysis used to compare level of these 61 metabolites in pulmonary tissues. Levels of metabolites were significantly different in the BLM and PHMG groups as compared with the control group. In particular, the BLM- and PHMG-induced pulmonary fibrosis models showed elevated collagen synthesis and oxidative stress and metabolic disturbance of TCA related organic acids including fumaric acid by NADPH oxidase. In addition, polyamine metabolism showed severe alteration in the PHMG group than that of the BLM group. CONCLUSION: This result suggests PHMG will be able to induce pulmonary fibrosis by arginine metabolism and NADPH oxidase signaling.

10.
J Anal Methods Chem ; 2019: 3201370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183245

RESUMO

The quantitative analysis of target substances is an important part of assessing the toxicity of diverse materials. Usually, the quantitation of target compounds is conducted by instrumental analysis such as chromatography and capillary electrophoresis. If solvents are used in the pretreatment step of the target analyte quantification, it would be crucial to examine the solvent effect on the quantitative analysis. Therefore, in this study, we assessed the solvent effects using four different solvents (methanol, hexane, phosphate buffered saline (PBS), and dimethyl sulfoxide (DMSO)) and three toxic compounds (benzene, toluene, and methylisothiazolinone (MIT)). Liquid working standards containing the toxic compounds were prepared by dilution with each solvent and analyzed by gas chromatography-mass spectrometry (GC-MS). As a result, we found that the response factor (RF) values of the target analytes were different, depending on the solvent types. In particular, benzene and toluene exhibited their highest RF values (33,674 ng-1 and 78,604 ng-1, respectively) in hexane, while the RF value of MIT was the highest (9,067 ng-1) in PBS. Considering the correlation (R 2) and relative standard deviation (RSD) values, all target analytes showed fairly good values (R 2 > 0.99 and RSD < 10%) in methanol and DMSO. In contrast, low R 2 (0.0562) and high RSD (10.6%) values of MIT were detected in hexane, while benzene and toluene exhibited relatively low R 2 and high RSD values in PBS (mean R 2 = 0.9892 ± 0.0146 and mean RSD = 13.3 ± 4.1%). Based on these findings, we concluded that the results and reliability of the quantitative analysis change depending on the analyte and solvent types. Therefore, in order to accurately assess the toxicity of target compounds, reliable analytical data should be obtained, preferentially by considering the solvent types.

11.
Toxicol In Vitro ; 57: 132-142, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30825645

RESUMO

A recent epidemiological study suggested that chronic exposure to cleaning detergents significantly reduced lung function in consumers. In this study, we identified the toxic mechanism of ammonium lauryl sulfate (ALS), the most common detergent in consumer products, using alveolar macrophage cells. In preliminary tests, cell viability sharply decreased between 40 and 200 µg/mL, thus we determined doses of 10, 20, and 50 µg/mL for further study. When treated at a 50 µg/mL for 24 h, cell viability was 67.7 ±â€¯3.4% of the control, and autophagosome-like vacuoles and a number of double membranes surrounding damaged mitochondria were observed in the cytosol. Intracellular ROS, the ATP amount, ER volume, acid cell compartments and mitochondrial potential rapidly reduced with dose, whereas the release of LDH and apoptotic bodies dramatically increased. Additionally, multiple cell death pathways were activated following exposure to ALS, and the expression of caveolin-1, p-Acetyl CoA carboxylase, p21, and p-ERK were greatly inhibited. Moreover, the secretion of inflammatory mediators and expression of innate- and adaptive-immune response-related proteins were remarkably reduced. Meanwhile, the secretion of TGF-ß was enhanced. Therefore, we conclude that ALS-induced apoptosis may be due to mitochondrial dysfunction triggered by the inhibition of caveolin-1, and that chronic pulmonary exposure to ALS may cause adverse health effects such as cancer and fibrosis by impairing the host's pulmonary immune system.


Assuntos
Caveolina 1/antagonistas & inibidores , Detergentes/toxicidade , Mitocôndrias/efeitos dos fármacos , Dodecilsulfato de Sódio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo
12.
Toxicology ; 414: 35-44, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629986

RESUMO

Polyhexamethyleneguanidine phosphate (PHMG-P) is a polymeric biocide with a guanidine group. It has multiple positive charges in physiological conditions due to nitrogen atom in the guanidine and this cationic property contributes antimicrobial effect by disrupting cell membranes. To determine whether the cationic nature of PHMG-P results in cytotoxicity in human cell lines, anionic compounds were treated with PHMG-P. The cytotoxic effect was evaluated with ROS production and HMGB1 release into media. To verify the protection effect of anion against PHMG-P-induced cell death in vivo, a zebrafish assay was adopted. In addition, membrane disruption by PHMG-P was evaluated using fluorescein diacetate and propidium iodine staining. As a result, anionic substances such as DNA and poly-l-glutamic acids, decreased PHMG-P induced cell death in a dose-dependent manner. While HMGB1 and ROS production increased with PHMG-P concentration, the addition of anionic compounds with PHMG-P reduced the ROS production and HMGB1 release. The mortality of the zebrafish increased with PHMG-P concentration and co-treatment of anionic compounds with PHMG-P decreased mortality in a dose-dependent manner. In addition, FDA and PI staining confirmed that PHMG-P disrupts plasma membrane. Taken together, a cationic property is considered to be one of the main causes of PHMG-P-induced mammalian cell toxicity.


Assuntos
Membrana Celular/efeitos dos fármacos , Desinfetantes/toxicidade , Guanidinas/toxicidade , Células A549 , Animais , Membrana Celular/metabolismo , Membrana Celular/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína HMGB1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Medição de Risco , Células THP-1 , Peixe-Zebra
13.
Food Chem Toxicol ; 125: 182-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30610934

RESUMO

The present study aimed to determine the effects of cigarette smoke on the regulation of hepatic cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes in male BALB/c mice exposed to nose-only cigarette smoke for 4 days. There were no significant increases in serum liver injury markers (alanine aminotransferase and aspartate aminotransferase) or oxidative stress (total antioxidant capacity, malondialdehyde, and glutathione disulfide/reduced glutathione) following cigarette smoke exposure, but malondialdehyde was elevated in the bronchoalveolar lavage fluid of smoke-exposed mice. Additionally, the hepatic microsomal protein levels of Cyp1a and Cyp2b, and the activities of ethoxyresorufin O-deethylase, pentoxyresorufin O-depenylase, and chlorzoxazone 6-hydrxylase, were elevated in smoke-exposed mice. Interestingly, the hepatic activities of GST toward 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, and ethacrynic acid, but not cumene hydroperoxide were enhanced by cigarette smoke exposure, which was consistent with the increased expression levels of mu- and pi-class GSTs, but not alpha-class GSTs, observed in immunoblot analyses. These findings indicate that the short-term inhalation of cigarette smoke induces drug-metabolizing enzymes such as CYP1A, CYP2B, and mu/pi-class GSTs in the absence of hepatic injury and oxidative stress. Furthermore, smoking may alter hepatic drug metabolism, as well as the disposition and toxicity of xenobiotics, including some therapeutic drugs and cigarette smoke constituents.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa Transferase/metabolismo , Fígado/enzimologia , Fumaça , Tabaco , Animais , Camundongos , Nariz
14.
Neurosci Res ; 149: 14-21, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30685495

RESUMO

Manganese-enhanced magnetic resonance imaging (MEMRI) is based on neuronal activity-dependent manganese uptake, and provides information about nervous system function. However, systematic studies of pain processing using MEMRI are rare, and few investigations of pain using MEMRI have been performed in the spinal cord. Herein, we investigated the pain dependence of manganese ions administered in the rat spinal cord. MnCl2 was administered into the spinal cord via an intrathecal catheter before formalin injection into the right hind paw (50 µL of 5% formalin). The duration of flinching behavior was recorded and analyzed to measure formalin-induced pain. After the behavioral test, rats were sacrificed with an overdose of urethane (50 mg/kg), and spine samples were extracted and post-fixed in 4% paraformaldehyde solution. The samples were stored in 30% sucrose until molecular resonance (MR) scanning was performed. In axial Mn2+ enhancement images of the spinal cord, Mn2+ levels were found to be significantly elevated on the ipsilateral side of the spinal cord in formalin-injected rats. To confirm pain-dependent Mn enhancement in the spinal cord, c-Fos expression was analyzed, and was found to be increased in the formalin-injected rats. These results indicate that MEMRI is useful for functional analysis of the spinal cord under pain conditions. The gray matter appears to be the focus of intense paramagnetic signals. MEMRI may provide an effective technique for visualizing activity-dependent patterns in the spinal cord.

15.
J Appl Toxicol ; 39(3): 510-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30485468

RESUMO

Cigarette smoke is known to be associated with the incidence of a variety of pulmonary diseases, and alveolar macrophages are a key player in the defense mechanism against inhalable toxicants. Herein, we have found that a hydrophilic fraction in smoke extracts from 3R4F reference cigarettes (CSE) contains high concentrations of volatile substances compared to cigarette smoke condensate (amphoteric fraction). We also identified the toxic mechanism of CSE using MH-S, a mouse alveolar macrophage cell line. CSE decreased cell viability accompanying increased lactate dehydrogenase release. Additionally, mitochondrial volume and the potential increased along with enhanced expression of mitochondrial fusion proteins and decreased adenosine triphosphate production. Similarly, CSE clearly induced increase of catalase activity and intracellular calcium concentration and decrease of endoplasmic reticulum and lysosome volume at the highest dose. More interestingly, damaged organelles accumulated in the cytosol, and CSE-containing particles specifically penetrated to mitochondria. Meanwhile, any significant change in autophagy related protein expression was not found in CSE-treated cells. Subsequently, we evaluated the effects of CSE on secretion of inflammatory related cytokines and chemokines, considering the relationship between organelle damage and the disturbed immune response. Very importantly, we found that expression of innate and adaptive immunity related mediators is disrupted following CSE exposure. Taken together, we suggest that CSE may cause the accumulation of damaged organelles in the cytoplasm by impairing selective autophagic function. In addition, this accumulation is responsible for the inadequate ability of immune cells to repair the damage of lung tissue following exposure to CSE.

16.
Chem Commun (Camb) ; 55(4): 447-450, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30474665

RESUMO

As a robust radioanalytical method for tracking carbonaceous particulates in vivo, polycyclic aromatic hydrocarbons from diesel exhaust were labeled with a radioactive-iodine-tagged pyrene analogue. Single-photon emission computed tomography and biodistribution studies showed high uptake and slow clearance of this matter in the respiratory system, which may underlie its severe toxicity.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos/farmacocinética , Emissões de Veículos , Animais , Iodo/química , Camundongos , Hidrocarbonetos Policíclicos Aromáticos/administração & dosagem , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Pirenos/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
17.
Toxicol Lett ; 303: 55-66, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30579903

RESUMO

Cigarette smoke is responsible for many fatal pulmonary diseases, however, the toxic mechanism is still unclear. In this study, we first confirmed that whole cigarette smoke condensates (WCSC) contain hydrophilic elements, lipophilic and gaseous components. Then, we treated BEAS-2B cells, a normal human bronchial epithelial cell line, at dosages of 0.25, 0.5, and 1% for 24 h and explored the toxic mechanism. Cell viability decreased in a dose-dependent manner, and fission and fusion of mitochondria, damage of endoplasmic reticulume (ER) structures, and formation of autophagosome-like vacuoles were found in cells treated with 1% WCSC. Mitochondrial and ER volumes, lysosomal fluorescence intensity, LDH release, and intracellular ROS levels notably decreased at the highest doses compared with the control, whereas intracellular calcium ion and NO levels were significantly elevated accompanying G2/M phase arrest. Expression of an iron-binding nuclear protein-related gene (pirin) was the most up-regulated in the WCSC-treated cells with enhanced expression of antioxidant-related genes, whereas expression of carbonic anhydrase IX gene, a marker of tumor hypoxia, was the most down-regulated. Additionally, levels of apoptosis (BAX, Apaf-1, and cleavage of caspase-3 and PARP), autophagy (p62 and LC3B-II), ER stress (PERK, IRE-1a, Bip, and CHOP), antioxidant (SOD-1 and SOD-2), and MAPkinase activation (p-ERK, p-p38, and p-JNK)-related proteins were clearly enhanced following exposure to WCSC, whereas expression of several mitochondrial dynamics-related proteins was reduced with dose. Interestingly, expression of ferritin protein (light chain) was dramatically enhanced near the ER along with that of p62 protein. More importantly, the hypoxia inducible factor-1 pathway and ferroptosis were proposed among the 20 terms in KEGG pathway analysis, and secretion of IL-6 and IL-8, which are involved in hypoxia-induced inflammation, were clearly elevated with dose. Taken together, we suggest that WCSC may induce ferroptosis in bronchial epithelial cells via ER stress and disturbed homeostasis in mitochondrial dynamics caused by induction of hypoxia conditions.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Fator Apoptótico 1 Ativador de Proteases/genética , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Autofagossomos/efeitos dos fármacos , Brônquios/citologia , Brônquios/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
Inhal Toxicol ; 31(13-14): 457-467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31971030

RESUMO

Objective: Humidifier-disinfectant-induced lung injury is a new syndrome associated with a high mortality rate and characterized by severe hypersensitivity pneumonitis, acute interstitial pneumonia, or acute respiratory distress syndrome. Polyhexamethylene guanidine phosphate (PHMG-P), a guanidine-based antimicrobial agent, is a major component associated with severe lung injury. In-depth studies are needed to determine how PHMG-P affects pathogenesis at the molecular level. Therefore, in this study, we analyzed short-term (4 weeks) and long-term (10 weeks) PHMG-P-exposure-specific gene-expression patterns in rats to improve our understanding of time-dependent changes in fibrosis.Materials and methods: Gene-expression profiles were analyzed in rat lung tissues using DNA microarrays and bioinformatics tools.Results: Clustering analysis of gene-expression data showed different gene-alteration patterns in the short- and long-term exposure groups and higher sensitivity to gene-expression changes in the long-term exposure group than in the short-term exposure group. Supervised analysis revealed 34 short-term and 335 long-term exposure-specific genes, and functional analysis revealed that short-term exposure-specific genes were involved in PHMG-P-induced initial inflammatory responses, whereas long-term exposure-specific genes were involved in PHMG-P-related induction of chronic lung fibrosis.Conclusion: The results of transcriptomic analysis were consistent with lung histopathology results. These findings indicated that exposure-time-specific changes in gene expression closely reflected time-dependent pathological changes in PHMG-P-induced lung injury.

19.
Environ Health Toxicol ; 33(3): e2018012-0, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30286588

RESUMO

Cigarette smoke is a major risk factor for several diseases, including chronic obstructive pulmonary and cardiovascular diseases. The toxicity of the cigarette smoke can be determined in vitro. The cytotoxicity test of the cigarette smoke is commonly conducted using the cigarette smoke condensate (CSC) and cigarette smoke extract (CSE). The CSC and CSE methods are well known for sampling of the particles and water-soluble compounds in the cigarette smoke, respectively. In this study, the CSC and CSE were analyzed by using a gas chromatography-mass spectrometry (GC-MS) system equipped with a wax column for separation of the volatile organic compounds. The cytotoxic effect of the CSC and CSE were evaluated thoroughly by comparing the analytical results of the CSC and CSE samples. The total concentration of the volatile organic compounds detected in the CSC sample was similar to that in the CSE sample based on the peak area. Except for the dimethyl sulfoxide solvent, nicotine had the highest concentration in the CSC sample, while acetonitrile had the highest concentration in the CSE sample. The compositions were as follows: (1) CSC sample: 55.8% nicotine, 18.0% nicotyrine, 3.20% 1,2,3-propanetriol, triacetate, 1.28% ethyl chloride, 1.22% phenol, etc. and (2) CSE sample: 18.7% acetonitrile, 18.0% acetone, 12.5% 2-hydroxy-2-methyl-propanenitrile, 8.98% nicotine, 5.86% nicotyrine, etc. In this manner, to accurately examine the cytotoxicity of the cigarette smoke using CSC or CSE, the components and their concentrations in the CSC and CSE samples should be considered.

20.
J Toxicol Sci ; 43(8): 485-492, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30078834

RESUMO

Polyhexamethylene guanidine phosphate (PHMG) is an antimicrobial biocide that causes severe lung injury accompanied with inflammation and subsequent fibrosis. Cytokines mediate the inflammatory response, leading to fibrosis in injured tissues. PHMG is known to induce the expression of various cytokines in vitro and in vivo. In the present study, we investigated the involvement of three MAPK subfamilies (JNK, p38 MAPK, and ERK) in PHMG-induced cytokine expression in A549 human lung epithelial cells. Our in vivo and in vitro data indicated that PHMG induced an increase in mRNA expression of IL-6 and TNF-α, and enhanced the phosphorylation of JNK, p38 MAPK, and ERK. Further, we investigated the involvement of MAPKs in PHMG-induced mRNA expression of IL-6 and TNF-α using JNK, p38 MAPK, and ERK inhibitors in A549 cells. Pre-treatment with the JNK inhibitor but not the p38 MAPK or ERK inhibitor, significantly attenuated the PHMG-induced mRNA expression of IL-6 and TNF-α. These results suggest that the activation of JNK is involved at least partially in the induction of IL-6 or TNF-α expression by PHMG in A549 cells.


Assuntos
Anti-Infecciosos/efeitos adversos , Células Epiteliais/metabolismo , Guanidinas/efeitos adversos , Interleucina-6/metabolismo , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Células A549 , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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