Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.530
Filtrar
1.
Am J Pathol ; 190(3): 711-722, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32093901

RESUMO

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor-like receptor and receptor activity-modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM+/+) or -deficient (ADM+/-) mice were exposed to normoxia or hyperoxia through postnatal days (PNDs) 1 to 14, and the hyperoxia-exposed mice were allowed to recover in normoxia for an additional 56 days. Lung injury and development and PH were quantified at different time points. Human pulmonary microvascular endothelial cells were also used to examine the effects of AM signaling on the NOS3 pathway and angiogenesis. Lung blood vessels and NOS3 expression decreased and the extent of hyperoxia-induced BPD and PH increased in ADM+/- mice compared with ADM+/+ mice. Hyperoxia-induced apoptosis and PH resolved by PND14 and PND70, respectively, in ADM+/+ mice but not in ADM+/- mice. Knockdown of ADM, calcitonin receptor-like receptor, and receptor activity-modifying protein 2 in vitro decreased NOS3 expression, nitric oxide generation, and angiogenesis. Furthermore, NOS3 knockdown abrogated the angiogenic effects of AM. Collectively, these results indicate that AM resolves hyperoxic lung injury via NOS3.


Assuntos
Adrenomedulina/farmacologia , Displasia Broncopulmonar/tratamento farmacológico , Hiperóxia/complicações , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/fisiopatologia , Células Endoteliais/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/fisiopatologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/genética , Proteína 2 Modificadora da Atividade de Receptores/genética , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Transdução de Sinais
2.
Invest Ophthalmol Vis Sci ; 61(2): 3, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031575

RESUMO

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs as a consequence of postnatal hyperoxia exposure in premature infants, resulting in vasoproliferation in the retina. The tetraspan protein epithelial membrane protein-2 (EMP2) is highly expressed in the retinal pigment epithelium (RPE) in adults, and it controls vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line. We, therefore, hypothesized that Emp2 knockout (Emp2 KO) protects against neovascularization in murine oxygen-induced retinopathy (OIR). Methods: Eyes were obtained from wildtype (WT) and Emp2 KO mouse pups at P7, P12, P17, and P21 after normoxia or hyperoxia (P7-P12) exposure. Following hyperoxia exposure, RNA sequencing was performed using the retina/choroid layers obtained from WT and Emp2 KO at P17. Retinal sections from P7, P12, P17, and P21 were evaluated for Emp2, hypoxia-inducible factor 1α (Hif1α), and VEGF expression. Whole mount images were generated to assess vaso-obliteration at P12 and neovascularization at P17. Results: Emp2 KO OIR mice demonstrated a decrease in pathologic neovascularization at P17 compared with WT OIR mice through evaluation of retinal vascular whole mount images. This protection was accompanied by a decrease in Hif1α at P12 and VEGFA expression at P17 in Emp2 KO animals compared with the WT animals in OIR conditions. Collectively, our results suggest that EMP2 enhances the effects of neovascularization through modulation of angiogenic signaling. Conclusions: The protection of Emp2 KO mice against pathologic neovascularization through attenuation of HIF and VEGF upregulation in OIR suggests that hypoxia-induced upregulation of EMP2 expression in the neuroretina modulates HIF-mediated neuroretinal VEGF expression.


Assuntos
Glicoproteínas de Membrana/fisiologia , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade/patologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Animais Recém-Nascidos , Linhagem Celular , Hiperóxia/fisiopatologia , Hipóxia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/patologia , Oxigênio/toxicidade , Epitélio Pigmentado da Retina/metabolismo , Vasos Retinianos/patologia , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Invest Ophthalmol Vis Sci ; 61(2): 4, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031576

RESUMO

Purpose: Oxidative stress affects the retinal pigment epithelium (RPE) leading to development of vascular eye diseases. Cholecalciferol (VIT-D) is a known modulator of oxidative stress and angiogenesis. This in vitro study was carried out to evaluate the protective role of VIT-D on RPE cells incubated under hyperoxic conditions. Methods: Cadaver primary RPE (PRPE) cells were cultured in hyperoxia (40% O2) with or without VIT-D (α-1, 25(OH) 2D3). The functional and physiological effects of PRPE cells with VIT-D treatment were analyzed using molecular and biochemical tools. Results: Vascular signaling modulators, such as vascular endothelial growth factor (VEGF) and Notch, were reduced in hyperoxic conditions but significantly upregulated in the presence of VIT-D. Additionally, PRPE conditioned medium with VIT-D induced the tubulogenesis in primary human umbilical vein endothelial cells (HUVEC) cells. VIT-D supplementation restored phagocytosis and transmembrane potential in PRPE cells cultured under hyperoxia. Conclusions: VIT-D protects RPE cells and promotes angiogenesis under hyperoxic insult. These findings may give impetus to the potential of VIT-D as a therapeutic agent in hyperoxia induced retinal vascular diseases.


Assuntos
Colecalciferol/farmacologia , Hiperóxia/fisiopatologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Vitaminas/farmacologia , Adolescente , Adulto , Cadáver , Células Cultivadas , Criança , Pré-Escolar , Células Endoteliais da Veia Umbilical Humana , Humanos , Potenciais da Membrana/fisiologia , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Receptores Notch/metabolismo , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 71-76, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31948528

RESUMO

OBJECTIVE: To study the protective effect of asiaticoside against hyperoxia-induced bronchopulmonary dysplasia in neonatal rats based on the microRNA-155 (miR-155)/suppressor of cytokine signaling-1 (SOCS1) axis. METHODS: Neonatal rats were randomly divided into a control group, a model group, a low-dose asiaticoside group (10 mg/kg), a middle-dose asiaticoside group (25 mg/kg), a high-dose asiaticoside group (50 mg/kg), and a budesonide group (1.5 mg/kg), with 12 rats in each group. All rats except those in the control group were exposed to a high concentration of oxygen for 14 days to establish a neonatal rat model of bronchopulmonary dysplasia. The low-, middle-, and high-dose asiaticoside groups were given asiaticoside at different doses by gavage, and those in the budesonide group were given budesonide aerosol treatment. Hematoxylin and eosin staining was used to observe lung tissue development and measure radial alveolar count (RAC) and mean linear intercept (MLI). Superoxide dismutase (SOD) and malondialdehyde (MDA) detection kits were used to measure the levels of SOD and MDA in lung tissue. ELISA was used to measure the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Quantitative real-time PCR was used to measure the mRNA expression of miR-155 and SOCS1 in lung tissue. Western blotting was used to measure the protein expression of SOCS1 in lung tissue. RESULTS: Compared with the control group, the model group had the symptoms of bronchopulmonary dysplasia such as a disordered structure of lung tissue, enlargement of alveolar fusion, uneven alveolar septa, enlargement of average alveolar space, and a reduction in alveolar number. The model group also had significant increases in MLI, MDA level in lung tissue, serum levels of IL-6 and TNF-α, and miR-155 level in lung tissue (P<0.05) and significant reductions in RAC, SOD level, and mRNA and protein expression of SOCS1 in lung tissue (P<0.05). Compared with the model group, the low-, middle-, and high-dose asiaticoside groups and the budesonide group had significant improvement in the above symptoms of bronchopulmonary dysplasia, significant reductions in MLI, MDA level in lung tissue, serum levels of IL-6 and TNF-α, and miR-155 level in lung tissue (P<0.05), and significant increases in RAC, SOD level, and mRNA and protein expression of SOCS1 in lung tissue (P<0.05). Asiaticoside improved the above symptoms and indices in a dose-dependent manner. There were no significant differences in the above indices between the high-dose asiaticoside and budesonide groups (P>0.05). CONCLUSIONS: Asiaticoside can alleviate inflammation injury induced by hyperoxia in neonatal rats and improve the symptoms of bronchopulmonary dysplasia in a dose-dependent manner, possibly by down-regulating the expression of miR-155 and up-regulating the expression of SOCS1.


Assuntos
Displasia Broncopulmonar , Hiperóxia , Animais , Animais Recém-Nascidos , Pulmão , MicroRNAs , Ratos , Triterpenos
5.
Braz J Med Biol Res ; 53(2): e8917, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994602

RESUMO

This study investigates the effect of the overexpression of the placental growth factor (PGF) and hyperoxia on lung development and determines whether anti-PGF antibody ameliorates hyperoxia-mediated impairment of lung development in newborn rats. After exposure to normoxic conditions for seven days, newborn rats subjected to normoxia were intraperitoneally or intratracheally injected with physiological saline, adenovirus-negative control (Ad-NC), or adenovirus-PGF (Ad-PGF) to create the Normoxia, Normoxia+Ad-NC, and Normoxia+Ad-PGF groups, respectively. Newborn rats subjected to hyperoxia were intraperitoneally injected with physiological saline or anti-PGF antibodies to create the Hyperoxia and Hyperoxia+anti-PGF groups, respectively. Our results revealed significant augmentation in the levels of PGF and its receptor Flt-1 in the lung tissues of newborn rats belonging to the Normoxia+Ad-PGF or Hyperoxia groups. PGF overexpression in these groups caused lung injury in newborn rats, while anti-PGF antibody treatment significantly cured the hyperoxia-induced lung injury. Moreover, PGF overexpression significantly increased TNF-α and Il-6 levels in the bronchoalveolar lavage (BAL) fluid of the Normoxia+Ad-PGF and Hyperoxia groups. However, their levels were significantly reduced in the BAL fluid of the Hyperoxia+anti-PGF group. Immunohistochemical analysis revealed that PGF overexpression and hyperoxia treatment significantly increased the expression of the angiogenesis marker, CD34. However, its expression was significantly decreased upon administration of anti-PGF antibodies (compared to the control group under hyperoxia). In conclusion, PGF overexpression impairs lung development in newborn rats while its inhibition using an anti-PGF antibody ameliorates the same. These results provided new insights for the clinical management of bronchopulmonary dysplasia in premature infants.


Assuntos
Anticorpos Monoclonais/metabolismo , Autoanticorpos/metabolismo , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Fator de Crescimento Placentário/metabolismo , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/imunologia , Autoanticorpos/imunologia , Modelos Animais de Doenças , Feminino , Hiperóxia/complicações , Hiperóxia/diagnóstico por imagem , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/patologia , Microscopia Eletrônica de Varredura , Fator de Crescimento Placentário/imunologia , Gravidez , Ratos
6.
J Stroke Cerebrovasc Dis ; 29(2): 104556, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31818682

RESUMO

BACKGROUND: Ischemic stroke is an emergency with elevated risk for morbidity and mortality. Hypoxia is harmful in acute ischemic stroke. Recent evidence raises concerns regarding hyperoxia as well in acute illness, and for supplemental oxygen therapy when SpO2greater than 92%. Current AHA/ASA guidelines recommend maintaining SpO2greater than 94%. In this study, we aimed to assess the relationship between the oxygenation levels within the first 6-hour of ischemic stroke admission and mortality. METHODS: With the approval of the Human Studies Committee (IRB #: 13.0396), we performed a retrospective cohort study of ischemic stroke patients consecutively admitted to our hospital in the years 2013-14 and 2017-18 (n = 1479). Relationship between the first 6 hours oxygenation status and in-house mortality was assessed. SpO2/FiO2 ratio was used as the oxygenation outcome parameter. Patients who were intubated at admission were excluded. Additionally, demographics, baseline confounding factors, neurological status, and laboratory values on admission were examined for their association with mortality in a multivariate logistic regression analysis. RESULTS: Mean age of patients was 64 ± 15 years. Time interval from last seen normal to hospital admission was 7 ± 5 hours (mean ± standard deviation). NIHSS on arrival was 41-9 (median-IQR). Fourteen percent of patients received IV alteplase and 6% were treated with mechanical thrombectomy. Baseline SpO2 was 97 ± 2%, and 47% of the patients required supplemental oxygen treatment per AHA/ASA guidelines. In hospital mortality rate of this cohort was 5.7%. Lower mean SpO2 /FiO2 levels were strongly correlated with increasing mortality rates (R2 = .973). Age (1.048 [1.028-1.068]), NIHSS (1.120 [1.088-1.154]), WBC (1.116 [1.061-1.175]) and Mean SpO2/FiO2 (.995 [.992-.999]) independently risk associated with mortality. CONCLUSIONS: Baseline oxygenation varies within the acute ischemic stroke patient population. In this retrospective cohort study, we are reporting a strong association between lower SpO2/FiO2 levels in the first few hours of admission and mortality. In the light of these results, we plan to prospectively assess the role of oxygenation further in the context of recanalization status of stroke.


Assuntos
Isquemia Encefálica/sangue , Hiperóxia/sangue , Oxigênio/sangue , Acidente Vascular Cerebral/sangue , Idoso , Biomarcadores/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/mortalidade , Isquemia Encefálica/terapia , Feminino , Mortalidade Hospitalar , Humanos , Hiperóxia/diagnóstico , Hiperóxia/mortalidade , Hiperóxia/terapia , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/terapia , Trombectomia , Terapia Trombolítica , Fatores de Tempo , Resultado do Tratamento
8.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R399-R409, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850819

RESUMO

During ramp-incremental (RI) exercise to exhaustion, the near-infrared spectroscopy-derived deoxygenated hemoglobin ([HHb]) signal in the vastus lateralis muscle shows a linear increase up to a point at which a plateau-like response is manifested ([HHb]bp). This study investigated if 1) the [HHb]bp is affected by different fractions of inspired O2 (FIO2) [hypoxia (16%; HYPO); normoxia (21%; NORM); hyperoxia (30%; HYPER)]; and 2) an abrupt change to hyperoxic-inspired gas just before the occurrence of the [HHb]bp (HYPERSWITCH) would affect the [HHb] plateau-like response. Ten physically active male participants reported to the laboratory on four separate occasions to perform an RI test to exhaustion in NORM, HYPO, and HYPER and an RI test to exhaustion with an abrupt increase in FIO2 (30%; HYPERSWITCH) 15 W before the power output (PO) associated with [HHb]bp in normoxia. PO, [HHb], tissue O2 (StO2), and pulse O2 saturation (SpO2) were recorded continuously. Peak PO was significantly lower in HYPO (290 ± 21 W) and higher in HYPER (321 ± 22 W) and HYPERSWITCH (320 ± 19 W) compared with NORM (311 ± 18 W). The PO associated with [HHb]bp was not different between NORM and HYPER (246 ± 23 vs. 247 ± 24 W), but it was lower in HYPO (198 ± 31 W) than NORM and HYPER. The PO associated with the [HHb]bp in HYPERSWITCH (240 ± 23) was not different compared with NORM. HYPER and HYPERSWITCH resulted in greater StO2 and SpO2 compared with NORM. These results suggest that the [HHb]bp response is not dependent of O2 driving pressure and that other physiological mechanisms might determine its occurrence.


Assuntos
Hemoglobinas/metabolismo , Inalação , Contração Muscular , Fadiga Muscular , Consumo de Oxigênio , Oxigênio/sangue , Músculo Quadríceps/irrigação sanguínea , Músculo Quadríceps/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Ciclismo , Biomarcadores/sangue , Humanos , Hiperóxia/sangue , Hiperóxia/fisiopatologia , Hipóxia/sangue , Hipóxia/fisiopatologia , Masculino , Valor Preditivo dos Testes , Distribuição Aleatória , Fatores de Tempo , Adulto Jovem
9.
Undersea Hyperb Med ; 46(5): 723-724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683374
10.
Top Magn Reson Imaging ; 28(5): 285-297, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31592995

RESUMO

The Human Placenta Project has focused attention on the need for noninvasive magnetic resonance imaging (MRI)-based techniques to diagnose and monitor placental function throughout pregnancy. The hope is that the management of placenta-related pathologies would be improved if physicians had more direct, real-time measures of placental health to guide clinical decision making. As oxygen alters signal intensity on MRI and oxygen transport is a key function of the placenta, many of the MRI methods under development are focused on quantifying oxygen transport or oxygen content of the placenta. For example, measurements from blood oxygen level-dependent imaging of the placenta during maternal hyperoxia correspond to outcomes in twin pregnancies, suggesting that some aspects of placental oxygen transport can be monitored by MRI. Additional methods are being developed to accurately quantify baseline placental oxygenation by MRI relaxometry. However, direct validation of placental MRI methods is challenging and therefore animal studies and ex vivo studies of human placentas are needed. Here we provide an overview of the current state of the art of oxygen transport and quantification with MRI. We suggest that as these techniques are being developed, increased focus be placed on ensuring they are robust and reliable across individuals and standardized to enable predictive diagnostic models to be generated from the data. The field is still several years away from establishing the clinical benefit of monitoring placental function in real time with MRI, but the promise of individual personalized diagnosis and monitoring of placental disease in real time continues to motivate this effort.


Assuntos
Hiperóxia/diagnóstico por imagem , Hiperóxia/patologia , Imagem por Ressonância Magnética/métodos , Oxigênio/sangue , Placenta/diagnóstico por imagem , Placenta/patologia , Animais , Feminino , Humanos , Gravidez
11.
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
12.
Undersea Hyperb Med ; 46(4): 509-519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509907

RESUMO

Nitric oxide (NO) may protect against gas bubble formation and risk of decompression sickness. We have previously shown that the crucial co-factor tetrahydrobiopterin (BH4) is oxidized in a dose-dependent manner when exposed to hyperoxia similar to diving conditions but with minor effects on the NO production by nitric oxide synthase. By manipulating the intracellular redox state, we further investigated the relationship between BH4 levels and production of NO in human endothelial cells (HUVECs). HUVECs were cultured with and without ascorbic acid (AA) and the glutathione (GSH) synthesis inhibitor buthionine sulfoximine, prior to hyperoxic exposure. The levels of biopterins and GSH were determined in cell lysates while the production of NO was determined in intact cells. Omitting AA resulted in a 91% decrease in BH4 levels (0.49 ± 0.08 to 0.04 ± 0.01 pmol/106 cells, p⟨0.001) at 20 kPa oxygen (O2), and 88% decrease (0.24 ± 0.03 to 0.03 ± 0.01 pmol/106 cells, p=0.01) after exposure to 60 kPa O2. The NO generation was decreased by 23% (74.5 ± 2.2 to 57.3 ± 5.6 pmol/min/mg protein, p⟨0.001) at 20 kPa O2, but no significant change was observed at 60 kPa O2. GSH depletion had no effects on the NO generation. No correlation was found between NO generation and the corresponding intracellular BH4 concentration (p=0.675, r=-0.055) or the BH4 to BH2 ratio (p=0.983, r=0.003), determined across 18 in vitro experiments. Decreased BH4 in HUVECs, due to hyperoxia or lack of ascorbic acid, does not imply corresponding decreases in NO generation.


Assuntos
Ácido Ascórbico/administração & dosagem , Biopterina/análogos & derivados , Células Endoteliais/metabolismo , Hiperóxia/metabolismo , Óxido Nítrico/biossíntese , Antimetabólitos , Biopterina/análise , Biopterina/metabolismo , Butionina Sulfoximina , Doença da Descompressão/etiologia , Doença da Descompressão/prevenção & controle , Endotélio Vascular , Glutationa/análise , Glutationa/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Óxido Nítrico Sintase/metabolismo , Oxirredução , Oxigênio , Pressão Parcial
13.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(8): 978-982, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31537223

RESUMO

OBJECTIVE: To investigate the effect of overexpression of microRNA-21-5p (miR-21-5p) on early apoptosis of type II alveolar epithelial cells (AEC II) in rats with hyperoxic acute lung injury (HALI). METHODS: The Sprague-Dawley (SD) rats were randomly divided into four groups: control group (CON group), hyperoxia group (H group), overexpression group (OE group) and empty vector group (EV group), with 20 rats in each group. HALI animal model was made by inhaling high concentration oxygen (oxygen concentration ≥ 90%); CON group was arranged to inhale room air. The miR-21-5p adeno-associated virus-6 (AAV-6) overexpression vectors or empty vectors were dripped into the lungs of OE group and EV group through tracheal tube, respectively. The hyperoxia model was prepared after 3 weeks of feeding. At 0, 24, 48 and 60 hours after making model, 5 rats were selected to detect lung injury parameters: oxygenation index (OI), respiratory index (RI), wet/dry ratio (W/D), pathological injury score of lung tissue; real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-21-5p in AEC II, and flow cytometry was used to detect the early apoptotic rate of AEC II. RESULTS: (1) The lung injury parameters: in H group, the OI gradually decreased with time, but the RI, lung W/D ratio and pathological score increased gradually with time, the difference between CON group was statistically significant at 24 hours [OI (mmHg, 1 mmHg = 0.133 kPa): 336.04±5.79 vs. 400.22±19.70, RI: 0.20±0.02 vs. 0.10±0.06, lung W/D ratio: 5.04±0.09 vs. 4.85±0.09, lung tissue pathological score: 0.13±0.01 vs. 0.07±0.01, all P < 0.05]. It indicated that HALI model could be successfully established by inhaling high concentration oxygen continuously. (2) The expression of miR-21-5p: the miR-21-5p was gradually increased in H, OE and EV groups, and the expression of miR-21-5p was significantly higher than that in CON group at 24, 48 and 60 hours. Compared with H group, the expression of miR-21-5p was significantly increased further in OE group at 0, 24, 48 and 60 hours (2-ΔΔCt: 3.75±0.11 vs. 0.98±0.14, 3.98±0.12 vs. 1.18±0.13, 4.28±0.18 vs. 1.49±0.06, 4.66±0.12 vs. 1.80±0.12, all P < 0.05). (3) The early apoptosis of AEC II: the early apoptosis rate gradually increased with time in H, OE and EV groups, and the early apoptosis of AEC II was significantly higher than that in CON group at 24, 48 and 60 hours. Compared with H group, the early apoptosis rate was significantly decreased in OE group at 24, 48 and 60 hours [(1.22±0.63)% vs. (2.84±0.59)%, (5.76±0.18)% vs. (13.10±2.01)%, (29.48±0.48)% vs. (49.04±1.36)%, all P < 0.05]. (4) There was no significant difference in the expression of miR-21-5p and the early apoptosis of AEC II cells between EV group and H group at each time point. CONCLUSIONS: Overexpression of miR-21-5p could inhibit the early apoptosis of AECII in rats with HALI.


Assuntos
Lesão Pulmonar Aguda , Hiperóxia , MicroRNAs/metabolismo , Células Epiteliais Alveolares , Animais , Apoptose , Pulmão , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
14.
Diving Hyperb Med ; 49(3): 154-160, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31523789

RESUMO

BACKGROUND: The risk of oxygen toxicity has become a prominent issue due to the increasingly widespread administration of hyperbaric oxygen (HBO) therapy, as well as the expansion of diving techniques to include oxygen-enriched gas mixtures and technical diving. However, current methods used to calculate the cumulative risk of oxygen toxicity during an HBO exposure i.e., the unit pulmonary toxic dose concept, and the safe boundaries for central nervous system oxygen toxicity (CNS-OT), are based on a simple linear relationship with an inspired partial pressure of oxygen (PO2) and are not supported by recent data. METHODS: The power equation: Toxicity Index = t2 × PO2c, where t represents time and c represents the power term, was derived from the chemical reactions producing reactive oxygen species or reactive nitrogen species. RESULTS: The toxicity index was shown to have a good predictive capability using PO2 with a power c of 6.8 for CNS-OT and 4.57 for pulmonary oxygen toxicity. The pulmonary oxygen toxicity index (PO2 in atmospheres absolute, time in h) should not exceed 250. The CNS-OT index (PO2 in atmospheres absolute, time in min) should not exceed 26,108 for a 1% risk. CONCLUSION: The limited use of this toxicity index in the diving community, after more than a decade since its publication in the literature, establishes the need for a handy, user-friendly implementation of the power equation.


Assuntos
Doenças do Sistema Nervoso Central/induzido quimicamente , Oxigenação Hiperbárica , Hiperóxia , Pneumopatias/induzido quimicamente , Oxigênio/toxicidade , Sistema Nervoso Central , Mergulho/fisiologia , Humanos , Oxigenação Hiperbárica/efeitos adversos , Pressão Parcial
15.
Hypertension ; 74(4): 843-853, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476902

RESUMO

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides(LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1ß expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.


Assuntos
Hiperóxia/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lipopolissacarídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperóxia/complicações , Hiperóxia/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle
16.
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
17.
Arch Pharm Res ; 42(10): 902-908, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31388826

RESUMO

Lycium barbarum polysaccharide (LBP), an active component from Goji berry which is a traditional Chinese medicine, has anti-inflammatory and antioxidant features. The aim of our study was to investigate whether LBP has any role in hyperoxia-induced acute lung injury (ALI). Using a murine model of hyperoxia-induced ALI, we investigate the effect of LBP on pulmonary pathological changes as well as Sirtuin 1 (SIRT1) and the nucleotide binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome. Exposure to 100% oxygen for 72 h in male C57BL/6 mice resulted in increased protein levels of tumor necrosis factor-α and interleukin-1ß in lung tissues, and aggravated lung histological alterations. These hyperoxia-induced changes and mortality were improved by LBP. LBP markedly suppressed the activation of NLRP3 inflammasome both in vivo and in vitro. Moreover, LBP upregulated SIRT1 expression compared with vehicle-treated group. Importantly, knockdown of SIRT1 reversed the inhibitory effect of LBP on NLRP3 inflammasome activation in vitro. LBP meliorated hyperoxia-induced ALI in mice by SIRT1-dependent inhibition of NLRP3 inflammasome activation.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Hiperóxia/tratamento farmacológico , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Hiperóxia/metabolismo , Hiperóxia/patologia , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
18.
Med Sci Monit ; 25: 6074-6084, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411185

RESUMO

BACKGROUND Bronchopulmonary dysplasia (BPD) is a major complication of extreme prematurity, characterized by alveolar simplification and pulmonary malfunction. Hyperoxia-induced lung injury in neonatal rats has been used as a model of BPD, as indicated by lung architectural change and alveolar simplification that resembles clinical feature of BPD. ß-defensin-2 (BD2) plays an important role in lung diseases by inhibiting inflammation response. However, little is known about its role in BPD. The aim of this study was to determine the effect of human BD2 (hBD2) gene on hyperoxia-induced animal model of BPD. MATERIAL AND METHODS The neonatal rats were exposed to 90% oxygen (O2) continuously for 14 days to mimic the BPD-like lung injury. These rats were then randomly assigned to the following four groups: in room air (air), in 90% O2, in 90% O2 with null adenovirus vector infection (O2+Ad), and in 90% O2 with gene therapy through adenovirus transfected hBD2 (O2+Ad-hBD2). Morphology of lungs, pulmonary function and expression of inflammatory cytokines on P7, P10, P14, and P21 were documented and compared across the 4 groups. RESULTS The overexpression of hBD2 mediated by the adenovirus vector was successfully constructed. hBD2 gene therapy increased hBD2 mRNA expression, increased radial alveolar count (RAC), lung volume and compliance, decreased mean linear intercept (MLI), tissue damping, and elastance. Furthermore, pro-inflammatory cytokines IL-1ß, IL-6, and TNF-alpha were inhibited and anti-inflammatory cytokines IL-10 was increased in the lungs of rats in O2+Ad-hBD2 group. CONCLUSIONS In hyperoxia-induced rat models of BPD, hBD2 promotes alveolarization and improves pulmonary function. The mechanism may contribute in alleviating inflammation response and inhibiting pro-inflammatory factors including IL-1ß, IL-6, and TNF-alpha.


Assuntos
Lesão Pulmonar/terapia , beta-Defensinas/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Hiperóxia/complicações , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/fisiopatologia , Lesão Pulmonar/etiologia , Oxigênio/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , beta-Defensinas/fisiologia
19.
Ren Fail ; 41(1): 733-741, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31424299

RESUMO

Aim: Supplemental oxygen is often used to treat neonates with respiratory disorders. Human and animal studies have demonstrated that neonatal hyperoxia increases oxidative stress and induces damage and collagen deposition in kidney during the perinatal period. Cathelicidin LL-37 is one important group of human antimicrobial peptides which exhibits antioxidant activity and its overexpression resists hyperoxia-induced oxidative stress. This study was designed to evaluate the protective effects of cathelicidin in hyperoxia-induced kidney injury in newborn rats. Methods: Sprague-Dawley rat pups were reared in either room air (RA) or hyperoxia (85% O2) and were randomly treated with low-dose (4 mg/kg) and high-dose (8 mg/kg) cathelicidin in normal saline (NS) administered intraperitoneally on postnatal days 1-6. The following six groups were obtained: RA + NS, RA + low-dose cathelicidin, RA + high-dose cathelicidin, O2 + NS, O2 + low-dose cathelicidin, and O2 + high-dose cathelicidin. Kidneys were taken for Western blot and histological analyses on postnatal day 7. Results: The hyperoxia-reared rats exhibited significantly lower body weights and anti-inflammatory M2 macrophages, but the kidney injury scores, oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells, pro-inflammatory M1 macrophages, collagen deposition, and NF-κB expression were higher than did the RA-reared rats. Conclusions: Cathelicidin treatment attenuated kidney injury as evidenced by lower kidney injury scores, 8-OHdG-positive cells, collagen deposition, and reversion of hyperoxia-induced M1/M2 macrophage polarization. The role of Cathelicidin in ameliorates kidney injury of the hyperoxia newborn rats was accompanied by decreased NF-κB expression, which probably through the modulating NF-κB activity in the kidney.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Hiperóxia/complicações , Nefropatias/prevenção & controle , Oxigenoterapia/efeitos adversos , Oxigênio/efeitos adversos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Ativação de Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/administração & dosagem , Oxigenoterapia/métodos , Gravidez , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Transdução de Sinais/efeitos dos fármacos
20.
Curr Opin Anaesthesiol ; 32(6): 783-791, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31464698

RESUMO

PURPOSE OF REVIEW: The topic of perioperative hyperoxia remains controversial, with valid arguments on both the 'pro' and 'con' side. On the 'pro' side, the prevention of surgical site infections was a strong argument, leading to the recommendation of the use of hyperoxia in the guidelines of the Center for Disease Control and the WHO. On the 'con' side, the pathophysiology of hyperoxia has increasingly been acknowledged, in particular the pulmonary side effects and aggravation of ischaemia/reperfusion injuries. RECENT FINDINGS: Some 'pro' articles leading to the Center for Disease Control and WHO guidelines advocating perioperative hyperoxia have been retracted, and the recommendations were downgraded from 'strong' to 'conditional'. At the same time, evidence that supports a tailored, more restrictive use of oxygen, for example, in patients with myocardial infarction or following cardiac arrest, is accumulating. SUMMARY: The change in recommendation exemplifies that despite much work performed on the field of hyperoxia recently, evidence on either side of the argument remains weak. Outcome-based research is needed for reaching a definite recommendation.


Assuntos
Oxigênio/administração & dosagem , Humanos , Hiperóxia , Oxigênio/análise , Período Perioperatório , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA