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1.
Toxicol Lett ; 319: 119-128, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682869

RESUMO

Long-term exposure to fine particulate matter (PM2.5) may cause or exacerbate many diseases, including respiratory inflammation. However, the full mechanism is not yet fully understood. The newly discovered long chain non-coding RNA, though unable to encode proteins, regulates multiple life activities and participates in the development of inflammation. In this study, we set up a cell inflammation model by using normal bronchial 16HBE cells exposed to PM2.5. High-throughput sequencing, as well as real-time fluorescent quantitative PCR detection and validation, was performed on the inflamed cells to evaluate the expression level of long chain noncoding RNA that helped us to identify the LncRNA LOC101927514. Inhibiting LncRNA LOC101927514 expression by RNAi, reflected in a reduction in inflammation, is driven by PM2.5. In addition, we identify LncRNA LOC101927514 to be located within the nucleus and binds to STAT3, altering the inflammatory state of the cells and IL6 and IL8 release. This study identifies that LncRNA LOC101927514 is a new potential target for future treatment of the inflammatory response activated by PM2.5 in the respiratory system.


Assuntos
Poluentes Atmosféricos/toxicidade , Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Material Particulado/toxicidade , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Contagem de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-8/biossíntese , Interleucina-8/genética , Fosforilação , Ligação Proteica , RNA Longo não Codificante/metabolismo
2.
Medicine (Baltimore) ; 98(47): e17942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764793

RESUMO

BACKGROUND: Anticholinergic administration prior to flexible bronchoscopy has been investigated, but studies have not yielded consistent results. METHODS: Patients were randomized 1:1 to receive nebulized 4 ml ipratropium bromide (1 mg, n = 125) or placebo (n = 125) for 15 minutes as premedication, 20 to 40 minutes before bronchoscopy. Airway secretions, bleeding, patient discomfort, procedure time, and procedure-related adverse events were compared between the groups. RESULTS: Nebulized ipratropium bromide prior to bronchoscopy could reduce airway secretions and patient discomfort (P = .02; P < .001, respectively), but not tracheobronchial bleeding or procedure time (P = .51, P = .36, respectively). Chest nodule or mass was the most common indication for performing bronchoscopy. The adverse events were higher in ipratropium bromide group, and hypertension was the most common complication. CONCLUSION: Nebulized ipratropium bromide prior to bronchoscopy is a more effective regimen that shows a practical benefit on the airway secretions and patient comfort, though these effects may not translate into any marked reduction in bleeding or of procedure time under general anesthesia. We suggest that routine nebulized ipratropium bromide premedication for bronchoscopy could be useful and beneficial. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1800016881.


Assuntos
Secreções Corporais/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Broncoscopia , Ipratrópio/administração & dosagem , Traqueia/efeitos dos fármacos , Administração por Inalação , Brônquios/fisiologia , Broncodilatadores/farmacologia , Método Duplo-Cego , Feminino , Humanos , Ipratrópio/farmacologia , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pré-Medicação , Traqueia/fisiologia
3.
Mol Immunol ; 114: 571-577, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31525576

RESUMO

Asthma is a chronic inflammatory disorder of airway affecting people from childhood to old age, and is characterized by airway epithelial dysfunction. Cucurbitacin E (CuE), a tetracyclic triterpene isolated from Cucurbitaceae plants, has been recently proved to exert anti-inflammation and immunology regulation activities. Nevertheless, its roles in asthma remains poorly defined. In the current study, CuE had little cytotoxicity on cell viability of human bronchial epithelial cell line BEAS-2B. Moreover, lipopolysaccharide (LPS) exposure inhibited cell viability and induced cell apoptosis, which was reversed following CuE pretreatment. Additionally, CuE administration suppressed LPS-induced inflammatory cytokine production, including TNF-α, IL-6, and IL-8. Simultaneously, supplementation with CuE decreased the transcripts and releases of mucin 5AC (MUC5AC) in LPS-treated BEAS-2B cells. Intriguingly, CuE inhibited LPS-evoked activation of the high-mobility group box1 (HMGB1)-TLR4-NF-κB signaling by reducing the expression of HMGB1, TLR4 and p-p65 NF-κB. Notably, restoring this pathway by elevating HMGB1 expression largely offset the protective function of CuE against LPS-triggered cell injury, inflammatory response and MUC5AC expression. Consequently, these findings highlight that CuE can ameliorate human bronchial epithelial cell insult and inflammation under LPS-simulated asthmatic conditions by blocking the HMGB1-TLR4-NF-κB signaling, thereby supporting its usefulness as a promising therapeutic agent against asthma.


Assuntos
Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/metabolismo , Brônquios/metabolismo , Linhagem Celular , Células Cultivadas , Células Epiteliais/metabolismo , Proteína HMGB1/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Mucina-5AC/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Triterpenos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500220

RESUMO

In chronic obstructive pulmonary disease (COPD), the bronchial epithelium is the first immune barrier that is triggered by cigarette smoke. Although vitamin D (vitD) has proven anti-inflammatory and antimicrobial effects in alveolar macrophages, little is known about the direct role of vitD on cigarette smoke-exposed bronchial epithelial cells. We examined the effects of vitD on a human bronchial epithelial cell line (16HBE) and on air-liquid culture of primary bronchial epithelial cells (PBEC) of COPD patients and controls exposed for 24 h to cigarette smoke extract (CSE). VitD decreased CSE-induced IL-8 secretion by 16HBE cells, but not by PBEC. VitD significantly increased the expression of the antimicrobial peptide cathelicidin in 16HBE and PBEC of both COPD subjects and controls. VitD did not affect epithelial to mesenchymal transition or epithelial MMP-9 expression and was not able to restore impaired wound healing by CSE in 16HBE cells. VitD increased the expression of its own catabolic enzyme CYP24A1 thereby maintaining its negative feedback. In conclusion, vitD supplementation may potentially reduce infectious exacerbations in COPD by the upregulation of cathelicidin in the bronchial epithelium.


Assuntos
Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Vitamina D/análogos & derivados , Idoso , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Brônquios/metabolismo , Brônquios/patologia , Estudos de Casos e Controles , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Interleucina-8/metabolismo , Masculino , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
6.
Biomed Pharmacother ; 118: 109315, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545256

RESUMO

Qingyan formulation (QF) is a common preparation that is often used to control inflammation in the haze environment. However, the efficacy and effective constituents of QF are still uncertain and difficult to identify. This paper aims to evaluate the efficacy by simulating a haze environment and determine its anti-inflammatory compounds by UPLC/Q-TOF-MS/MS combing with bioactivity screening. The therapeutic effect of QF in the simulated haze environment was confirmed from the aspects of lung histomorphology and inflammatory factor expression levels. QF showed strong anti-inflammatory activity with the minimum effective concentration reaching 1.5 g/kg. Potential anti-inflammatory components were screened by the NF-κB activity assay system and simultaneously identified based on mass spectral data. Then, the potential active compounds were verified by molecular biological methods, the minimum effective concentration can reach 0.1 mg/L. Six structural types of NF-κB inhibitors (phenolic acid, scopolamine, hydroxycinnamic acid, flavonoid, dihydroflavone and steroid) were identified. Further cytokine assays confirmed their potential anti-inflammatory effects of NF-κB inhibitors. This strategy clearly demonstrates that QF has a significant therapeutic effect on respiratory diseases caused by haze, so it is necessary to promote its commercialization and wider application.


Assuntos
Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fumaça , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Brônquios/efeitos dos fármacos , Brônquios/patologia , Brônquios/fisiopatologia , Bronquite/tratamento farmacológico , Bronquite/patologia , Doença Crônica , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/sangue , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Camundongos , NF-kappa B/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/fisiopatologia
7.
Int J Chron Obstruct Pulmon Dis ; 14: 1517-1526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371937

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a disease of continuous progress and environmental factors may affect the progress. COPD patients' activity tolerance and quality of life are associated with air quality. COPD exacerbation from the perspective of geographical air quality has not been reported. Objectives: To explore environmental effect of two different geographical places on COPD exacerbation and the effect of cigarette smoke extract and carbon particles on bronchial epithelial cell viability. Methods: Total 139 COPD patients, who lived in Beijing during summer and temporarily migrated to Sanya city in winter, have been enrolled. Respiratory symptoms and lung function data were collected when they were living in Beijing or Sanya, respectively. Effect of cigarette smoke extract plus ultrafine carbon particles on airway epithelial cells were studied. Measurements and main results: Air pollution as measured by air quality index (AQI) in Beijing summer (113.1±14.2) was significantly worse than that in Sanya winter (49.4±8.9, p<0.001). The COPD Assessment Test (CAT) score was significantly higher in Beijing (26.4±7.1) than that in Sanya (20.0±8.0, p=0.019). Modified Medical Research Council dyspnea scale was also significantly higher in Beijing (2.9±0.9) than that in Sanya (1.9±0.8, p<0.001). FEV1 was significantly improved when the patients were in Sanya (48.88±24.78%) compared to that in Beijing (41.79±20.06%, p<0.01). Compared with Beijing and Sanya, the relative risk (RR) of hospitalization and acute exacerbation were 1.64 and 3.36, respectively. In vitro study demonstrated that apoptosis of BEAS2B cells in response to cigarette smoke extract plus ultrafine carbon particles (25.50±2.10%) was significantly higher than that of control culture (2.30±1.05%, p<0.01). Conclusion: These findings suggested that ambient air pollution cause COPD exacerbation, and that air pollutants particle matters induce apoptosis of airway epithelial cells.


Assuntos
Poluição do Ar/efeitos adversos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Saúde da População Urbana , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Pequim , Brônquios/efeitos dos fármacos , Brônquios/patologia , Linhagem Celular , Progressão da Doença , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Material Particulado/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/patologia , Medição de Risco , Fatores de Risco , Estações do Ano , Fumaça/efeitos adversos , Fatores de Tempo
8.
Mol Pharmacol ; 96(4): 515-525, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427400

RESUMO

ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del-cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR-mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine-nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes. SIGNIFICANCE STATEMENT: These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.


Assuntos
Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Arginase/antagonistas & inibidores , Arginina/metabolismo , Benzodioxóis/farmacologia , Fibrose Cística/metabolismo , Óxido Nítrico/metabolismo , Quinolonas/farmacologia , Animais , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Cultivadas , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Citosol/metabolismo , Combinação de Medicamentos , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Mutação , Nariz/citologia , Nariz/efeitos dos fármacos
9.
Food Funct ; 10(8): 4661-4673, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292579

RESUMO

Hydroxysafflor yellow A (HSYA) is the main active ingredient of edible plant safflower. HSYA has demonstrated anti-inflammatory effects. The inflammatory response is the key mechanism responsible for asthma, and the pro-inflammatory platelet-activating factor (PAF) is known to play a role in the pathology of bronchial asthma. In this study, we stimulated human bronchial smooth muscle cells (HBSMCs) with PAF and examined the effects of HSYA on the resulting asthma-related process. PAF stimulation induced HBSMC activation, induced proliferation, increased expression of the pro-inflammatory cytokines interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α, and activated asthma-related signaling pathways. All these effects were significantly inhibited by treatment with HSYA (9, 27, 81 µmol L-1). The effects of HSYA were prevented by the addition of a PAF receptor (PAFR) antagonist or by PAFR gene silencing with small interfering RNA. These results suggest that HSYA may inhibit PAF-induced activation of HBSMCs by targeting the PAFR. Overall, these findings provide evidence that HSYA can be applied as a potential therapeutic agent in the treatment of bronchial asthma.


Assuntos
Brônquios/efeitos dos fármacos , Chalcona/análogos & derivados , Músculo Liso/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quinonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Brônquios/metabolismo , Chalcona/farmacologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Músculo Liso/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Ativação de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas-G/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Med Sci Monit ; 25: 5356-5368, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31323016

RESUMO

BACKGROUND B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a Bcl-2 family member with sequence homology to pro-apoptotic BAX and BAK, but its physiological and pathological roles remain largely unclear. Exposure of cells to cadmium may cause DNA damage, decrease DNA repair capacity, and increase genomic instability. MATERIAL AND METHODS The present study investigated the effects of BOK on the toxicity of cadmium chloride (CdCl2) to human bronchial epithelial (16HBE) cells. We constructed BOK over-expressing (16HBE-BOK) cells and BOK knockdown (16HBE-shBOK) cells using the BOK-ORF plasmid and BOK-siRNA. qRT-PCR for BOK mRNA expression. We used Trypan blue exclusion assay for cell growth, MTT colorimetric assays for cells inhibition rate, and Comet assays for detecting damaged DNA. RESULTS CdCl2, at various concentrations and exposure times, increased BOK mRNA. 16HBE-BOK cells (BOK over-expressing) proliferated more than 16HBE cells after 72 h; 16HBE-shBOK (BOK knockdown) cells proliferated less. In addition, BOK deficiency enhanced cell death induced by CdCl2. Similarly, CdCl2- and H2O2-induced DNA damage was greater in BOK-deficient cells. CONCLUSIONS These findings support a role for BOK in CdCl2-induced DNA damage and cell death.


Assuntos
Cloreto de Cádmio/toxicidade , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Dano ao DNA , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , RNA Mensageiro/metabolismo
11.
Biol Pharm Bull ; 42(9): 1605-1607, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243195

RESUMO

Recently, we demonstrated that Rac1 upregulation is involved in augmented bronchial smooth muscle (BSM) contractions of antigen-challenged mice. However, change in G protein-coupled receptor (GPCR)-induced Rac1 activation remains unknown in BSMs of repeatedly antigen-challenged (Chal.) mice. We here examined carbachol (CCh)-induced Rac1 activation in BSMs of Chal. mice. Gene expression levels of both Rac1 and Rac-guanine nucleotide exchange factors (GEFs), such as Tiam1 and Trio, were increased in BSMs of Chal. mice. Furthermore, CCh-induced Rac1 activation was inhibited by pretreatment with Rac1-GEF inhibitor NSC23766 and Rac1 inhibitor EHT1864 in BSMs of sensitized-control (S.C.) and Chal. mice. Compared with S.C. mice, CCh-induced Rac1 activation was increased in BSMs of Chal. mice. In conclusion, we reported that increased CCh-induced Rac1 activation via Tiam1 and Trio upregulation, in addition to upregulate Rac1, may be involved in increased CCh-induced BSM contractions in Chal. mice.


Assuntos
Brônquios/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Neuropeptídeos/fisiologia , Fosfoproteínas/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Aminoquinolinas/farmacologia , Animais , Antígenos , Asma/genética , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Carbacol , Fatores de Troca do Nucleotídeo Guanina/genética , Masculino , Camundongos Endogâmicos BALB C , Agonistas Muscarínicos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/genética , Ovalbumina , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Pirimidinas/farmacologia , Pironas/farmacologia , Quinolinas/farmacologia , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genética , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/genética
12.
Nutrients ; 11(6)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181780

RESUMO

Allium genus plants, such as leek (Allium porrum), are rich sources of anti-inflammatory and anti-oxidant secondary metabolites; this is of interest because it demonstrates their suitability as pharmacological alternatives for inflammatory processes, including allergy treatment. The composition of methanolic leek extract (LE) was analyzed by GC-MS and LC-IT/MS, and the total phenolic content and antioxidant capacity were quantified by colorimetric methods. Its pharmacological potential was analyzed in human bronchial epithelial Calu-3 cells, human mast cells LAD2, and humanized rat basophiles RBL-2H3. LE exhibited a cytotoxic effect on Calu-3 cells and HumRBL-2H3 cells only at high concentrations and in a dose-dependent manner. Moreover, LE decreased the degranulation of LAD2 and HumRBL-2H3 cells. LE treatment also significantly prevented alterations in transepithelial electrical resistance values and mRNA levels of glutathione-S-transferase (GST), c-Jun, and NFκB after treatment with H2O2 in ALI-cultured Calu-3 cells. Finally, ALI-cultured Calu-3 cells treated with LE showed lower permeability to Ole e 1 compared to untreated cells. A reduction in IL-6 secretion in ALI-cultured Calu-3 cells treated with LE was also observed. In summary, the results obtained in this work suggest that A. porrum extract may have potential anti-allergic effects due to its antioxidant and anti-inflammatory properties. This study provides several important insights into how LE can protect against allergy.


Assuntos
Antialérgicos/farmacologia , Brônquios/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Cebolas/química , Fenóis/uso terapêutico , Animais , Antialérgicos/análise , Antialérgicos/uso terapêutico , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/análise , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Brônquios/citologia , Brônquios/metabolismo , Linhagem Celular , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/prevenção & controle , Inflamação/metabolismo , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Fenóis/análise , Fenóis/farmacologia , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos
13.
J Pharmacol Exp Ther ; 370(1): 127-136, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085697

RESUMO

AZD8871 is a novel muscarinic antagonist and ß 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the ß 2-adrenoceptor over the ß 1 and ß 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and ß 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Triazóis/efeitos adversos , Triazóis/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Cães , Cobaias , Humanos , Masculino , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Receptor Muscarínico M2/metabolismo , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Triazóis/administração & dosagem , Triazóis/farmacocinética
14.
Environ Toxicol ; 34(7): 869-877, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033183

RESUMO

As a human carcinogen, coal tar pitch (CTP) can significantly increase the risk of lung cancer. However, the mechanism underlying CTP-induced lung carcinogenesis has not been well understood. This study aims to explore the role of the LncRNA-ENST00000501520 in the proliferation of malignant-transformed human bronchial epithelial cells (BAES-2B) induced by CTP extract for the first time. BEAS-2B cells were stimulated with 2.4 µg/mL CTP extract, and then passaged for three times, which were named passage 1 and then passaged until passage 30 (named as CTP group). The ENST000001520 of cells in CTP group was interfered using siRNA. The results showed that ENST000001520 located in cell nucleus (>80%) had no or weak ability of protein encoding. After interference of ENST000001520, the migration and proliferation of cells in CTP group were inhibited, and the cell cycle was arrested in the G0/G1 phase; however, the apoptosis of cells in CTP group was promoted. The target genes (SKB1, CLTB, TAP2, PIPK2, and SOCS3) of ENST000001520 were screened out, and the mRNA and protein expression of SBK1 and SOCS3 was significantly decreased after ENST000001520 interference. SBK1 and SOCS3 may play a promoting role in occurrence and development of cancers. The study suggests that LncRNA-ENST00000501520 could promote the proliferation in malignant-transformed BEAS-2B cells induced with CTP extract which may be mediated by target genes. This study may provide a new target for prevention and treatment of lung cancer.


Assuntos
Brônquios/efeitos dos fármacos , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Alcatrão/toxicidade , RNA Longo não Codificante/fisiologia , Mucosa Respiratória/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mucosa Respiratória/metabolismo
15.
Intensive Care Med ; 45(6): 834-843, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31020361

RESUMO

INTRODUCTION: Respiratory tract Candida spp. colonization is associated with more frequent bacterial ventilator-associated pneumonia (VAP). However, this colonization could be causally related to VAP or simply reflect the immune paralysis associated with multiple organ failure. OBJECTIVE: To prospectively evaluate the relationship between Candida spp. colonization and bacterial VAP in mechanically ventilated patients with multiple organ failure. INCLUSION: Patients receiving mechanical ventilation for > 4 days and presenting multiple organ failure were included. Tracheal colonization with Candida spp. was evaluated at inclusion (day 0, D0) and every 4 days until extubation. Quantitative proximal and tracheal cultures were performed at each VAP episode. Monocyte human leukocyte antigen-DR isotype (mHLA-DR) expression and the ratio of polymononuclear leukocytes to lymphocytes were used to evaluate immunoparalysis at D0 and D7. The relationship between fungal colonization and VAP was modelled using cause-specific models for repeated events with adjustment for time-dependent confounders and immune factors. RESULTS: A total of 213 patients, with a median age of 64, simplified acute physiology score II (SAPS II) score 55 and sequential organ failure assessment (SOFA) score 10, mainly admitted for medical reasons (n = 197, 92%), were enrolled in 2012-2015. The median ICU stay was 24 days and the mortality rate was 32% (69 cases). Median mHLA-DR was 5916 Ab-bound/cell [3863-8934]; median lymphocyte count, 0.9Giga/L [0.6-1.3]; neutrophil-to-lymphocyte ratio, 10.9 [6.5-19.7]. Overall, 146 cases (68.5%) had tracheal colonization with Candida spp. An episode of VAP occurred (either for the first or only time) in 62 (29.1%) cases 5.5 days (median) after D0; a second episode occurred in 12 (5.6%) cases, 15.5 days (median) after D0. After adjustment, bronchial colonization with Candida was not associated with VAP [adjusted cause-specific hazard ratio = 0.98 (0.59-1.65), p = 0.95]. CONCLUSION: In patients with mechanical ventilation for more than 4 days and multiple organ failure, bronchial colonization with Candida spp. was not associated with VAP, even after adjustment for immune function.


Assuntos
Candidíase/complicações , Pneumonia Associada à Ventilação Mecânica/etiologia , Adulto , Brônquios/efeitos dos fármacos , Brônquios/microbiologia , Candida/efeitos dos fármacos , Candida/patogenicidade , Candidíase/epidemiologia , Candidíase/fisiopatologia , Estudos de Coortes , Feminino , França/epidemiologia , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/fisiopatologia , Estudos Prospectivos , Fatores de Risco , Escala Psicológica Aguda Simplificada
16.
Pharmacol Rep ; 71(3): 517-521, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009843

RESUMO

BACKGROUND: Cyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3',5' cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. METHODS: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 µg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NOx) were also measured in serum. RESULTS: Pre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NOx and increased the levels of GSH in serum. CONCLUSIONS: Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.


Assuntos
Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Animais , Asma/metabolismo , Brônquios/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
17.
Artigo em Inglês | MEDLINE | ID: mdl-31009988

RESUMO

The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV1) and FOT (resistance at 5 Hz, R5; resistance at 5 minus 20 Hz, R5-20). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R5 and R5-20) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.


Assuntos
Broncodilatadores/farmacologia , Poeira , Volume Expiratório Forçado , Ataques Terroristas de 11 de Setembro , Capacidade Vital , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria
18.
Environ Pollut ; 250: 650-661, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31035147

RESUMO

Aldehydes are well-known air pollutants and often studied alone, while co-exposure to aldehyde mixtures is more common than single aldehydes. Unfortunately, it has been very little known about the (mechanism of) combined toxicity of aldehyde mixtures. Here, formaldehyde and acrolein were selected as the typical representatives of common aldehydes, and were used to explore to get in-depth insight into the mechanism of combined toxicity of aldehyde mixtures. The NOECs (non-observed effect concentrations) are 60 µmoL/L for formaldehyde, and 0.5 µmoL/L for acrolein, so acrolein is more toxic than formaldehyde. Formaldehyde and acrolein mixtures showed significant cytotoxicity and synergistic effects in a concentration/time-dependent way on BEAS-2B cells based on acute and chronic cytotoxicity assay. Acrolein was dominant in aldehyde mixtures in inducing cytotoxicity at environmentally relevant doses because of higher toxicity. Moreover, aldehyde mixtures significantly synergistically increased the intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, while caused an antagonistic effects on glutathione (GSH). Besides, formaldehyde could significantly potentiated the activation of environmental stress sensitive Nrf2 pathway induced by acrolein, even at doses at which formaldehyde treatment alone had no any response. Furthermore, as the downstream components of Nrf2 pathway, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) and heme oxygenase-1 (HO-1) were significantly synergistically induced by formaldehyde and acrolein mixtures. Antioxidants N-acetylcysteine and reduced glutathione could significantly suppress the acute and chronic combined cytotoxicity of acrolein and formaldehyde mixtures, and changed their interactions (synergism) on cytotoxicity. Taken together, aldehyde mixtures have higher toxicity than that expected for additivity based on single aldehydes even at environmentally relevant concentrations, and the combined cytotoxicity may be enhanced through oxidative stress and the related Nrf2 pathway. Prolonged exposure to pollutants containing aldehyde mixtures through inhalation may have more serious threat to respiratory system in animal and human.


Assuntos
Acroleína/toxicidade , Poluentes Atmosféricos/toxicidade , Brônquios/efeitos dos fármacos , Citotoxinas/toxicidade , Formaldeído/toxicidade , Antioxidantes/química , Brônquios/citologia , Catalase/metabolismo , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Glutationa/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
19.
Basic Clin Pharmacol Toxicol ; 125(3): 304-314, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30861304

RESUMO

Reactive oxygen species (ROS) is regarded as a critical denominator in nanoparticle toxicology and inflammation. Previously, we have shown that silica nanoparticles sized 50 nm (Si50) induce release of CXCL8 and IL-6 from BEAS-2B cells, via mechanisms involving NFκB, p38 MAP kinase and TGF-α-activated EGF receptor. In the present study, the role of ROS-mediated mechanisms in the concentration-dependent Si50 induction of CXCL8 and IL-6 responses was examined. Si50 (200 µg/mL) induced a time-dependent ROS formation and a postponed increase in expression of haem oxygenase (HO-1) mRNA and protein. Pre-treatment with the ROS inhibitors N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI) partially attenuated CXCL8 and IL-6 responses to 200 µg/mL, but not to 100 µg/mL Si50. The release of TGF-α induced by Si50 (200 µg/mL) was significantly reduced by NAC, but not by DPI nor siRNA against NADPH oxidase DUOX-1 (siDUOX-1). Furthermore, siDUOX-1 reduced Si50-induced CXCL8, but not IL-6. Both p38 and p65 phosphorylations were inhibited by siDUOX-1, but for NAC only p65 phosphorylation reached a significant reduction. Neither NAC nor DPI reduced Si50-induced CXCL8 and IL-6 gene expressions. In conclusion, Si50-induced CXCL8 and IL-6 involved both ROS-dependent and ROS-independent mechanisms. Notably, the role of ROS seemed restricted to effects of higher concentrations of Si50 and not mediated via the gene expression.


Assuntos
Brônquios/efeitos dos fármacos , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Dióxido de Silício/toxicidade , Brônquios/citologia , Brônquios/imunologia , Linhagem Celular , Oxidases Duais/genética , Oxidases Duais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucina-8/imunologia , Interleucina-8/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Tamanho da Partícula , Fosforilação/efeitos dos fármacos , Fosforilação/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Transcrição RelA/metabolismo
20.
Pulm Pharmacol Ther ; 56: 39-50, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30876907

RESUMO

Combining a long-acting ß2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.


Assuntos
Benzoxazinas/farmacologia , Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Músculo Liso/efeitos dos fármacos , Brometo de Tiotrópio/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Idoso , Benzoxazinas/administração & dosagem , Brônquios/metabolismo , Broncodilatadores/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Músculo Liso/metabolismo , Brometo de Tiotrópio/administração & dosagem
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