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1.
J Infect Dis ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34865064

RESUMO

BACKGROUND: COVID-19 disproportionally affects pregnant women and their newborn, yet little is known about the variables that modulate the maternal-fetal immune response to infection. METHODS: We prospectively studied socioeconomic, biologic and clinical factors affecting humoral immunity in 87 unvaccinated pregnant women admitted to hospital in the Buenos Aires metropolitan area for symptoms consistent with COVID-19 disease. RESULTS: The number of days between symptom onset and childbirth predicted maternal and newborn virus Spike protein Receptor Binding Domain (RBD)-specific IgG. These findings suggest newborns may benefit less when mothers deliver soon after COVID-19 infection. Similarly, a longer time between symptom onset and birth predicted higher in utero transfer of maternal IgG and its concentration in cord blood. Older gestational ages at birth were associated with lower maternal IgG: cord blood IgG ratios. Eighty seven percent of women with confirmed SARS-CoV-2 infection developed RBD-specific IgA responses in breast milk within 96 h of childbirth. IgA was not significantly associated with time from infection but correlated with maternal serum IgG and placental transfer. CONCLUSIONS: These results demonstrate the combined role of biologic, clinical and socioeconomic variables associated with maternal SARS-CoV-2 RBD-specific antibodies and supports early vaccination strategies for COVID-19 in socioeconomically vulnerable pregnant women.

2.
Pediatrics ; 148(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34599008

RESUMO

In this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in "crosstalk" between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase-associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.


Assuntos
Injúria Renal Aguda , Injúria Renal Aguda/complicações , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Biomarcadores/urina , Cafeína/uso terapêutico , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Recém-Nascido , Recém-Nascido Prematuro , Rim/efeitos dos fármacos , Rim/fisiologia , Lipocalina-2/urina , Estudos Multicêntricos como Assunto , Consumo de Oxigênio , Terapia de Substituição Renal/instrumentação , Pesquisa , Fatores de Risco , Teofilina/uso terapêutico , Equilíbrio Hidroeletrolítico
3.
Antioxidants (Basel) ; 10(5)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919055

RESUMO

BACKGROUND: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1ß expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. METHODS: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. RESULTS: Expression of IL-1ß, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1ß expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1ß. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. CONCLUSIONS: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1ß synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1ß directly inhibits transcription of the IL1ß gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

4.
Antioxidants (Basel) ; 10(2)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672905

RESUMO

Maternal selenium (Se) deficiency is associated with decreased neonatal Se levels, which increases the risk for neonatal morbidities. There is a hierarchy to selenoprotein expression after Se deficiency in adult rodents, depending on the particular protein and organ evaluated. However, it is unknown how limited Se supply during pregnancy impacts neonatal selenoprotein expression. We used an Se-deficient diet to induce perinatal Se deficiency (SeD), initiated 2-4 weeks before onset of breeding and continuing through gestation. Neonatal plasma, liver, heart, kidney, and lung were collected on the day of birth and assessed for selenoproteins, factors required for Se processing, and non-Se containing antioxidant enzymes (AOE). Maternal SeD reduced neonatal circulating and hepatic glutathione peroxidase (GPx) activity, as well as hepatic expression of Gpx1 and selenophosphate synthetase 2 (Sps2). In contrast, the impact of maternal SeD on hepatic thioredoxin reductase 1, hepatic non-Se containing AOEs, as well as cardiac, renal, and pulmonary GPx activity, varied based on duration of maternal exposure to SeD diet. We conclude that the neonatal liver and circulation demonstrate earlier depletion in selenoenzyme activity after maternal SeD. Our data indicate that prolonged maternal SeD may escalate risk to the neonate by progressively diminishing Se-containing AOE across multiple organs.

5.
Respir Res ; 22(1): 57, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596914

RESUMO

BACKGROUND: MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD). METHODS: Here we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-α), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants. RESULTS: miR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situ hybridization of human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-α. To further confirm the target relationship between miR-219 and PDGFR-α, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR-219 increased significantly after miR-219 mimic treatment, while the level of PDGFR-α declined markedly. LNA exposure increased PDGFR-α. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation. CONCLUSIONS: Taken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-α. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.


Assuntos
Displasia Broncopulmonar/metabolismo , MicroRNAs/biossíntese , Alvéolos Pulmonares/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/biossíntese , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/terapia , Estudos de Coortes , Pressão Positiva Contínua nas Vias Aéreas/métodos , Humanos , Recém-Nascido , Recém-Nascido Prematuro/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estudos Prospectivos , Alvéolos Pulmonares/patologia
6.
Redox Biol ; 38: 101797, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254076

RESUMO

Cellular antioxidants protect against hyperoxic lung injury. The role of the glutathione (GSH) system in lung development and bronchopulmonary dysplasia (BPD) pathogenesis has not been systematically investigated. The current study utilized GSH reductase-deficient (Gsr-KO) neonatal mice to test the hypothesis that early disruption of the GSH system negatively impacts lung development and hyperoxic responses. Lungs from wild-type (Gsr-WT) and Gsr-KO mice were analyzed for histopathology, developmental markers, redox indices, and transcriptome profiling at different developmental stages following exposure to room air or hyperoxia (85% O2) for up to 14 d. Lungs from Gsr-KO mice exhibited alveolar epithelial dysplasia in the embryonic and neonatal periods with relatively normal lung architecture in adulthood. GSH and its oxidized form (GSSG) were 50-70% lower at E19-PND14 in Gsr-KO lungs than in age-matched Gsr-WT. Differential gene expression between Gsr-WT and Gsr-KO lungs was analyzed at discrete developmental stages. Gsr-KO lungs exhibited downregulated cell cycle and DNA damage checkpoint genes at E19, as well as lung lipid metabolism and surfactant genes at PND5. In addition to abnormal baseline lung morphometry, Gsr-KO mice displayed a blunted response to hyperoxia. Hyperoxia caused a more robust upregulation of the lung thioredoxin system in Gsr-KO compared to Gsr-WT. Gsr-dependent, hyperoxia-responsive genes were highly associated with abnormal cytoskeleton, skeletal-muscular function, and tissue morphology at PND5. Overall, our data in Gsr-KO mice implicate the GSH system as a key regulator of lung development, cellular differentiation, and hyperoxic responses in neonatal mice.


Assuntos
Hiperóxia , Animais , Animais Recém-Nascidos , Glutationa , Glutationa Redutase/genética , Hiperóxia/genética , Pulmão , Camundongos , Oxirredutases
7.
Front Immunol ; 11: 595282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224150

RESUMO

Background: Selenium (Se) levels decrease in the circulation during acute inflammatory states and sepsis, and are inversely associated with morbidity and mortality. A more specific understanding of where selenoproteins and Se processing are compromised during insult is needed. We investigated the acute signaling response in selenoenzymes and Se processing machinery in multiple organs after innate immune activation in response to systemic lipopolysaccharide (LPS). Methods: Wild type (WT) adult male C57/B6 mice were exposed to LPS (5 mg/kg, intraperitoneal). Blood, liver, lung, kidney and spleen were collected from control mice as well as 2, 4, 8, and 24 h after LPS. Plasma Se concentration was determined by ICP-MS. Liver, lung, kidney and spleen were evaluated for mRNA and protein content of selenoenzymes and proteins required to process Se. Results: After 8 h of endotoxemia, plasma levels of Se and the Se transporter protein, SELENOP were significantly decreased. Consistent with this timing, the transcription and protein content of several hepatic selenoenzymes, including SELENOP, glutathione peroxidase 1 and 4 were significantly decreased. Furthermore, hepatic transcription and protein content of factors required for the Se processing, including selenophosphate synthetase 2 (Sps2), phosphoseryl tRNA kinase (Pstk), selenocysteine synthase (SepsecS), and selenocysteine lyase (Scly) were significantly decreased. Significant LPS-induced downregulation of these key selenium processing enzymes was observed in isolated hepatocytes. In contrast to the acute and dynamic changes observed in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. Conclusion: Hepatic selenoenzyme production and Se processing factors decreased after endotoxemia. This was temporally associated with decreased circulating Se. In contrast to these active changes in the regulation of Se processing in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. These findings highlight the need to further study the impact of innate immune challenges on Se processing in the liver and the impact of targeted therapeutic Se replacement strategies during innate immune challenge.


Assuntos
Endotoxemia/imunologia , Fígado/imunologia , Selenoproteínas/imunologia , Animais , Endotoxemia/sangue , Glutationa Peroxidase , Hepatócitos , Rim/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Selênio/sangue , Baço/imunologia
8.
Life Sci ; 259: 118285, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798556

RESUMO

AIMS: Interleukin-1ß (IL-1ß) contributes to the development of bronchopulmonary dysplasia (BPD). Thioredoxin reductase-1 (Txnrd1) inhibition activates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent responses. Txnrd1 activity is selenium (Se) dependent and Se deficiency is common in prematurity. Auranofin (AFN), a Txnrd1 inhibitor, decreases IL-1ß levels and increases Nrf2 activation in lipopolysaccharide (LPS) treated alveolar macrophages. In lung epithelia, AFN-induced Nrf2 activation is Se dependent. We tested the hypothesis that the effects of Txnrd1 inhibition in alveolar macrophages are Se dependent. MAIN METHODS: To establish Se sufficient (Se+) and deficient (Se-) conditions, alveolar (MH-S) macrophages were cultured in 2.5% fetal bovine serum (FBS) ± 25 nM Na2SeO3. Se- (2.5% FBS) and Se+ (2.5% FBS + 25 nM Na2SeO3) cells were cultured in the presence or absence of 0.05 µg/mL LPS and/or 0.5 µM AFN. Nrf2 activation was determined by measuring NADPH quinone oxidoreductase-1 (Nqo1) and glutathione levels. IL-1ß mRNA (Il1b) and protein levels were measured using qRT-PCR and ELISA. Data were analyzed by ANOVA followed by Tukey's post-hoc. KEY FINDINGS: We detected an independent effect of AFN, but not LPS, on Nqo1 expression and GSH levels in Se+ and Se- cells. LPS significantly increased Il1b and IL-1ß levels in both groups. AFN-mediated attenuation of this effect was not impacted by Se status. SIGNIFICANCE: The beneficial effects of Txnrd1 inhibition in alveolar macrophages are Se-independent and therefore unlikely to be diminished by clinical Se deficiency.


Assuntos
Auranofina/farmacologia , Macrófagos Alveolares/metabolismo , Tiorredoxina Redutase 1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Auranofina/metabolismo , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Glutationa/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Macrófagos/metabolismo , Macrófagos Alveolares/fisiologia , Camundongos , Cultura Primária de Células , Selênio/metabolismo , Selênio/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo
9.
Oxid Med Cell Longev ; 2020: 2908271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32587658

RESUMO

Thioredoxin reductase-1 (TXNRD1) inhibition activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and prevents acute lung injury (ALI). Heme oxygenase-1 (HO-1) induction following TXNRD1 inhibition is Nrf2-dependent in airway epithelial (club) cells in vitro. The influence of club cell HO-1 on lung development and lung injury responses is poorly understood. The present studies characterized the effects of hyperoxia on club cell-specific HO-1 knockout (KO) mice. These mice were generated by crossing Hmox1 flox mice with transgenic mice expressing cre recombinase under control of the club cell-specific Scgb1a1 promoter. Baseline analyses of lung architecture and function performed in age-matched adult wild-type and KO mice indicated an increased alveolar size and airway resistance in HO-1 KO mice. In subsequent experiments, adult wild-type and HO-1 KO mice were either continuously exposed to >95% hyperoxia or room air for 72 h or exposed to >95 hyperoxia for 48 h followed by recovery in room air for 48 h. Injury was quantitatively assessed by calculating right lung/body weight ratios (g/kg). Analyses indicated an independent effect of hyperoxia but not genotype on right lung/body weight ratios in both wild-type and HO-1 KO mice. The magnitude of increases in right lung/body weight ratios was similar in mice of both genotypes. In the recovery model, an independent effect of hyperoxia but not genotype was also detected. In contrast to the continuous exposure model, right lung/body weight ratio mice were significantly elevated in HO-1 KO but not wild-type mice. Though club cell HO-1 does not alter hyperoxic sensitivity in adult mice, it significantly influences lung development and resolution of lung injury following acute hyperoxic exposure.


Assuntos
Envelhecimento/patologia , Células Epiteliais/enzimologia , Deleção de Genes , Heme Oxigenase-1/metabolismo , Hiperóxia/enzimologia , Hiperóxia/patologia , Animais , Animais Recém-Nascidos , Cruzamentos Genéticos , Células Epiteliais/patologia , Feminino , Genótipo , Integrases/metabolismo , Pulmão/embriologia , Lesão Pulmonar/enzimologia , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Recombinação Genética/genética , Uteroglobina/metabolismo
10.
Free Radic Biol Med ; 154: 84-94, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376456

RESUMO

Electron Paramagnetic Resonance (EPR) spectroscopy coupled with spin traps/probes enables quantitative determination of reactive nitrogen and oxygen species (RNOS). Even with numerous studies using spin probes, the methodology has not been rigorously investigated. The autoxidation of spin probes has been commonly overlooked. Using the spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH), the present study has tested the effects of metal chelators, temperature, and oxygen content on the autoxidation of spin probes, where an optimized condition is refined for cell studies. The apparent rate of CMH autoxidation under this condition is 7.01 ± 1.60 nM/min, indicating low sensitivity and great variation of the CMH method and that CMH autoxidation rate should be subtracted from the generation rate of CMH-detectable oxidants (simplified as oxidants below) in samples. Oxidants in RAW264.7 cells are detected at an initial rate of 4.0 ± 0.7 pmol/min/106 cells, which is not considered as the rate of basal oxidants generation because the same method has failed to detect oxidant generation from the stimulation of phorbol-12-mysirate-13-acetate (PMA, 0.1 nmol/106 cells) in cells (2.5 ± 0.9 for PMA vs. 2.1 ± 1.5 pmol/min/106 cells for dimethyl sulfoxide (DMSO)-treated cells). In contrast, the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), which exhibits minimal autoxidation, reveals differences between PMA and DMSO treatment (0.26 ± 0.09 vs. -0.06 ± 0.12 pmol/min/106 cells), which challenges previous claims that spin probes are more sensitive than spin traps. We have also found that low temperature EPR measurements of frozen samples of CMH autoxidation provide lower signal intensity and greater variation compared to RT measurements of fresh samples. The current study establishes an example for method development of RNOS detection, where experimental details are rigorously considered and tested, and raises questions on the applications of spin probes and spin traps.


Assuntos
Oxidantes , Oxigênio , Temperatura Baixa , Óxidos N-Cíclicos , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres , Espécies Reativas de Oxigênio , Marcadores de Spin
11.
J Perinatol ; 40(9): 1286-1295, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32277164

RESUMO

As a result of preterm birth, immature kidneys are exposed to interventions in the NICU that promote survival, but are nephrotoxic. Furthermore, the duration of renal development may be truncated in these vulnerable neonates. Immaturity and nephrotoxic exposures predispose preterm newborns to acute kidney injury (AKI), particularly in the low birth weight and extremely preterm gestational age groups. Several studies have associated preterm birth as a risk factor for future chronic kidney disease (CKD). However, only a few publications have investigated the impact of neonatal AKI on CKD development. Here, we will review the evidence linking preterm birth and AKI in the NICU to CKD and highlight the knowledge gaps and opportunities for future research. For neonatal intensive care studies, we propose the inclusion of AKI as an important short-term morbidity outcome and CKD findings such as a reduced glomerular filtration rate in the assessment of long-term outcomes.


Assuntos
Injúria Renal Aguda , Nascimento Prematuro , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Morbidade , Gravidez , Nascimento Prematuro/epidemiologia , Fatores de Risco
12.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1165-L1171, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32292070

RESUMO

Bronchopulmonary dysplasia (BPD), a long-term respiratory morbidity of prematurity, is characterized by attenuated alveolar and vascular development. Supplemental oxygen and immature antioxidant defenses contribute to BPD development. Our group identified thioredoxin reductase-1 (TXNRD1) as a therapeutic target to prevent BPD. The present studies evaluated the impact of the TXNRD1 inhibitor aurothioglucose (ATG) on pulmonary responses and gene expression in newborn C57BL/6 pups treated with saline or ATG (25 mg/kg ip) within 12 h of birth and exposed to room air (21% O2) or hyperoxia (>95% O2) for 72 h. Purified RNA from lung tissues was sequenced, and differential expression was evaluated. Hyperoxic exposure altered ~2,000 genes, including pathways involved in glutathione metabolism, intrinsic apoptosis signaling, and cell cycle regulation. The isolated effect of ATG treatment was limited primarily to genes that regulate angiogenesis and vascularization. In separate studies, pups were treated as described above and returned to room air until 14 days. Vascular density analyses were performed, and ANOVA indicated an independent effect of hyperoxia on vascular density and alveolar architecture at 14 days. Consistent with RNA-seq analyses, ATG significantly increased vascular density in room air, but not in hyperoxia-exposed pups. These findings provide insights into the mechanisms by which TXNRD1 inhibitors may enhance lung development.


Assuntos
Ar , Aurotioglucose/farmacologia , Hiperóxia/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Doença Aguda , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , DNA/biossíntese , Glutationa/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/embriologia , Alvéolos Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos
13.
Nitric Oxide ; 97: 27-32, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32014495

RESUMO

Hydrogen sulfide, nitric oxide, and carbon monoxide are endogenously produced gases that regulate various signaling pathways. The role of these transmitters is complex as constitutive production of these molecules may have anti-inflammatory, anti-microbial, and/or vasodilatory effects whereas induced production or formation of secondary metabolites may lead to cellular death. Given this fine line between friend and foe, therapeutic attenuation of these molecules' production has involved both inhibition of endogenous formation and therapeutic supplementation. All three gases have been implicated as regulators of critical aspects of neonatal physiology, and in turn, comorbidities including necrotizing enterocolitis, hypoxic ischemic encephalopathy, and pulmonary hypertension. In this review, we present current perspectives on these associations, highlight areas where insights remain sparse, and identify areas for potential for future investigations.


Assuntos
Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Animais , Humanos , Transdução de Sinais
14.
Clin Perinatol ; 46(3): 435-447, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31345539

RESUMO

Fetal development occurs in a relatively hypoxemic environment, and birth represents significant oxidative stress. Premature infants are disadvantaged by a lack of maternal antioxidant transfer and impaired endogenous antioxidant responses. O2 metabolism is essential for life and its biochemical reactions are dynamic, compartmentalized, and difficult to characterize in vivo. There is a growing appreciation for the role of reactive oxygen species in nonpathologic processes, including regulation of cell signaling and mitochondrial function. There are several gaps in the knowledge about the role of reactive oxygen species in normal development and how oxidative stress alters normal signaling and subsequent development.


Assuntos
Doenças do Prematuro/sangue , Recém-Nascido Prematuro , Estresse Oxidativo , Oxigenoterapia/efeitos adversos , Oxigênio/efeitos adversos , Humanos , Recém-Nascido , Doenças do Prematuro/terapia
15.
BMC Pediatr ; 19(1): 227, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31279333

RESUMO

BACKGROUND: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. METHODS: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. DISCUSSION: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. TRIAL REGISTRATION: Does not apply for this study.


Assuntos
Displasia Broncopulmonar/epidemiologia , Doenças do Prematuro/epidemiologia , Recém-Nascido de muito Baixo Peso , Estudos Multicêntricos como Assunto/métodos , Animais , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/genética , Doença Crônica , Progressão da Doença , Exposição Ambiental , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/genética , Unidades de Terapia Intensiva Neonatal , Pesquisa Interdisciplinar , Colaboração Intersetorial , Pneumopatias/etiologia , Aprendizado de Máquina , Masculino , Camundongos , Pais , Estudos Prospectivos , Testes de Função Respiratória
16.
Neurobiol Aging ; 81: 9-21, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31207469

RESUMO

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O3) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.


Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Apolipoproteína E3 , Exposição Ambiental/efeitos adversos , Transtornos da Memória/etiologia , Ozônio/efeitos adversos , Animais , Apolipoproteína E4 , Genótipo , Masculino , Estresse Oxidativo , Fatores de Risco
17.
Redox Biol ; 26: 101238, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31200239

RESUMO

L-NG-Nitro arginine methyl ester (L-NAME) has been widely applied for several decades in both basic and clinical research as an antagonist of nitric oxide synthase (NOS). Herein, we show that L-NAME slowly releases NO from its guanidino nitro group. Daily pretreatment of rats with L-NAME potentiated mesenteric vasodilation induced by nitrodilators such as nitroglycerin, but not by NO. Release of NO also occurred with the NOS-inactive enantiomer D-NAME, but not with L-arginine or another NOS inhibitor L-NMMA, consistent with the presence or absence of a nitro group in their structure and their nitrodilator-potentiating effects. Metabolic conversion of the nitro group to NO-related breakdown products was confirmed using isotopically-labeled L-NAME. Consistent with Fenton chemistry, transition metals and reactive oxygen species accelerated the release of NO from L-NAME. Both NO production from L-NAME and its nitrodilator-potentiating effects were augmented under inflammation. NO release by L-NAME can confound its intended NOS-inhibiting effects, possibly by contributing to a putative intracellular NO store in the vasculature.


Assuntos
Inibidores Enzimáticos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Nitroglicerina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Arginina/farmacologia , Feminino , Artérias Mesentéricas/efeitos dos fármacos , Camundongos , Miografia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ovinos , Estereoisomerismo , Vasodilatação/fisiologia , ômega-N-Metilarginina/farmacologia
18.
Free Radic Biol Med ; 142: 138-145, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30769161

RESUMO

Preterm birth is a primary cause of worldwide childhood mortality. Bronchopulmonary dysplasia, characterized by impaired alveolar and lung vascular development, affects 25-50% of extremely low birth weight (BW; <1 kg) infants. Abnormalities in lung function persist into childhood in affected infants and are second only to asthma in terms of childhood respiratory disease healthcare costs. While advances in the medical care of preterm infants have reduced mortality, the incidence of BPD has not decreased in the past 10 years. Reactive oxygen intermediates play a key role in the development of lung disease but, despite promising preclinical therapies, antioxidants have failed to translate into meaningful clinical interventions to decrease the incidence of lung disease in premature infants. In this review we will summarize the state of the art research developments in regards to antioxidants and premature lung disease and discuss the limitations of antioxidant therapies in order to more fully comprehend the reasons why therapeutic antioxidant administration failed to prevent BPD. Finally we will review promising therapeutic strategies and targets.


Assuntos
Antioxidantes/uso terapêutico , Displasia Broncopulmonar/terapia , Suplementos Nutricionais , Fator 2 Relacionado a NF-E2/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tiorredoxinas/agonistas , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Criança , Glutationa/administração & dosagem , Glutationa/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Unidades de Terapia Intensiva Neonatal , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiopatologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Medicina de Precisão/métodos , Espécies Reativas de Oxigênio/metabolismo , Selênio/administração & dosagem , Selênio/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
19.
Oxid Med Cell Longev ; 2019: 7945983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805084

RESUMO

Background: Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice. Hypothesis: The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice in vivo and lung epithelia in vitro. Methods: Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. In vitro, murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO). Results: In vivo, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. In vitro, AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels. Conclusions: Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between in vivo and in vitro results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.


Assuntos
Antioxidantes/metabolismo , Displasia Broncopulmonar/enzimologia , Displasia Broncopulmonar/patologia , Glutationa/metabolismo , Tiorredoxina Redutase 1/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Aurotioglucose , Displasia Broncopulmonar/genética , Células Epiteliais/metabolismo , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa Peroxidase/metabolismo , Hiperóxia/genética , Hiperóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiorredoxina Redutase 1/metabolismo
20.
Antioxid Redox Signal ; 31(12): 858-873, 2019 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-30648397

RESUMO

Significance: Redox homeostasis is finely tuned and governed by distinct intracellular mechanisms. The dysregulation of this either by external or internal events is a fundamental pathophysiologic base for many pulmonary diseases. Recent Advances: Based on recent discoveries, it is increasingly clear that cellular redox state and oxidation of signaling molecules are critical modulators of lung disease and represent a final common pathway that leads to poor respiratory outcomes. Critical Issues: Based on the wide variety of stimuli that alter specific redox signaling pathways, improved understanding of the disease and patient-specific alterations are needed for the development of therapeutic targets. Further Directions: For the full comprehension of redox signaling in pulmonary disease, it is essential to recognize the role of reactive oxygen intermediates in modulating biological responses. This review summarizes current knowledge of redox signaling in pulmonary development and pulmonary vascular disease.


Assuntos
Pulmão/crescimento & desenvolvimento , Compostos de Sulfidrila/metabolismo , Remodelação Vascular , Animais , Humanos , Pulmão/metabolismo , Oxirredução , Transdução de Sinais
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