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1.
Toxicol Lett ; 322: 58-65, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962155

RESUMO

High-level concentrations of chlorine (Cl2) can cause life-threatening lung injuries and the objective in this study was to understand the pathogenesis of short-term sequelae of Cl2-induced lung injury and to evaluate whether pre-treatment with the antioxidant N-acetyl cysteine (NAC) could counteract these injuries using Cl2-exposed precision-cut lung slices (PCLS). The lungs of Sprague-Dawley rats were filled with agarose solution and cut into 250 µm-thick slices that were exposed to Cl2 (20-600 ppm) and incubated for 30 min. The tissue slices were pre-treated with NAC (5-25 mM) before exposure to Cl2. Toxicological responses were analyzed after 5 h by measurement of LDH, WST-1 and inflammatory mediators (IL-1ß, IL-6 and CINC-1) in medium or lung tissue homogenate. Exposure to Cl2 induced a concentration-dependent cytotoxicity (LDH/WST-1) and IL-1ß release in medium. Similar cytokine response was detected in tissue homogenate. Contraction of larger airways was measured using electric-field-stimulation method, 200 ppm and control slices had similar contraction level (39 ± 5%) but in the 400 ppm Cl2 group, the evoked contraction was smaller (7 ± 3%) possibly due to tissue damage. NAC-treatment improved cell viability and reduced tissue damage and the contraction was similar to control levels (50 ± 11%) in the NAC treated Cl2-exposed slices. In conclusion, Cl2 induced a concentration-dependent lung tissue damage that was effectively prevented with pre-treatment with NAC. There is a great need to improve the medical treatment of acute lung injury and this PCLS method offers a way to identify and to test new concepts of treatment of Cl2-induced lung injuries.


Assuntos
Acetilcisteína/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cloro/toxicidade , Mediadores da Inflamação/metabolismo , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Ratos Sprague-Dawley
2.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569732

RESUMO

Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.


Assuntos
Decorina/biossíntese , Sangue Fetal/citologia , Receptores de Hialuronatos/sangue , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Hiperóxia/complicações , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/terapia , Ratos
4.
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
5.
Am J Chin Med ; 47(6): 1237-1251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31495180

RESUMO

Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury caused by the loss of vascular barrier integrity. Black ginseng (BG), steamed and dried ginseng nine times, exhibits various pharmacological activities such as antibacterial, antihyperglycemic, anti-atopic, antibacterial, and anti-inflammatory activities. In this study, we investigated the beneficial effects of black ginseng extract (BGE) against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated ECs and mice. BGE significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, BGE activated Akt, which helped maintain endothelial integrity. Furthermore, BGE reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that BGE may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.


Assuntos
Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Panax/química , Material Particulado/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Pneumonia/etiologia , Pneumonia/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Ulus Travma Acil Cerrahi Derg ; 25(5): 433-439, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31475327

RESUMO

BACKGROUND: Pulmonary contusion (PC) is an important life-threatening clinical condition characterized by lung injury and inflammation. Caffeic acid phenethyl ester (CAPE) is a biological agent with potent antioxidant and anti-inflammatory effects. This study aimed to investigate the potential effects of CAPE on tissue damage, nuclear factor kappa-beta (Nf-κß) activity, inducible nitric oxide synthase (iNOS) synthesis, and pulmonary apoptosis in an experimental PC model. METHODS: Forty adult Wistar albino rats were used in this study and divided into four groups as follows: control, PC, PC + CAPE, and CAPE. CAPE was administered intraperitoneally for seven days following PC formation (10 µmol/kg, dissolved in dimethyl sulfoxide). Wet/dry weight ratio in lung tissue was determined. The pulmonary tissue was examined using hematoxylin-eosin and Masson's trichrome histochemical staining and also by scanning electron microscopy. Nf-κß and iNOS activities in the lungs were determined by the indirect immunohistochemical method. Pulmonary apoptosis was detected by the TUNEL method. RESULTS: Increased leukocyte infiltration score, pulmonary edema, alveolar damage, and increased Nf-κß and iNOS activities were determined in the PC group. CAPE administration inhibited Nf-κß and iNOS activities and pulmonary apoptosis. CONCLUSION: In this study, the findings showed that CAPE inhibited tissue damage by suppressing inflammatory mediators of Nf-κß and iNOS activities. Also, CAPE was found to be protective in the lung tissue and could be used as a therapeutic agent.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Lesão Pulmonar/metabolismo , NF-kappa B/metabolismo , Álcool Feniletílico/análogos & derivados , Pneumonia/metabolismo , Animais , Álcool Feniletílico/farmacologia , Ratos , Ratos Wistar
7.
Biomed Pharmacother ; 117: 109194, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387174

RESUMO

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a major complication after lung transplantation. Annexin A1 (AnxA1) ameliorates inflammation in various injured organs. This study aimed to determine the effects and mechanism of AnxA1 on LIRI after lung transplantation. METHODS: Thirty-two rats were randomized into sham, saline, Ac2-26 and Ac2-26/L groups. Rats in the saline, Ac2-26 and Ac2-26/L groups underwent left lung transplantation and received saline, Ac2-26, and Ac2-26/L-NIO, respectively. After 24 h of reperfusion, serum and transplanted lung tissues were examined. RESULTS: The partial pressure of oxygen (PaO2) was increased in the Ac2-26 group compared to that in the saline group but was decreased by L-NIO treatment. In the Ac2-26 group, the wet-to-dry (W/D) weight ratios, total protein concentrations, proinflammatory factors and inducible nitric oxide synthase levels were notably decreased, but the concentrations of anti-inflammatory factors and endothelial nitric oxide synthase levels were significantly increased. Ac2-26 attenuated histological injury and cell apoptosis, and this improvement was reversed by L-NIO. CONCLUSIONS: Ac2-26 reduced LIRI and improved alveoli-capillary permeability by inhibiting oxygen stress, inflammation and apoptosis. The protective effect of Ac2-26 on LIRI largely depended on the endothelial nitric oxide synthase pathway.


Assuntos
Anexina A1/farmacologia , Lesão Pulmonar/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Peptídeos/farmacologia , Traumatismo por Reperfusão/metabolismo , Animais , Anexina A1/metabolismo , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
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 J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426531

RESUMO

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.


Assuntos
Apoptose , Células Epiteliais/metabolismo , Gefitinibe/efeitos adversos , Lesão Pulmonar/metabolismo , Pneumonia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Receptores ErbB/metabolismo , Gefitinibe/uso terapêutico , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Animais , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Crescimento Transformador alfa , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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.
PLoS One ; 14(7): e0219211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276543

RESUMO

OBJECTIVE: Asphyxia of newborns is a severe and frequent challenge of the peri- and postnatal period. The purpose of this study was to study early morphological, immunological and structural alterations in lung tissue after asphyxia and hemorrhage (AH). METHODS: 44 neonatal piglets (age 32 hrs) underwent asphyxia and hemorrhage (AH) and were treated according to the international liaison committee of resuscitation (ILCOR) guidelines. For this study, 15 piglets (blood transfusion (RBC) n = 9; NaCl n = 6, mean age 31 hrs) were randomly picked. 4 hours after ROSC (return of spontaneous circulation), lung tissue and blood samples were collected. RESULTS: An elevation of myeloperoxidase (MPO) activity was observed 4 hrs after AH accompanied by an increase of surfactant D after RBC treatment. After AH tight junction proteins Claudin 18 and junctional adhesion molecule 1 (JAM1) were down-regulated, whereas Occludin was increased. Furthermore, after AH and RBC treatment dephosphorylated active form of Connexin 43 was increased. CONCLUSIONS: AH in neonatal pigs is associated with early lung injury, inflammation and alterations of tight junctions (Claudin, Occludin, JAM-1) and gap junctions (Connexin 43) in lung tissue, which contributes to the development of lung edema and impaired function.


Assuntos
Asfixia Neonatal/fisiopatologia , Lesão Pulmonar/fisiopatologia , Pulmão/fisiopatologia , Animais , Animais Recém-Nascidos/metabolismo , Asfixia/fisiopatologia , Asfixia Neonatal/metabolismo , Moléculas de Adesão Celular/metabolismo , Claudinas/metabolismo , Conexina 43/metabolismo , Modelos Animais de Doenças , Junções Comunicantes , Lesão Pulmonar/metabolismo , Ocludina/metabolismo , Peroxidase/análise , Proteína D Associada a Surfactante Pulmonar/análise , Choque Hemorrágico/imunologia , Choque Hemorrágico/metabolismo , Suínos , Junções Íntimas/metabolismo
14.
Redox Biol ; 26: 101264, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31279222

RESUMO

The association between airborne fine particulate matter (PM2.5) concentration and the risk of respiratory diseases has been well documented by epidemiological studies. However, the mechanism underlying the harmful effect of PM2.5 has not been fully understood. In this study, we exposed the C57BL/6J mice to airborne PM2.5 for 3 months (mean daily concentration ~50 or ~110 µg/m3, defined as PM2.5-3L or PM2.5-3H) or 6 months (mean daily concentration ~50 µg/m3, defined as PM2.5-6L) through a whole-body exposure system. Histological and biochemical analysis revealed that PM2.5-3H exposure caused more severe lung injury than did PM2.5-3L, and the difference was greater than that of PM2.5-6L vs PM2.5-3L exposure. With RNA-sequencing technique, we found that the lungs exposed with different concentration of PM2.5 have distinct transcriptional profiles. PM2.5-3H exposure caused more differentially expressed genes (DEGs) in lungs than did PM2.5-3L or PM2.5-6L. The DEGs induced by PM2.5-3L or PM2.5-6L exposure were mainly enriched in immune pathways, including Hematopoietic cell lineage and Cytokine-cytokine receptor interaction, while the DEGs induced by PM2.5-3H exposure were mainly enriched in cardiovascular disease pathways, including Hypertrophic cardiomyopathy and Dilated cardiomyopathy. In addition, we found that upregulation of Cd5l and reduction of Hspa1 and peroxiredoxin-4 was associated with PM2.5-induced pulmonary inflammation and oxidative stress. These results may provide new insight into the cytotoxicity mechanism of PM2.5 and help to development of new strategies to attenuate air pollution associated respiratory disease.


Assuntos
Exposição Ambiental/efeitos adversos , Lesão Pulmonar/etiologia , Material Particulado/efeitos adversos , Animais , Biomarcadores , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos , Estresse Oxidativo , Fatores de Tempo , Transcriptoma
15.
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
16.
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
17.
Paediatr Respir Rev ; 31: 82-88, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103368

RESUMO

Birth prior to term interrupts the normal development of the respiratory system and consequently results in poor respiratory outcomes that persist throughout childhood. The mechanisms underpinning these poor respiratory outcomes are not well understood, but intrinsic abnormalities within the airway epithelium may be a contributing factor. Current evidence suggests that the airway epithelium is both structurally and functionally abnormal after preterm birth, with reports of epithelial thickening and goblet cell hyperplasia in addition to increased inflammation and apoptosis in the neonatal intensive care unit. However, studies focusing on the airway epithelium are limited and many questions remain unanswered; including whether abnormalities are a direct result of interrupted development, a consequence of exposure to inflammatory stimuli in the perinatal period or a combination of the two. In addition, the difficulty of accessing airway tissue has resulted in the majority of evidence being collected in the pre-surfactant era which may not reflect contemporary preterm birth. This review examines the consequences of preterm birth on the airway epithelium and explores the clinical relevance of currently available models whilst highlighting the need to develop a clinically relevant in vitro model to help further our understanding of the airway epithelium in preterm birth.


Assuntos
Apoptose , Displasia Broncopulmonar/embriologia , Inflamação , Nascimento Prematuro , Mucosa Respiratória/embriologia , Displasia Broncopulmonar/imunologia , Displasia Broncopulmonar/metabolismo , Corioamnionite/imunologia , Corioamnionite/metabolismo , Feminino , Células Caliciformes/patologia , Humanos , Hiperplasia , Recém-Nascido , Recém-Nascido Prematuro , /metabolismo , Unidades de Terapia Intensiva Neonatal , Lesão Pulmonar/etiologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Oxigenoterapia/efeitos adversos , Respiração com Pressão Positiva/efeitos adversos , Gravidez , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Ressuscitação/efeitos adversos
18.
Environ Sci Pollut Res Int ; 26(18): 18708-18718, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055741

RESUMO

Chrysotile accounts for some 90% to 95% of all the asbestos used worldwide. Scientific evidences have shown that asbestos (including chrysotile) exposure is associated with increased rates of lung cancer, asbestosis, and mesothelioma. However, molecular mechanisms underlying the toxicity effects of chrysotile are not clear. This study evaluated the oxidative stress in chronic lung toxicity caused by the intratracheal instillation (IT) of four kinds China representative chrysotile once a month for 12 months in Wistar rats. These results indicated that chrysotile exposure led to an obvious increase in lung mass and slowed the growth of body mass. Inflammation and fibrosis were observed by hematoxylin-eosin (HE) staining. Exposure to chrysotile significantly increased the accumulation of reactive oxygen species (ROS) and the level of lipid peroxidation and decreased antioxidant capacity in lung tissues. Furthermore, 1-6-month chrysotile exposure activated heme oxygenase-1 (HO-1) and heat shock protein 70 (HSP70) expression, whereas 12-month exposure caused significant decreases of two-factor expression levels in XK and MN groups when compared to negative control group. Therefore, our results suggested that chronic chrysotile pulmonary injury in Wistar rats is triggered by oxidative damage. Meanwhile, the oxidative damage of MN and XK was stronger than that of SSX and AKS, and the difference of oxidative damage in four chrysotile could have been brought by its properties, morphology, chemical composition, and particle size. With all the above mentioned in view, we hope that the revealed data in the experiment could contribute to the progress of further researches on the toxicity and mechanism of chrysotile.


Assuntos
Asbestos Serpentinas/toxicidade , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Asbestos Serpentinas/química , China , Heme Oxigenase-1/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/metabolismo , Lesão Pulmonar/metabolismo , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
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.
J Biol Chem ; 294(22): 8861-8871, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31000627

RESUMO

Mutations in the genes encoding telomerase reverse transcriptase (TERT) and telomerase's RNA components as well as shortened telomeres are risk factors for idiopathic pulmonary fibrosis, where repetitive injury to the alveolar epithelium is considered a key factor in pathogenesis. Given the importance of TERT in stem cells, we hypothesized that TERT plays an important role in epithelial repair and that its deficiency results in exacerbation of fibrosis by impairing this repair/regenerative process. To evaluate the role of TERT in epithelial cells, we generated type II alveolar epithelial cell (AECII)-specific TERT conditional knockout (SPC-Tert cKO) mice by crossing floxed Tert mice with inducible SPC-driven Cre mice. SPC-Tert cKO mice did not develop pulmonary fibrosis spontaneously up to 9 months of TERT deficiency. However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without a significant effect on AECII telomere length. Moreover, selective TERT deficiency in AECII diminished their proliferation and induced cellular senescence. These findings suggest that AECII-specific TERT deficiency enhances pulmonary fibrosis by heightening susceptibility to bleomycin-induced epithelial injury and diminishing epithelial regenerative capacity because of increased cellular senescence. We confirmed evidence for increased AECII senescence in idiopathic pulmonary fibrosis lungs, suggesting potential clinical relevance of the findings from our animal model. Our results suggest that TERT has a protective role in AECII, unlike its pro-fibrotic activity, observed previously in fibroblasts, indicating that TERT's role in pulmonary fibrosis is cell type-specific.


Assuntos
Senescência Celular , Fibrose Pulmonar/etiologia , Telomerase/genética , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Animais , Bleomicina/farmacologia , Proliferação de Células , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Telomerase/deficiência , Telomerase/metabolismo , Telômero/metabolismo , Encurtamento do Telômero
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