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1.
J Photochem Photobiol B ; 203: 111731, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31935633

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic inflammatory disease with a poor prognosis and very few available treatment options. Low-level laser therapy (LLLT) has been gaining prominence as a new and effective anti-inflammatory and immunomodulatory agent. Can lung inflammation and the airway remodeling be regulated by LLLT in an experimental model of IPF in C57Bl/6 mice? The present study investigated if laser attenuates cellular migration to the lungs, the airway remodeling as well as pro-fibrotic cytokines secretion from type II pneumocytes and fibroblasts. Mice were irradiated (780 nm and 30 mW) and then euthanized fifteen days after bleomycin-induced lung fibrosis. Lung inflammation and airway remodeling were evaluated through leukocyte counting in bronchoalveolar lavage fluid (BALF) and analysis of collagen in lung, respectively. Inflammatory cells in blood were also measured. For in vitro assays, bleomycin-activated fibroblasts and type II pneumocytes were irradiated with laser. The pro- and anti-inflammatory cytokines level in BALF as well as cells supernatant were measured by ELISA, and the TGFß in lung was evaluated by flow cytometry. Lung histology was used to analyze collagen fibers around the airways. LLLT reduced both migration of inflammatory cells and deposition of collagen fibers in the lungs. In addition, LLLT downregulated pro-inflammatory cytokines and upregulated the IL-10 secretion from fibroblasts and pneumocytes. Laser therapy greatly reduced total lung TGFß. Systemically, LLLT also reduced the inflammatory cells counted in blood. There is no statistical difference in inflammatory parameters studied between mice of the basal group and the laser-treated mice. Data obtained indicate that laser effectively attenuates the lung inflammation, and the airway remodeling in experimental pulmonary fibrosis is driven to restore the balance between the pro- and anti-inflammatory cytokines in lung and inhibit the pro-fibrotic cytokines secretion from fibroblasts.


Assuntos
Remodelação das Vias Aéreas , Citocinas/metabolismo , Fibrose Pulmonar Idiopática/radioterapia , Lasers , Animais , Líquido da Lavagem Broncoalveolar/química , Células Cultivadas , Citocinas/análise , Modelos Animais de Doenças , Regulação para Baixo/efeitos da radiação , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Fibrose Pulmonar Idiopática/patologia , Terapia a Laser , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/efeitos da radiação
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 845-851, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694095

RESUMO

Objective: To explore the role of S100A8, the receptor for advanced glycation endproducts (RAGE) and Caveolin-1 in neutrophilic asthmatic rats, and to further study the intervention of roxithromycin and the possible mechanisms. Methods: Male Brown Norway rats were randomly assigned to a control group, an asthma group and a Roxithromycin group. The asthmatic rat model was established by intraperitoneal injection of ovalbumin (OVA) and Freund's complete adjuvant (FCA) mixture, and aerosol inhalation of OVA. Rats in the Roxithromycin group were given roxithromycin injection 30 mg/kg 30 minutes before each challenge. Rats in the control and the asthma groups were replaced with equal volumes of saline, respectively. Bronchoalveolar lavage fluid (BALF) neutrophil percentage (Neu%) and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. The concentration of inflammatory cytokines and S100A8 were quantified by enzyme-linked immunosorbent assay (ELISA), and the expression of Caveolin-1 and RAGE at protein levels were detected by immunohistochemistry and Western blot. Results: Neu% in BALF of the asthma group was significantly higher than those of the control group, and Neu% in the Roxithromycin group was lower than the asthma group (all P<0.01). Pulmonary histology revealed that there were a large number of inflammatory cells infiltrated in the bronchial and perivascular, pulmonary interstitial and alveolar spaces, and the bronchial wall and smooth muscles were thickened obviously in the asthma group. Rats in the Roxithromycin group showed milder inflammation and airway remodeling change than the asthma group. There was no obvious pathological damage in the control group. The concentration of IL-6 and IL-17 in BALF and serum of rats in the asthma group were significantly higher than those in the control group (P<0.01), and Roxithromycin inhibited the high expression of these cytokines (P<0.05). The expression of S100A8 and RAGE in the asthma group were significantly higher than those in the control group [(20.6±4.4) vs (7.1±2.0) ng/L; (885±118) vs (462±102) ng/L; (14.2±1.7) vs (7.6±1.8) ng/L; (774±166) vs (406±69) ng/L, all P<0.05], and Roxithromycin inhibited the high expression of these proteins [(14.3±3.7) vs (20.6±4.4) ng/L; (650±53) vs (885±118) ng/L; (10.4±1.2) vs (14.2±1.7) ng/L; (560±64) vs (728±72) ng/L] (all P<0.05). Meanwhile, the expression of Caveolin-1 in the asthma group was significantly lower than that in the control group (P<0.01), and Roxithromycin up-regulated its expression (P<0.01). Correlation analysis showed that there was a significantly positive correlation between the expression of S100A8 and RAGE (r=0.706, P<0.01), while there was a significantly negative correlation between the expression of S100A8 and Caveolin-1 (r=-0.775, P<0.01), and between the expression of Caveolin-1 and RAGE (r=-0.919, P<0.01). Conclusion: S100A8 and Caveolin-1 may play an important role in neutrophilic asthma via RAGE, and Roxithromycin may exerts anti-inflammatory effects and inhibition of airway remodeling partly through this signaling pathway.


Assuntos
Antibacterianos/farmacologia , Asma/tratamento farmacológico , Calgranulina A/efeitos dos fármacos , Caveolina 1/efeitos dos fármacos , Roxitromicina/farmacologia , Remodelação das Vias Aéreas , Animais , Antibacterianos/administração & dosagem , Western Blotting , Líquido da Lavagem Broncoalveolar , Calgranulina A/metabolismo , Caveolina 1/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Pulmão/fisiopatologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ovalbumina , Ratos , Receptor para Produtos Finais de Glicação Avançada , Roxitromicina/administração & dosagem
3.
BMC Complement Altern Med ; 19(1): 316, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744482

RESUMO

BACKGROUND: Icariin (ICA) is the major active ingredient extracted from Chinese herbal medicine Epimedium, which has the effects of improving cardiovascular function, inducing tumor cell differentiation and increasing bone formation. It is still rarely reported that ICA can exert its therapeutic potential in asthma via anti-airway remodeling. The point of the study was to estimate the role of ICA in anti-. airway remodeling and its possible mechanism of action in a mouse ovalbumin. (OVA)-induced asthma model. METHODS: Hematoxylin and Eosin Staining were performed for measuring airway remodeling related indicators. ELISA, Western blot and Immunohistochemistr-. y (IHC) were used for analyzing the level of protein. RT-PCR was used for analyzing the level of mRNA. RESULTS: On days 1 and 8, mice were sensitized to OVA by intraperitoneal injection. From day 16 to day 43, previously sensitized mice were exposed to OVA once daily by nebulizer. Interventions were performed orally with ICA (ICA low, medium and high dose groups) or dexamethasone 1 h prior to each OVA exposure. ICA improves pulmonary function, attenuates pulmonary inflammation and airway remodeling in mice exposed to OVA. Histological and Western blot analysis of the lungs show that ICA suppressed transforming growth factor beta 1 and vascular endothelial growth factor expression. Increase in interleukin 13 and endothelin-1 in serum and bronchoalveolar lavage fluid in OVA-induced asthmatic mice are also decreased by ICA. ICA attenuates airway smooth muscle cell proliferation, as well as key factors in the MAPK/Erk pathway. CONCLUSIONS: The fact that ICA can alleviate OVA-induced asthma at least partly through inhibition of ASMC proliferation via MAPK/Erk pathway provides a solid theoretical basis for ICA as a replacement therapy for asthma. These data reveal the underlying reasons of the use of ICA-rich herbs in Traditional Chinese Medicine to achieve good results in treating asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Epimedium/química , Flavonoides/administração & dosagem , Animais , Asma/genética , Asma/metabolismo , Asma/fisiopatologia , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Exp Mol Pathol ; 111: 104315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31629729

RESUMO

Caveolin is a structural protein of flask-shaped invaginations of the plasma membrane termed as caveolae and is widely expressed on the endothelial cells, smooth muscle cells and fibroblasts in the different parts of the body including the lung tissues. The expression of caveolin-1 in the lung tissues is important to prevent the fibrogenic actions of TGF-ß1 in lung fibrosis of different etiology including idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease and allergen-induced airway remodeling. Caveolin-1-mediated internalization and degradation of TGF-ß1 receptors may possibly account for the decreased actions of TGF-ß1. Studies have shown that the deficiency of caveolin-1 is very important in inducing lung fibrosis and its upregulation is reported to prevent lung fibrosis. The biological actions of caveolin-1 involve signaling pathways including JNK signaling, IL-4, STAT-3, miR199a-5p, CXCR4+ and CXCL12. The present review discusses the key role of caveolin and associated signaling pathways in the pathogenesis of lung fibrosis of different etiology.


Assuntos
Caveolina 1/fisiologia , Fibrose Pulmonar/etiologia , Remodelação das Vias Aéreas/fisiologia , Animais , Citocinas/metabolismo , Epigênese Genética , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
5.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
6.
Phytomedicine ; 64: 153076, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473579

RESUMO

BACKGROUND: Long-term exposure to aeroallergens such as house dust mite (HDM) could result in airway inflammation and airway remodeling, characteristic features of allergic asthma. Huangqi-Fangfeng (HF), an important "couplet medicines" of Yu-Ping-Feng-San (YPFS), mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. PURPOSE: To evaluate the effects of HF on airway remodeling of allergic asthma in a murine model and to investigate the underlying mechanisms in vivo and in vitro. METHODS: The main components of HF were analyzed by HPLC. The HDM-induced asthma mice model was established to study the effects of HF on airway inflammation and airway remodeling in vivo. Enhanced pause (Penh) index value was used as an indicator of airway hyper-reactivity. Bronchoalveolar lavage fluid (BALF) was processed for differential cell counting and determination of cytokines production. The lungs were fixed in 4% paraformaldehyde for histological examination after staining with H&E, trichrome and IHC. Production of interleukin (IL)-4, IL-5, IL-13, and transforming growth factor beta-1 (TGF-ß1) in BALF and lung tissues, IgE in serum were measured by ELISAs. Expression of epithelial markers and mesenchymal markers were detected by immunohistochemistry and western blots. The effects of HF and its components on epithelial-mesenchymal transition (EMT) were detected in human bronchial epithelial cells (16HBE) treated with TGF-ß1 and HDM. RESULTS: The main components of Huangqi-Fangfeng detected by HPLC were Calycosin, Formononetin and Cimifugin. In HDM-induced allergic asthma mice model, respiratory exposure to HDM lead to airway hyperresponsiveness and thickening of the smooth muscle layer in the airway. TGF-ß1 levels increased in mice airways while epithelial cells lost expression of E-cadherin and gained expression of the mesenchymal proteins N-cadherin, α-SMA and collagen І. These changes were relieved by treatment with HF. Furthermore, restored epithelial markers expression treated with individual components were also detectable in 16HBE cells. CONCLUSION: These results demonstrated that Huangqi-Fangfeng protected against allergic airway remodeling through inhibiting epithelial-mesenchymal transition process in mice via regulating epithelial derived TGF-ß1.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Animais , Antiasmáticos/química , Apiaceae/química , Asma/etiologia , Asma/patologia , Brônquios/citologia , Líquido da Lavagem Broncoalveolar , Cromonas/análise , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Células Epiteliais/efeitos dos fármacos , Humanos , Isoflavonas/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador beta1/metabolismo
7.
Zhonghua Yi Xue Za Zhi ; 99(32): 2542-2546, 2019 Aug 27.
Artigo em Chinês | MEDLINE | ID: mdl-31484284

RESUMO

Objective: To observe the expression of the Receptor of Advanced glycation end products (RAGE) in asthmatic rats, and explore the intervention of Roxithromycin. Methods: A total of 18 Specific Pathogen Free-class Brown Norway male rats were randomly divided into control group, asthma model group and Roxithromycin group, with 6 rats in each group. The asthmatic model was sensitized by intraperitoneal injection of Ovalbumin (OVA)+Al(OH)(3), and challenged with OVA. Rats in Roxithromycin group were given Roxithromycin 30 mg/kg 30 minutes before each challenge. Rats in control group and asthma model group were treated with equal volume of saline. The concentrations of RAGE and interleukin (IL)-4 in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent (ELISA); the pathological changes of lung tissues were observed by HE-staining; the thickness of airway wall and airway smooth muscle were measured by Image-Pro Plus; the relative expression of RAGE in lung tissues were detected by Western blot. Results: In asthma model group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously higher than those in control group [(494±32) vs (327±45) ng/L; (32.4±5.8) vs (13.1±2.9) ng/L; (553±38) vs (399±56) ng/L; (37.8±3.4) vs (19.4±2.5) ng/L] (all P<0.01); in Roxithromycin group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously lower than those in asthma model group [(438±18) vs (494±32) ng/L; (22.8±6.0) vs (32.4±5.8) ng/L; (444±42) vs (553±38) ng/L; (25.6±4.5) vs (37.8±3.4) ng/L] (all P<0.05). In asthma model group, the bronchial wall was thickened, the lumen was narrow, the mucosal wrinkles were significantly increased, edema appeared under the mucosa, and a large number of inflammatory cells infiltrated and aggregated in the bronchi, perivascular and alveolar spaces; the thickness of airway wall and airway smooth muscle were significantly increased than those in control group (P<0.01); in Roxithromycin group, airway inflammation and remodeling were alleviated compared with those in asthma model group (P<0.05). In asthma model group, the expression of RAGE in lung tissues were significantly increased than those in control group (P<0.01); in Roxithromycin group, the expression of RAGE were significantly decreased than those in asthma model group (P<0.01). There were positive correlations between the expression of RAGE and IL-4 in BALF and serum (r=0.782, 0.804, all P<0.01); there were positive correlations between RAGE and total white cell counts, eosinophil counts, smooth muscle thickness (r=0.897, 0.927, 0.860, all P<0.01). Conclusions: The increasing of RAGE in asthmatic rats are positively correlated with airway inflammation and airway remodeling. Roxithromycin may inhibit the development of asthma by reducing the expression of RAGE.


Assuntos
Asma , Remodelação das Vias Aéreas , Animais , Líquido da Lavagem Broncoalveolar , Produtos Finais de Glicação Avançada , Pulmão , Masculino , Ovalbumina , Ratos , Roxitromicina
8.
Biomed Pharmacother ; 119: 109429, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505422

RESUMO

Asthma is a common obstructive airway disease characterized by inflammation and remodeling with a progressive decline in lung function. Fangxiao Formula (FXF) is an herbal medicine that has achieved significant clinical benefits toward asthma patients, but the relevant mechanism has not yet been clarified. The aim of this study was to determine the inhibitory effects of FXF on airway inflammation and remodeling, and investigate the activities of TGF­ß/Smads signaling pathway in the rat asthma model. Rats were sensitized by ovalbumin (OVA) for six weeks to establish the asthma experimental model. OVA-challenged animals were randomly divided into 5 groups and received different concentrations of FXF or dexamethasone. The animals in blank control group received saline only. Lung tissues were collected and analyzed for determining the inflammatory cells infiltration, HE and PAS staining, airway wall thickness and collagen deposition. The productions of inflammatory cytokine productions were analyzed by ELISA in the bronchoalveolar lavage (BAL) fluid. Immunohistochemical analysis was performed to measure the expression of α-SMA and PCNA in lung tissue after the treatment of FXF. The levels of TGF-ß were assessed by both immunohistology and western blotting, and the expression of p-Smad2/3 proteins were determined by western blotting analysis. Our results indicated that FXF attenuated the infiltration of inflammatory cells, decreased the production of Th2 cytokines and simultaneously increased the levels of Th1 cytokine in the asthma rat model. In addition, FXF reduced allergen-induced increased airway wall thickness, goblet cell hyperplasia and collagen deposition. Furthermore, the expression levels of TGF-ß and p-Smad3 were obviously reduced after the treatment of FXF. These results indicate that FXF alleviates airway inflammation and remodeling by restoring the balance of Th1/Th2 cytokines and the TGF-ß/Smad-3 pathway, therefor providing potential therapeutic approach for asthmatic patients.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/fisiopatologia , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Pulmão/patologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Hiperplasia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
9.
Respir Res ; 20(1): 181, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399087

RESUMO

BACKGROUND: KRAS is a GTPase that activates pathways involved in cell growth, differentiation and survival. In normal cells, KRAS-activity is tightly controlled, but with specific mutations, the KRAS protein is persistently activated, giving cells a growth advantage resulting in cancer. While a great deal of attention has been focused on the role of mutated KRAS as a common driver mutation for lung adenocarcinoma, little is known about the role of KRAS in regulating normal human airway differentiation. METHODS: To assess the role of KRAS signaling in regulating differentiation of the human airway epithelium, primary human airway basal stem/progenitor cells (BC) from nonsmokers were cultured on air-liquid interface (ALI) cultures to mimic the airway epithelium in vitro. Modulation of KRAS signaling was achieved using siRNA-mediated knockdown of KRAS or lentivirus-mediated over-expression of wild-type KRAS or the constitutively active G12 V mutant. The impact on differentiation was quantified using TaqMan quantitative PCR, immunofluorescent and immunohistochemical staining analysis for cell type specific markers. Finally, the impact of cigarette smoke exposure on KRAS and RAS protein family activity in the airway epithelium was assessed in vitro and in vivo. RESULTS: siRNA-mediated knockdown of KRAS decreased differentiation of BC into secretory and ciliated cells with a corresponding shift toward squamous cell differentiation. Conversely, activation of KRAS signaling via lentivirus mediated over-expression of the constitutively active G12 V KRAS mutant had the opposite effect, resulting in increased secretory and ciliated cell differentiation and decreased squamous cell differentiation. Exposure of BC to cigarette smoke extract increased KRAS and RAS protein family activation in vitro. Consistent with these observations, airway epithelium brushed from healthy smokers had elevated RAS activation compared to nonsmokers. CONCLUSIONS: Together, these data suggest that KRAS-dependent signaling plays an important role in regulating the balance of secretory, ciliated and squamous cell differentiation of the human airway epithelium and that cigarette smoking-induced airway epithelial remodeling is mediated in part by abnormal activation of KRAS-dependent signaling mechanisms.


Assuntos
Diferenciação Celular/fisiologia , Fumar Cigarros/efeitos adversos , Fumar Cigarros/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Mucosa Respiratória/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Fumar Cigarros/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Adulto Jovem
10.
Int J Chron Obstruct Pulmon Dis ; 14: 1603-1610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409985

RESUMO

COPD is a common and highly destructive disease with huge impacts on people and health services throughout the world. It is mainly caused by cigarette smoking though environmental pollution is also significant. There are no current treatments that affect the overall course of COPD; current drugs focus on symptomatic relief and to some extent reducing exacerbation rates. There is an urgent need for in-depth studies of the fundamental pathogenic mechanisms that underpin COPD. This is vital, given the fact that nearly 40%-60% of the small airway and alveolar damage occurs in COPD well before the first measurable changes in lung function are detected. These individuals are also at a high risk of lung cancer. Current COPD research is mostly centered around late disease and/or innate immune activation within the airway lumen, but the actual damage to the airway wall has early onset. COPD is the end result of complex mechanisms, possibly triggered through initial epithelial activation. To change the disease trajectory, it is crucial to understand the mechanisms in the epithelium that are switched on early in smokers. One such mechanism we believe is the process of epithelial to mesenchymal transition. This article highlights the importance of this profound epithelial cell plasticity in COPD and also its regulation. We consider that understanding early changes in COPD will open new windows for therapy.


Assuntos
Fumar Cigarros , Transição Epitelial-Mesenquimal , Pulmão , Doença Pulmonar Obstrutiva Crônica , Remodelação das Vias Aéreas , Fumar Cigarros/patologia , Fumar Cigarros/fisiopatologia , Progressão da Doença , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
11.
Phytother Res ; 33(11): 3008-3015, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435973

RESUMO

Airway remodeling is one important feature of childhood asthma, which is one of the most common chronic childhood diseases. Phenotype switching of airway smooth muscle cells (ASMCs), defined as a reversible switching between contractile and proliferative phenotypes, plays an important role in the process of airway remodeling. Esculetin has shown antiinflammatory action in animal models of asthma; however, the effects of esculetin on ASMC phenotype switching have not been investigated. In the present study, platelet-derived growth factor (PDGF) was used to induce the phenotype modulation of ASMCs. The results demonstrated that esculetin pretreatment mitigated the PDGF-caused inhibitory effects on expressions of contractile phenotype protein markers, including calponin and SM22α. Esculetin also inhibited PDGF-induced migration and proliferation of ASMCs. Besides, the PDGF-induced expressions of extracellular matrix components, collagen I and fibronectin, were attenuated by esculetin pretreatment. Furthermore, PDGF-caused activation of PI3K/Akt pathway in ASMCs was inhibited by esculetin. These findings suggest that esculetin might exert its inhibitory effect on PDGF-induced ASMC phenotype switching through inhibition of PI3K/Akt pathway.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Umbeliferonas/farmacologia , Remodelação das Vias Aéreas/fisiologia , Asma/metabolismo , Asma/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Colágeno Tipo I/metabolismo , Humanos , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/fisiologia
12.
Int J Chron Obstruct Pulmon Dis ; 14: 1333-1342, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31296985

RESUMO

Purpose: The diagnosis and severity of chronic obstructive pulmonary disease (COPD) are defined by airflow limitation using spirometry. However, COPD has diverse clinical features, and several phenotypes based on non-spirometric data have been investigated. To identify novel phenotypes of COPD using radiologic data obtained by three-dimensional computed tomography (3D-CT). Patients and methods: The inner luminal area and wall thickness of third- to sixth-generation bronchi and the percentage of the low-attenuation area (less than -950 HU) of the lungs were measured using 3D-CT in patients with COPD. Using the radiologic data, hierarchical clustering was performed. Respiratory reactance and resistance were measured to evaluate functional differences among the clusters. Results: Four clusters were identified among 167 patients with COPD: Cluster I, mild emphysema with severe airway changes, severe airflow limitation, and high exacerbation risk; Cluster II, mild emphysema with moderate airway changes, mild airflow limitation, and mild dyspnea; Cluster III, severe emphysema with moderate airway changes, severe airflow limitation, and increased dyspnea; and Cluster IV, moderate emphysema with mild airway changes, mild airflow limitation, low exacerbation risk, and mild dyspnea. Cluster I had the highest respiratory resistance among the four clusters. Clusters I and III had higher respiratory reactance than Clusters II and IV. Conclusions: The 3D-CT-based radiologic phenotypes were associated with the clinical features of COPD. Measurement of respiratory resistance and reactance may help to identify phenotypic differences.


Assuntos
Dispneia/diagnóstico por imagem , Imagem Tridimensional , Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Remodelação das Vias Aéreas , Resistência das Vias Respiratórias , Análise por Conglomerados , Estudos Transversais , Dispneia/fisiopatologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/fisiopatologia , Índice de Gravidade de Doença
13.
Eur Respir Rev ; 28(152)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31285287

RESUMO

Chronic obstructive pulmonary disease (COPD) is characterised by nonreversible proximal bronchial obstruction leading to major respiratory disability. However, patient phenotypes better capture the heterogeneously reported complaints and symptoms of COPD. Recent studies provided evidence that classical bronchial obstruction does not properly reflect respiratory disability, and symptoms now form the new paradigm for assessment of disease severity and guidance of therapeutic strategies. The aim of this review was to explore pathways addressing COPD pathogenesis beyond proximal bronchial obstruction and to highlight innovative and promising tools for phenotyping and bedside assessment. Distal small airways imaging allows quantitative characterisation of emphysema and functional air trapping. Micro-computed tomography and parametric response mapping suggest small airways disease precedes emphysema destruction. Small airways can be assessed functionally using nitrogen washout, probing ventilation at conductive or acinar levels, and forced oscillation technique. These tests may better correlate with respiratory symptoms and may well capture bronchodilation effects beyond proximal obstruction.Knowledge of inflammation-based processes has not provided well-identified targets so far, and eosinophils probably play a minor role. Adaptative immunity or specific small airways secretory protein may provide new therapeutic targets. Pulmonary vasculature is involved in emphysema through capillary loss, microvascular lesions or hypoxia-induced remodelling, thereby impacting respiratory disability.


Assuntos
Pulmão/diagnóstico por imagem , Testes Imediatos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Testes de Função Respiratória , Microtomografia por Raio-X , Remodelação das Vias Aéreas , Animais , Avaliação da Deficiência , Hemodinâmica , Humanos , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Respiração , Índice de Gravidade de Doença , Remodelação Vascular
14.
Phytother Res ; 33(10): 2702-2713, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313371

RESUMO

Chrysophanol (CHR), a purified active constituent extracted from Rheum palmatum L., possesses anti-inflammatory activity. This study aimed to evaluate its effects on asthma-associated airway inflammation and remodeling. BALB/c mice were sensitized and challenged by ovalbumin (OVA) and administrated with different doses of CHR. We found that CHR decreased OVA-induced pulmonary inflammation: the levels of interleukin (IL)-4, IL-5, and IL-13, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase were downregulated. CHR also attenuated airway remodeling induced by OVA challenge-CHR inhibited pulmonary α-smooth muscle actin expression. Moreover, both the nuclear translocation and activity of NF-κB p65 were inhibited by CHR in the asthmatic lung. Enhanced autophagy was initiated in the lung by OVA challenge as evidenced by upregulated light chain 3 beta, autophagy-related protein 5, and Beclin 1. CHR suppressed OVA-induced alterations in these autophagy-related molecules. In vitro, CHR (2 or 20 µM) was used to treat human pulmonary epithelial BEAS-2B cells in the presence of 10 ng/ml recombinant TNF-α. CHR not only exhibited the antiproliferation effect but also inhibited the activation of nuclear factor-kappa B (NF-kB) signaling pathway in TNF-α-treated BEAS-2B cells. In conclusion, our study indicates that CHR has the potential to ameliorate asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antraquinonas/farmacologia , Asma/tratamento farmacológico , NF-kappa B/fisiologia , Animais , Antraquinonas/uso terapêutico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
15.
Biomed Res Int ; 2019: 2025636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341890

RESUMO

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.


Assuntos
Remodelação das Vias Aéreas , Barreira Alveolocapilar , Fumar Cigarros , Matriz Extracelular , Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Barreira Alveolocapilar/metabolismo , Barreira Alveolocapilar/patologia , Fumar Cigarros/efeitos adversos , Fumar Cigarros/metabolismo , Fumar Cigarros/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Tempo
16.
PLoS One ; 14(6): e0219081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31247032

RESUMO

BACKGROUND: The abnormal proliferation and migration of airway smooth muscle (ASM) cells contributes to airway remodeling during asthma. MiR-19a has been demonstrated to promote cell proliferation and angiogenesis of several cancer types by regulating the PTEN/PI3K/AKT pathway. Our previous study has shown that High-mobility group box protein 1 (HMGB1) is involved in the pathogenesis of airway remodeling using a mouse model of chronic asthma. However, the effects of HMGB1 on proliferation and migration of ASM cells and its underlying mechanisms remain unknown. METHODS: Human ASM cells were obtained by primary explant techniques. MiR-19a expression was evaluated using qRT-PCR. Cell proliferation and migration were evaluated by the CCK-8 and the transwell migration assays, respectively. Transfection studies of ASM cells were performed to identify the underlying mechanisms. RESULTS: HMGB1 stimulated ASM cell proliferation and migration in a dose-dependent manner. The expression levels of miR-19a and the PTEN and AKT signaling proteins were also modulated by HMGB1. Functional studies indicated that overexpression of miR-19a enhanced the proliferation and migration of ASM cells, whereas inhibition of miR-19a decreased the proliferation and migration of ASM cells. Western blot analysis demonstrated that miR-19a negatively regulated PTEN expression and positively regulated p-AKT expression. MiR-19 only regulates the proliferation of HASM cells induced by HMGB1, but not PDGF, EGF, TGF-ß1. Furthermore, we demonstrated that miR-19 contributed to the promoting effects of HMGB1 on ASM cells by targeting PTEN 3'-UTR. CONCLUSION: Our results demonstrated that HMGB1 induced proliferation and migration of ASM cells via the miR-19a /PTEN/AKT axis and provided direct evidence on the role of HMGB1 in ASM cells proliferation in vitro. The present study further indicated that miR-19a may be explored as a potential novel therapeutic target to reverse proliferation and migration of ASM cells.


Assuntos
Proteína HMGB1/metabolismo , MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Regiões 3' não Traduzidas , Remodelação das Vias Aéreas/genética , Remodelação das Vias Aéreas/fisiologia , Asma/genética , Asma/metabolismo , Asma/patologia , Brônquios/citologia , Brônquios/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
17.
Acupunct Med ; 37(4): 228-236, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31155877

RESUMO

BACKGROUND: Asthma is a chronic inflammatory disease that affects millions of people worldwide. Chronic asthma is commonly resistant to steroid therapy. Acupuncture has an anti-inflammatory effect and has been widely used as an add-on therapy for asthma. OBJECTIVE: To evaluate the effects of acupuncture on the inflammatory response and airway remodelling in the bronchioles of an asthma mouse model. METHODS: A chronic asthma model was produced in female BALB/c mice by ovalbumin (OVA) sensitisation. 32 mice were randomised into four groups: control; asthma (OVA); OVA+BL13; and OVA+BL13+ST36. OVA was administered by intraperitoneal injection on days 0 and 14 followed by aerosol exposure of 1% OVA three times a week for 6 weeks. Manual acupuncture (MA) was performed three times a week for 6 weeks at BL13 alone, or BL13 in combination with ST36, in the two MA-treated groups. At the end of the experiment, blood samples were collected to determine eosinophil and neutrophil counts and lung tissue was prepared for histological examination. RESULTS: A pronounced reduction in the neutrophil count was achieved after MA at BL13+ST36 (P=0.005) while the eosinophil count was lowered after MA both at BL13 (P=0.007) and BL13+ST36 (P=0.006). Reduction in the bronchiolar epithelial and smooth muscle thickness and the number of goblet cells was observed after MA at BL13 (P=0.001, P=0.001 and P=0.002, respectively) and BL13+ST36 (P=0.001, P=0.002 and P=0.001, respectively). CONCLUSION: Acupuncture can reduce the inflammatory response and prevent airway remodelling in a chronic asthma mouse model.


Assuntos
Pontos de Acupuntura , Terapia por Acupuntura , Remodelação das Vias Aéreas , Asma/imunologia , Asma/terapia , Animais , Asma/fisiopatologia , Doença Crônica/terapia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C
18.
BMC Pulm Med ; 19(1): 103, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170951

RESUMO

BACKGROUND: This study assessed the effects of ursolic acid (UA) on airway-vessel remodeling and muscle atrophy in cigarette smoke (CS)-induced emphysema rats and investigated potential underlying mechanisms. METHODS: Emphysema was induced in a rat model with 3 months of CS exposure. Histology and immunohistochemistry (IHC) stains were used to assess airway-vessel remodeling and muscle atrophy-associated changes. Levels of cleaved-caspase3, 8-OHdG, and S100A4 were measured in airways and associated vessels to evaluate cell apoptosis, oxidant stress, epithelial-to-mesenchymal transition (EMT), and endothelial-to-mesenchymal transition (EndMT)-associated factors. Western blot and/or IHC analyses were performed to measure transforming growth factor-beta 1(TGF-ß1)/Smad2.3, alpha-smooth muscle actin (α-SMA), and insulin-like growth factor 1 (IGF1) expression. We also gave cultured HBE and HUVEC cells Cigarette Smoke Extract (CSE) administration and UA intervention. Using Western blot method to measure TGF-ß1/Smad2.3, α-SMA, S100A4, and IGF1 molecules expression. RESULTS: UA decreased oxidant stress and cell apoptosis in airway and accompanying vascular walls of cigarette smoke-induced emphysema model rats. UA alleviated EMT, EndMT, changes associated with airway-vessel remodeling and muscle atrophy. The UA effects were associated with IGF1 and TGF-ß1/Smad2.3 pathways. CONCLUSIONS: UA reduced EMT, EndMT, airway-vessel remodeling, and musculi soleus atrophy in CS-induced emphysema model rats at least partly through IGF1 and TGF-ß1/Smad2.3 signaling pathways.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Músculo Esquelético/patologia , Enfisema Pulmonar/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Atrofia/etiologia , Atrofia/prevenção & controle , Inibidores de Ciclo-Oxigenase/farmacologia , Transição Epitelial-Mesenquimal/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Enfisema Pulmonar/etiologia , Ratos , Ratos Wistar , Proteína Smad2/metabolismo , Fumaça/efeitos adversos , Fator de Crescimento Transformador beta1/metabolismo
19.
Cell Tissue Res ; 378(1): 67-80, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31101982

RESUMO

The aim of this study is to investigate the potential roles of miR-943-3p and its target gene secreted frizzled-related proteins4 (SFRP4) in allergic asthma and elucidate its underlying mechanism, which may prompt a new clue about developing novel treatments of this disease. An allergic asthma mouse model was generated by challenging with ovalbumin (OVA); lung pathological features of mice were viewed using H&E staining; thickness of subepithelial fibrosis and smooth muscle was measured using Masson's trichrome staining. Inflammatory cells from bronchoalveolar lavage fluid (BALF) were counted based on Diff-Quik staining and morphometric analysis. Expressions of miR-943-3p, SFRP4 and Wnt signal pathway-associated proteins were detected using RT-PCR or immunoblotting, respectively. SFRP4 was downregulated in the bronchial biopsies of allergic asthma patients and represented a unique intersection between differentially expressed genes (DEGs) and genes in the Wnt signal pathway. Both miR-943-3p upregulation and SFRP4 downregulation were detected in allergic asthma patients and OVA-induced mice. Besides, OVA-induced mice possessed more inflammatory cells in BALF including macrophage (mac), eosinophil (eos), lymphocyte (lym) and neutrophil (neu), higher expression of collagen, ß-catenin and c-Myc as well as thicker subepithelial fibrosis and smooth muscle in lung than control mice. In vivo delivery of miR-943-3p agomir worsened these symptoms, while both miR-943-3p antagomir and Ad-SFRP4 administration effectively alleviated this disease. Taken together, miR-943-3p accelerated the progression of airway inflammation and remodeling in allergic asthma via suppressing the activity of SFRP4 through Wnt signaling pathway in asthma patients and OVA-induced mice.


Assuntos
Asma/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Proteínas Wnt/metabolismo , Adulto , Remodelação das Vias Aéreas , Animais , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Via de Sinalização Wnt , Adulto Jovem
20.
J Coll Physicians Surg Pak ; 29(6): 537-540, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133152

RESUMO

OBJECTIVE: To determine the effect of dexamethasone on regulating the TGF-ß1/Smad3 signalling pathway in airway remodelling model of asthmatic rats. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Pathology, The First Hospital of Wuhan, Hubei Province, China, from February 2017 to April 2018. METHODOLOGY: Thirty male SPF Sprague-Dawley rats were randomly divided into the control group, the model group and the dexamethasone group, with 10 rats in each group. Rats were sensitised and excited by ovalbumin (OVA) to establish the model of bronchial asthma. The bronchial basement membrane perimeter (Pbm), the bronchial wall thickness (Wat), the smooth muscle thickness (Wam), collagenous fiber thickness (Wac) and other airway remodelling indices were measured and calculated by image analysis system. The expressions of TGF-ß1 and Smad3 mRNA and protein in lung tissue of each group of rats were detected by RT-PCR and Western blot. RESULTS: Wat/Pbm, Wai/Pbm and Wam/Pbm in the model group were higher compared with those in the control group (all p<0.001); Wat/Pbm, Wai/Pbm, and Wam/Pbm in the dexamethasone group were significantly lower than those in the model group (all p<0.001). Relative expression levels of TGF-ß1, Smad3 mRNA and protein in the model group were higher than those in the control group (all p<0.001); the relative expression levels of TGF-ß1, Smad3 mRNA and protein in the dexamethasone group were lower than those in the model group (all p<0.001). CONCLUSION: Dexamethasone may antagonize airway remodeling by regulating TGF-ß1/Smad3 signaling pathway, which likely to play a role in the treatment of bronchial asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Asma/metabolismo , Brônquios/patologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Smad/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética
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