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1.
Yakugaku Zasshi ; 140(1): 15-22, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902879

RESUMO

The development of serious lung diseases, such as pulmonary fibrosis, is associated with several drugs. A recent study has shown that the epithelial-mesenchymal transition (EMT) plays an essential role in the development of pulmonary fibrosis. However, the mechanisms underlying drug-induced EMT in alveolar epithelial cells have not been characterized. The present study showed that methotrexate (MTX), a drug known to cause lung injury, induced EMT-like phenotypic changes in an A549 cell model of the alveolar epithelium. We also found that the transforming growth factor (TGF)-ß1-mediated signaling pathway was associated with MTX-induced EMT. In addition, our results showed that certain secreted factors and microRNAs, a class of small noncoding RNAs, may be involved in MTX-induced EMT. The effects of COA-Cl, a novel synthetic small molecule, on TGF-ß1-induced EMT were evaluated to determine the therapeutic potential of COA-Cl against drug-induced lung injury. COA-Cl significantly suppressed TGF-ß1-induced EMT-like phenotypic changes, as evidenced by the inhibition of EMT-related transcription factors. Furthermore, MTX-induced EMT was completely suppressed by co-treatment with folic acid. Thus, these compounds may be promising therapeutic agents against drug-induced lung injury. In conclusion, the present study elucidated mechanisms underlying drug-induced EMT and highlighted a potential novel therapeutic approach to drug-induced lung diseases.


Assuntos
Lesão Pulmonar/induzido quimicamente , Metotrexato/efeitos adversos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/uso terapêutico , Humanos , Lesão Pulmonar/tratamento farmacológico , MicroRNAs , Terapia de Alvo Molecular , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/fisiologia
2.
Toxicol Lett ; 319: 49-57, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693926

RESUMO

Blast lung injury is associated with high morbidity and mortality. Vaporized perfluorocarbon (PFC) inhalation has been reported to attenuate acute respiratory distress syndrome in humans and animal models. However, the effect of vaporized PFC on blast lung injury is still unknown. In this study, we investigated the protective effects and potential underlying mechanisms of action of vaporized PFC on blast lung injury in a canine model. This was a prospective, controlled, animal study in adult male hybrid dogs randomized to sham, blast (B), blast plus mechanical ventilation (B + M), and blast plus PFC (B + P) groups. All groups except for the sham were exposed to blast wave. The B + P group was treated with vaporized PFC for 1.5 h followed by 5.5 h mechanical ventilation. B + M group received 7.5 h mechanical ventilation and B group was observed for 7.5 h. Blast lung injury was induced using a shock tube. Blood gas, inflammatory cytokines, and oxidative stress were measured. Expression of nuclear factor (NF)-κB activation, mitogen-activated protein kinase (MAPK) and nuclear factor, erythroid 2 like 2 (Nrf2) were measured using western blot. Lung injury observed after blast exposure was marked by increased histopathological scores, ratio of lung wet to dry weight. PFC treatment attenuated blast lung injury as indicated by histopathological scores and ratio of lung wet to dry weight. PFC treatment downregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malondialdehyde (MDA), and upregulated superoxide dismutase (SOD) activity. PFC also suppressed expression of MAPK/NF-κB and Nrf2 protein levels. Our results suggest that PFC attenuated blast-induced acute lung injury by inhibiting MAPK/NF-κB activation and inducing Nrf2 expression in dogs.


Assuntos
Traumatismos por Explosões/tratamento farmacológico , Fluorcarbonetos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração por Inalação , Animais , Traumatismos por Explosões/patologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Cães , Fluorcarbonetos/administração & dosagem , Pulmão/patologia , Lesão Pulmonar/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos
3.
Toxicol Lett ; 319: 168-174, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31698045

RESUMO

Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.


Assuntos
Alquilantes/toxicidade , Substâncias para a Guerra Química/toxicidade , Compostos de Mostarda/toxicidade , Doenças Respiratórias/induzido quimicamente , Animais , Humanos , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/patologia
4.
Arch. bronconeumol. (Ed. impr.) ; 55(12): 642-647, dic. 2019. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-186398

RESUMO

La aproximación terapéutica en fibrosis pulmonar idiopática ha cambiado sustancialmente en los últimos 5 años. Las guías nacionales e internacionales para el tratamiento farmacológico recomiendan el uso de 2 fármacos antifibróticos, nintedanib y pirfenidona, con un nivel elevado de evidencia científica a favor del beneficio de ambos fármacos, no solo porque enlentecen la progresión de la enfermedad sino también porque reducen el riesgo de muerte anual. Actualmente, dentro del manejo terapéutico de estos pacientes, se pone en valor tanto el uso de fármacos que actúan sobre mecanismos patogénicos de la enfermedad como el efecto positivo de mejorar la calidad de vida mediante un apoyo integral multidisciplinar que incluye nutrición, actividad física, educación, apoyo emocional y paliación de síntomas. Todo ello buscando que el paciente esté lo mejor posible el mayor tiempo posible desde el diagnóstico. Pero el objetivo de las nuevas terapias antifibróticas combinadas que en estos momentos se evalúan en ensayos clínicos persigue aumentar el beneficio terapéutico o parar completamente la progresión de la enfermedad mediante el potencial efecto sinérgico antifibrótico, al actuar sobre diferentes vías patogénicas a la vez. Finalmente, se investiga qué marcadores podrían ser útiles para identificar pacientes que se puedan beneficiar más de unos fármacos antifibróticos u otros, lo que permitiría optimizar recursos e iniciar los primeros pasos hacia una medicina de precisión en fibrosis pulmonar. A continuación, se revisan los principales puntos de mejora en el tratamiento farmacológico de la fibrosis pulmonar idiopática futuribles a corto, medio y largo plazo


The therapeutic approach in idiopathic pulmonary fibrosis has changed substantially over the past 5 years. National and international guidelines for the pharmacological treatment of IPF recommend 2 antifibrotic drugs, nintedanib and pirfenidone. The use of both these drugs is supported by high-level evidence, with benefits including not only slower disease progression but also a reduction in the annual risk of death. Currently, the therapeutic management of these patients prioritizes both the use of drugs that act on the pathogenic mechanisms of the disease, and the positive effect of improving quality of life with integrated multidisciplinary support, including nutrition, physical activity, education, emotional support, and palliation of symptoms. The overall aim is to ensure that the patient remains as well as possible for as long as possible after diagnosis. However, the goal of the new antifibrotic combinations that are currently under evaluation in clinical trials is to use the potential antifibrotic synergy to enhance the therapeutic benefit or completely halt disease progression, by acting simultaneously on different pathogenic pathways. Another line of investigation involves markers that might be useful for identifying patients who may benefit more from certain antifibrotics than from others, which would make it possible to optimize resources and take the first steps toward precision medicine in pulmonary fibrosis. Below, we review the main potential areas for improvement in the pharmacological treatment of idiopathic pulmonary fibrosis in the short, medium, and long term


Assuntos
Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Medicina de Precisão/tendências , Qualidade de Vida , Quimioterapia Combinada/tendências , Lesão Pulmonar/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Regeneração , Terapia Combinada/métodos
5.
Zhongguo Fei Ai Za Zhi ; 22(9): 579-582, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31526462

RESUMO

Radiation induced lung injury (RILI) is a serious complication in patients received thoracic radiotherapy. The main clinical symptom of RILI includes short of breath, low fever and cough, seriously affect the survival of patients. How to better prevent and treat RILI is an urgent problem. Target theory, cytokine theory, free radical theory, and vascular endothelial cell damage theory are the main mechanisms of RILI. Among them, reactive oxygen species (ROS) produced during radiotherapy can induce tissue damage throughout the course of RILI, and have a direct effect on both radiation pneumonitis and radiation-induced lung fibrosis. Anti-oxygen therapy including thiol compounds, antioxidant enzymes, and plant antioxidants have been applied in the prevention and treatment of RILI. This article reviews the research and application of antioxidant therapy in RILI.
.


Assuntos
Antioxidantes/farmacologia , Lesão Pulmonar/tratamento farmacológico , Lesões por Radiação/tratamento farmacológico , Animais , Antioxidantes/uso terapêutico , Humanos , Lesão Pulmonar/metabolismo , Lesões por Radiação/metabolismo
6.
Biomed Pharmacother ; 118: 109300, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545248

RESUMO

Severe acute pancreatitis (SAP) is a common acute clinical abdomen syndrome which is characterized by pancreatic self-digestion. As one of the major complication of SAP, acute lung injury is the main reason of high mortality. The traditional Chinese medicine Qingyi pellet (QYT) has been widely used for SAP in clinic. In our study, we constructed the severe acute pancreatitis-associated lung injury (SAP-ALI) rat model and treated with QYT, then characterized the protein from the lung tissue by using a mass spectrometry-based proteomic strategy. Our results showed that, in the SAP group, 9 proteins exhibited obvious changes according to the proteomic analysis. Among the 9 proteins, 7 proteins (alpha-2-macroglobulin, Cathepsin S, ras-related protein RAP-1A, integrin beta, protein phosphatase 2A, Intercellular adhesion molecule 1 and p38) were up-regulated, and 2 proteins (adapter molecule Crk and stathmin) were down-regulated. Interestingly, the data of the QYT group showed that adapter molecule Crk and stathmin were up-regulated, but the other 7 proteins were down-regulated. The kyoto encyclopedia of genes shows that the proteins act on PI3K-AKT, chemokine signaling pathways, apoptosis, leukocyte transendothelial migration and focal adhesion. Therefore, the therapeutic effects of QYT on SAP-ALI are potentially through the additive and/or synergistic interactions of numerous components.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Lesão Pulmonar/complicações , Lesão Pulmonar/tratamento farmacológico , Pancreatite/complicações , Proteômica , Doença Aguda , Animais , Gasometria , Medicamentos de Ervas Chinesas/farmacologia , Interleucina-6/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/sangue , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima/genética
7.
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
8.
Mol Med Rep ; 20(4): 3347-3354, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432172

RESUMO

Ulinastatin, a urinary trypsin inhibitor (UTI) is commonly used to treat patients with acute inflammatory disease. However, the underlying mechanisms of its anti­inflammatory effect in acute lung injury (ALI) are not fully understood. The present study aimed to investigate the protective effect of UTI and explore its potential mechanisms by using a rat model of lipopolysaccharide (LPS)­induced ALI. Rats were treated with 5 mg/kg LPS by intratracheal instillation. The histological changes in LPS­induced ALI was evaluated using hematoxylin and eosin staining and the myeloperoxidase (MPO) activity was determined using ELISA. The wet/dry ratio (W/D ratio) of the lungs was used to assess the severity of pulmonary edema and Evans blue dye was used to evaluate the severity of lung vascular leakage. The results demonstrated that LPS administration induced histological changes and significantly increased the lung W/D ratio, MPO activity and Evans blue dye extravasation compared with the control group. However, treatment with UTI attenuated LPS­induced ALI in rats by modifying histological changes and reducing the lung W/D ratio, MPO activity and Evans blue dye extravasation. In addition, LPS induced the secretion of numerous pro­inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor­α, interleukin (IL)­6, IL­1ß and interferon­Î³; however, these cytokines were strongly reduced following treatment with UTI. In addition, UTI was able to reduce cellular counts in BALF, including neutrophils and leukocytes. Western blotting demonstrated that UTI significantly blocked the LPS­stimulated MAPK and NF­κB signaling pathways. The results of the present study indicated that UTI could exert an anti­inflammatory effect on LPS­induced ALI by inhibiting the MAPK and NF­κB signaling pathways, which suggested that UTI may be considered as an effective drug in the treatment of ALI.


Assuntos
Glicoproteínas/farmacologia , Lipopolissacarídeos/toxicidade , Lesão Pulmonar , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pneumonia , Animais , Citocinas/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , NF-kappa B/metabolismo , Peroxidase/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Ratos , Ratos Sprague-Dawley
9.
BMC Pulm Med ; 19(1): 138, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362742

RESUMO

BACKGROUND: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD. METHODS: C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O2 to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks. RESULTS: Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice. CONCLUSIONS: Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.


Assuntos
Cafeína/farmacologia , Hiperóxia/complicações , Lesão Pulmonar/tratamento farmacológico , Neovascularização Fisiológica , Alvéolos Pulmonares/efeitos dos fármacos , Angiopoietina-1/metabolismo , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/metabolismo , Distribuição Aleatória , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Int Immunopharmacol ; 75: 105789, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401377

RESUMO

BACKGROUND: Sepsis occurs when an infection triggers deranged inflammatory responses. There exists no efficacious treatment for this condition. The transcriptional repressor B-cell Lymphoma 6 (BCL6) is known to act as an inhibitor of macrophage-mediated inflammatory responses. FX1, a novel specific BCL6 BTB inhibitor, is able to attenuate activity of B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Nevertheless, the effect of FX1 in inflammatory responses and sepsis remains unknown. OBJECTIVES: Here, we explored the effect and potential mechanisms of FX1 on the regulation of LPS-induced inflammatory responses in murine sepsis. METHOD: Mice models of LPS-induced sepsis were monitored for survival rate following FX1 administration. ELISA was used to assess how FX1 administration affected pro-inflammatory cytokines present in macrophages exposed to LPS and in the serum of mice sepsis models. Flow cytometric analysis, Western blot and qRT-PCR were performed to evaluate differences in macrophages immune responses after FX1 pre-treatment. Finally, the affinity of BCL6 binding to downstream target genes was checked by ChIP. RESULTS: The survival rate of mice models of LPS-induced sepsis was improved in following FX1 administration. FX1 decreased the production of inflammatory cytokines, attenuated macrophage infiltration activities and reduced monocytes chemotaxis activities, all of which suggest that FX1 exert anti-inflammatory effects. Mechanistically, FX1 may enhance the affinity of BCL6 binding to downstream target pro-inflammatory genes. CONCLUSIONS: These findings illustrated the anti-inflammatory properties and potential mechanisms of FX1 in sepsis caused by LPS. FX1 could potentially become a new immunosuppressive and anti-inflammatory drug candidate in sepsis therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Indóis/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Sepse/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Movimento Celular/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Células RAW 264.7 , Sepse/genética , Sepse/imunologia , Sepse/patologia , Tiazolidinedionas/farmacologia
11.
Food Funct ; 10(9): 5555-5565, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31429458

RESUMO

Exposure to chromium (Cr) causes a number of respiratory diseases, including lung cancer and pulmonary fibrosis. However, there is currently no safe treatment for Cr-induced lung damage. Here, we used in vivo and in vitro approaches to examine the protective effects of melatonin (MEL) on Cr-induced lung injury and to identify the underlying molecular mechanisms. We found that treatment of rats or a mouse lung epithelial cell MLE-12 with MEL attenuated K2Cr2O7-induced lung injury by reducing the production of oxidative stress and inflammatory mediators and inhibiting cell apoptosis. MEL treatment upregulated the expression of silent information regulator 1 (Sirt1), which deacetylated the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α). In turn, this increased the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and key anti-oxidant target genes. These results suggest that melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway. Dietary MEL supplement may be a potential new strategy for the treatment of Cr poisoning.


Assuntos
Cromo/toxicidade , Lesão Pulmonar/tratamento farmacológico , Melatonina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Animais , Suplementos Nutricionais/análise , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética
12.
Biomed Res Int ; 2019: 2476252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467875

RESUMO

Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.


Assuntos
Aldeídos/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Choque Hemorrágico/tratamento farmacológico , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Ocludina/genética , Ratos , Choque Hemorrágico/genética , Choque Hemorrágico/patologia , Fator de Necrose Tumoral alfa/genética , Proteína da Zônula de Oclusão-1/genética
13.
Artigo em Chinês | MEDLINE | ID: mdl-31245955

RESUMO

OBJECTIVE: To observe the effects of Shenmai injection(SM) on p38MAPK and the apoptosis-related genes in lung injury induced by intestinal ischemia reperfusion (I/R) in rats and to investigate the protective mechanism of SM. METHODS: Rat model of intestinal I/R injury was established with clamping of the superior mesenteric artery (SMA) for 60 min and then clamping was relieved for 60 min. Twenty-four SD rats were randomly divided into three groups with eight rats in each: control group, intestinal ischemia/reperfusion group(I/R group), Shenmai injection treated group (SM+I/R group). Lung wet/dry weight ratio(W/D), the contents of phosphatidylcholine (PC) and total phospholipid(TPL) which are the major ingredients of pulmonary surfactant were measured, as well as the expression levels of p38MAPK, Bcl-2 and Bax proteins in lung tissue were examined by using immunohistochemical method. RESULTS: Compared with control group, lung W/D was significantly increased, the contents of PC and TPL were significantly decreased, the protein expression levels of p38MAPK, Bcl-2 and Bax were significantly increased in I/R group (all P<0.01). But Bax protein expression was much greater than Bcl-2 protein expression, the ratio of Bcl-2 to Bax were significantly decreased in I/R group than that in control group (P<0.01). Compared with I/R group, lung W/D was significantly decreased, while the contents of PC and TPL were significantly increased, the p38MAPK and Bax protein expression levels were significantly decreased in SM+I/R group (all P<0.01); both Bcl-2 protein expression and the ratio of Bcl-2 to Bax were significantly increased in SM+I/R group than those in I/R group (P<0.01). The correlation analysis indicated that the expression level of p38MAPK protein in lung tissue was negatively correlated with the contents of PC and the ratio of Bcl-2 to Bax (r is -0.787 and -0.731, all P<0.01). CONCLUSION: SM can protect the lung injury induced by intestinal I/R injury, which may be mediated by inhibiting the activation of p38MAPK, improving the ratio of Bcl-2 to Bax to inhibit lung apoptosis.


Assuntos
Medicamentos de Ervas Chinesas , Lesão Pulmonar , Traumatismo por Reperfusão , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Apoptose , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Proteína X Associada a bcl-2 , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Int J Mol Med ; 44(2): 725-736, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173181

RESUMO

The one­lung ventilation (OLV) technique is vital in thoracic surgery. However, it can result in severe lung injury, which is difficult to manage. The main solution at present is the use of ventilation strategies, including continuous positive oxygen pressure, low tidal volume and high frequency ventilation, and the administering of drugs, including phenylephrine, dexmedetomidine and morphine. However, the protective effect of these methods on the lungs is not sufficient to improve the prognosis of patients. Therefore, how to develop a novel protective drug remains an open question. Nicorandil, a mitochondrial (mito)KATP­specific opener, serves an important role in cardioprotection, although its effect on lung injury remains unclear. The present study examined the protective role of nicorandil against collapse­induced lung injury in rabbits undergoing OLV. Changes in arterial oxygen saturation (SaO2), arterial partial pressure for oxygen (PaO2), wet/dry weight ratio, and the microstructure of tissues and cells were observed. Enzyme­linked immunosorbent assays were used to determine the concentrations of malondialdehyde (MDA) and tumor necrosis factor (TNF)­α, and the activity of superoxide dismutase (SOD) in rabbits treated with nicorandil. Terminal deoxynucleotidyl transferase transfer­mediated dUTP nick end­labeling was used to detect apoptosis and western blotting was used to analyze the relative proteins involved in apoptosis. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were used to examine the expression of hypoxia inducible factor 1α (HIF­1α), phosphatidylinositol­3­kinase (PI3K), protein kinase B (Akt) and nuclear factor (NF)­κB in the lungs of rabbits treated with nicorandil. The SaO2 and PaO2 in the high­dose group were significantly higher than those in the control group in the process of OLV. The wet/dry weight ratio, and the concentrations of MDA and TNF­α in the collapsed lung of the high­dose group were significantly lower than those in the control group. The activity of SOD in the high­dose group was significantly higher than that in the control group. The lung had improved microstructure and less apoptosis, which was determined by the Bax/Bcl2 ratio in the high­dose group. The expression levels of PI3K, phosphorylated Akt and HIF­1α were upregulated, whereas the expression of NF­κB was downregulated. In conclusion, nicorandil had a protective effect via inhibiting apoptosis in non­ventilated lung collapsed and re­expansion during OLV in the rabbit. It acted on mitoKATP through the PI3K/Akt signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Nicorandil/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Nicorandil/farmacologia , Ventilação Monopulmonar/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Coelhos
15.
Int Immunopharmacol ; 73: 414-423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152979

RESUMO

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and is mainly caused by hyperoxia exposure and mechanical ventilation. Alveolar simplification, pulmonary vascular abnormalities and pulmonary inflammation are the main pathological changes in hyperoxic lung injury animals. Lipoxin A4 (LXA4) is an important endogenous lipid that can mediate the regression of inflammation and plays a role in acute lung injury and asthma. The purpose of this study was to evaluate the effects of LXA4 on inflammation and lung function in neonatal rats with hyperoxic lung injury and to explore the mechanism of the PINK1 pathway. After 85% oxygen exposure in newborn rats for 7 days, the BPD model was established. We found that LXA4 could significantly reduce cell and protein infiltration and oxidative stress in rat lungs, improve pulmonary function and alveolar simplification, and promote weight gain. LXA4 inhibited the expression of TNF-α, MCP-1 and IL-1ß in serum and BALF from hyperoxic rats. Moreover, we found that LXA4 could reduce the expression of the PINK1 gene and down-regulate the expression of PINK1, Parkin, BNIP3L/Nix and the autophagic protein LC3B.These protective effects of LXA4 could be partially reversed by addition of BOC-2.Thus, we concluded that LXA4 can alleviate the airway inflammatory response, reduce the severity of lung injury and improve lung function in a hyperoxic rat model of BPD partly through the PINK1 signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hiperóxia/tratamento farmacológico , Lipoxinas/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Proteínas Quinases/metabolismo , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Lipoxinas/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Biomed Pharmacother ; 117: 109043, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31238259

RESUMO

Sepsis is a severe, life-threatening condition primarily caused by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. Male albino rats were divided into sham, control, 10-mg/kg bwt L-lysine, and 20-mg/kg bwt L-lysine groups. At the end of treatment, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. Furthermore, the effect of L-lysine on the cellular architecture of lung tissue was evaluated. L-Lysine significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor-alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts, and it increased the reduced glutathione levels and the glutathione peroxidase, superoxide dismutase, and catalase activities. A normal cellular architecture was noted in rats in the sham group, whereas proinflammatory changes, such as edema and neutrophilic infiltration, were detected in rats in the control group. L-lysine significantly ameliorated these proinflammatory changes. Thus, L-lysine has the potential for the treatment of sepsis-induced CLI.


Assuntos
Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lisina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Sepse/complicações , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Contagem de Células , Doença Crônica , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/patologia , Lisina/farmacologia , Masculino , Peroxidase/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Sepse/patologia , Superóxido Dismutase/metabolismo
17.
Mol Med Rep ; 20(1): 117-124, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115565

RESUMO

The adenosine A2a receptor agonist CGS21680 has been suggested to act as an anti­inflammatory agent that protects against cardiopulmonary bypass (CPB)­induced organ injury. However, the therapeutic effects of CGS21680 for CPB­induced lung injury have not been comprehensively evaluated. Using a juvenile rat model, the present study was designed to evaluated whether CGS21680 attenuates CPB­induced lung injury. Our juvenile rat CPB model was established by 60 min CPB with or without CGS21680 pretreatment (100 µg/kg, in the CPB priming solution). Rats in the Sham group only underwent cannulation and heparinization. Serum and pulmonary levels of inflammatory markers and histological features of pulmonary tissues were analyzed. All juvenile rats survived following CPB. Significantly elevated serum levels of tumor necrosis factor­α (TNF­α), myeloperoxidase (MPO) and interleukin­1ß (IL­1ß), and decreased glutathione peroxidase (GSH­PX) levels were observed in the CPB group compared to the Sham group (all P<0.05). TNF­α, MPO and IL­1ß were significantly decreased, while GSH­PX was markedly increased in the CGS group when compared to the CPB group. Consistently, pulmonary tissues from rats in the CPB group showed considerable amounts of damaged pneumocytes, severe edema, and increased alveolar macrophages, and significantly higher lung injury scores compared to the controls. Collectively, these changes were all further attenuated by CGS21680. Pretreatment with CGS21680 before CPB attenuated pulmonary injury, which may be related to the anti­inflammatory effects of CGS21680 downstream of A2a receptor activation.


Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/análogos & derivados , Inflamação/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Fenetilaminas/farmacologia , Adenosina/farmacologia , Animais , Ponte Cardiopulmonar/efeitos adversos , Modelos Animais de Doenças , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-1beta/genética , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/fisiopatologia , Peroxidase/genética , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina/genética , Fator de Necrose Tumoral alfa/genética
19.
Med Sci Monit ; 25: 2567-2576, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957795

RESUMO

BACKGROUND The aim of this study was to assess the effects and mechanisms of allicin in a sepsis-induced lung injury in vivo study. MATERIAL AND METHODS The rats (n=54) were divided into 6 groups: Normal, DMSO, LPS, LPS+LD, LPS+MD, and LPS+HD groups. After being treated by different methods, we collected the lung tissues of different groups and evaluated the pathology by HE staining and positive apoptosis cells by TUNEL. We assessed the W/D ratio, inflammatory cytokines (TNF-alpha, IL-6 and IL-1ß), and relative protein expressions (TLR4, MyD88, NF-kappaB, caspase-3, and caspase-9) by IHC assay. RESULTS Compared with LPS group, the lung injury and positive cell number of allicin treated groups were significantly improved with dose-dependent (P<0.05, respectively) and the W/D ratio and TNF-alpha, IL-6 and IL-1ß concentration were significantly down-regulation compared with those of LPS group with dose-dependent (P<0.05, respectively). By IHC, the TLR4, MyD88, NF-kappaB, caspase-3 and caspase-9 protein activities of allicin treated groups were significantly suppressed compared with those of LPS group (P<0.05, respectively) in lung tissues. CONCLUSIONS This in vivo study shows that allicin improved sepsis-induced lung injury by regulation of TLR4/MyD88/NF-kappaB.


Assuntos
Lesão Pulmonar/tratamento farmacológico , Ácidos Sulfínicos/metabolismo , Ácidos Sulfínicos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Diferenciação Celular , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Lesão Pulmonar/metabolismo , Masculino , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
20.
Respir Res ; 20(1): 76, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992001

RESUMO

BACKGROUND: Exposure to fine particulate matter (PM2.5) has been associated with respiratory morbidity and mortality. Identification of interventional measures that are efficacious against PM2.5-induced toxicity may provide public health benefits. This study examined the inhibitory effects of nutritional supplementation with fish oil as a source of omega-3 fatty acids and vitamin E (Vit E) on PM2.5-induced lung toxicity in rats. METHOD: Sixty four male Sprague Dawley rats were gavaged with phosphate buffered saline (PBS), corn oil (5 ml/kg), fish oil (150 mg/kg), or Vit E (75 mg/kg), respectively, once a day for 21 consecutive days prior to intratracheal instillation of PM2.5 (10 mg/kg) every other day for a total of 3 times. Serum and bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), superoxide dismutase (SOD), 8-epi-prostaglandin F2α (8-epi-PGF2α), interleukin-1ß (IL-1ß), C-reactive protein (CRP), IL-6, and tumor necrosis factor-ɑ (TNF-ɑ) were analyzed for markers of cell injury and inflammation. Additionally, histological alterations of lung tissues were examined by hematoxylin-eosin staining. RESULT: Exposure to PM2.5 resulted in lung toxicity, represented as increased levels of total proteins, LDH, 8-epi-PGF2α, IL-1ß and TNF-α, and increased infiltration of inflammatory cells, and decreased SOD in the BALFs, and systemic inflammation, as evinced by increased levels of CRP and IL-6 in serum. Strikingly, supplementation with fish oil but not Vit E significantly ameliorated PM2.5-induced lung toxicity and systemic inflammation. CONCLUSION: PM2.5 exposure induces oxidative stress, lung injury and inflammation, which is ameliorated significantly by fish oil and partially by Vit E.


Assuntos
Suplementos Nutricionais , Óleos de Peixe/administração & dosagem , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Material Particulado/toxicidade , Vitamina E/administração & dosagem , Poluentes Atmosféricos/toxicidade , Animais , Exposição por Inalação/efeitos adversos , Lesão Pulmonar/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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