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1.
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
2.
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
3.
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
4.
J Immunol ; 202(9): 2772-2781, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30944158

RESUMO

Inflammation in response to oxygen exposure is a major contributing factor in neonatal lung injury leading to bronchopulmonary dysplasia. Although increased levels of proinflammatory cytokines are seen in airway samples and blood from bronchopulmonary dysplasia patients, the innate immune responses in this common neonatal lung condition have not been well characterized. We previously reported that depletion of murine CD11b-expressing mononuclear phagocytes at birth led to severe acute hyperoxia-induced lung injury (HILI) and significant mortality. In this study, we further define the mononuclear phagocyte populations that are present in the neonatal lung and characterize their responses to hyperoxia exposure. We used myeloid depleter mice (CD11b-DTR and CCR2-DTR) to contrast the effects of depleting different monocyte/macrophage subpopulations on the innate immune response to hyperoxia. Using RNA sequencing and subsequent data analysis, we identified an IFN-γ-mediated role for interstitial monocytes/macrophages in acute HILI, in which decreased IFN-γ expression led to increased disease severity and increased Mmp9 mRNA expression. Importantly, intranasal administration of rIFN-γ largely rescued CD11b-DTR+ mice from severe HILI and decreased Mmp9 mRNA expression in Ly-6Clo and Ly-6Chi interstitial monocyte/macrophages. We conclude that the proinflammatory effects of hyperoxia exposure are, at least in part, because of the modulation of effectors downstream of IFN-γ by pulmonary monocytes/macrophages.


Assuntos
Antígenos Ly/imunologia , Hiperóxia/imunologia , Interferon gama/imunologia , Lesão Pulmonar/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/imunologia , Hiperóxia/patologia , Interferon gama/farmacologia , Lesão Pulmonar/patologia , Macrófagos/patologia , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Monócitos/patologia
5.
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
6.
Am J Physiol Lung Cell Mol Physiol ; 316(5): L903-L917, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30810065

RESUMO

High concentrations of oxygen (hyperoxia) are routinely used during anesthesia, and supplemental oxygen is also administered in connection with several other clinical conditions. Although prolonged hyperoxia is known to cause acute lung injury (ALI), whether short-duration hyperoxia causes lung toxicity remains unknown. We exposed mice to room air (RA or 21% O2) or 60% oxygen alone or in combination with 2% isoflurane for 2 h and determined the expression of oxidative stress marker genes, DNA damage and DNA repair genes, and expression of cell cycle regulatory proteins using quantitative PCR and Western analyses. Furthermore, we determined cellular apoptosis using TUNEL assay and assessed the DNA damage product 8-hydroxy-2'-deoxyguanosine (8-Oxo-dG) in the urine of 60% hyperoxia-exposed mice. Our study demonstrates that short-duration hyperoxia causes mitochondrial and nuclear DNA damage and that isoflurane abrogates this DNA damage and decreases apoptosis when used in conjunction with hyperoxia. In contrast, isoflurane mixed with RA caused significant 8-Oxo-dG accumulations in the mitochondria and nucleus. We further show that whereas NADPH oxidase is a major source of superoxide anion generated by isoflurane in normoxia, isoflurane inhibits superoxide generation in hyperoxia. Additionally, isoflurane also protected the mouse lungs against ALI (95% O2 for 36-h exposure). Our study established that short-duration hyperoxia causes genotoxicity in the lungs, which is abrogated when hyperoxia is used in conjunction with isoflurane, but isoflurane alone causes genotoxicity in the lung when delivered with ambient air.


Assuntos
Lesão Pulmonar Aguda , Dano ao DNA , Hiperóxia , Isoflurano/farmacologia , Pulmão , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Linhagem Celular , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/prevenção & controle , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , NADPH Oxidases/metabolismo , Superóxidos/metabolismo
7.
Am J Physiol Lung Cell Mol Physiol ; 316(3): L506-L518, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30652496

RESUMO

Infants born very prematurely (<28 wk gestation) have immature lungs and often require supplemental oxygen. However, long-term hyperoxia exposure can arrest lung development, leading to bronchopulmonary dysplasia (BPD), which increases acute and long-term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we assessed potential age-dependent adaptations in the control of breathing in an established rat model of BPD associated with hyperoxia. Hyperoxia exposure ( FIO2 ; 0.9 from 0 to 10 days of life) led to a BPD-like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (V̇e) and age-dependent changes in breath-to-breath variability. Hyperoxia-exposed rats had normal oxygen saturation ( SpO2 ) in room air but greater reductions in SpO2 during acute hypoxia (12% O2) that were likely due to lung injury. Moreover, acute ventilatory sensitivity was reduced at P12 to P14. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within six of eight or one of eight key brainstem regions, respectively, controlling breathing, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD-like phenotype and age-dependent adaptations in V̇e that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.


Assuntos
Displasia Broncopulmonar/metabolismo , Hiperóxia/metabolismo , Hipóxia/metabolismo , Lesão Pulmonar/metabolismo , Fatores Etários , Animais , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Hiperóxia/patologia , Hipertensão Pulmonar/metabolismo , Hipóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/patologia , Ratos
8.
Biomed Pharmacother ; 111: 733-739, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611998

RESUMO

INTRODUCTION: The disruption of the balance between antioxidants and oxidants plays a vital role in the pathogenesis of acute lung injury (ALI). Evidence has shown that Lycium barbarum polysaccharide (LBP) has antioxidant feature. We examined the efficacy and mechanisms of LBP on hyperoxia-induced acute lung injury (ALI) in the present study. MATERIALS AND METHODS: C57BL/6 wild-type (WT) mice and nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2-/-) mice were used in the present study. LBP was fed by gavages once daily for 1 week. Then, the mice were exposed to hyperoxia or room air for 72 h. Additional dosage of LBP was given per 24 h. RESULTS: Reactive oxygen species production was increased in WT mice exposed to hyperoxia. Inflammatory cytokines including interleukin (IL)-1ß as well as IL-6, and inflammatory cells were increased infiltration in the lung after 3 days hyperoxia exposure. Hyperoxia exposure also induced pulmonary edema and histopathological changes. These hyperoxia-induced changes were improved in LBP treated group. Moreover, elevated activities of heme oxygenase-1 and glutathione peroxidase and enhanced activation of Nrf2 were observed in mice treated with LBP. However, the benefit of LBP on hyperoxic ALI was abolished in Nrf2-/- mice. Moreover, our cell study showed that the LBP-induced activation of Nrf2 was dampened in pulmonary microvascular endothelial cells when the AMPK signal was inhibited by siRNA. CONCLUSIONS: LBP improves hyperoxic ALI via Nrf2-dependent manner. The LBP-induced activation of Nrf2 is mediated, at least in part, by AMPK pathway.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Hiperóxia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hiperóxia/tratamento farmacológico , Hiperóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/fisiologia
9.
Semin Thorac Cardiovasc Surg ; 31(2): 188-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30278268

RESUMO

The objectives were to investigate if after hypoxia or ischemia, normoxic reperfusion is associated with less oxidant stress (OS), inflammation, and myocardial injury than hyperoxic reperfusion. In this study, cardiomyocytes (H9c2 cells) were cultured in hypoxia, followed by reoxygenation in normoxia or hyperoxia. Cardiomyocyte OS, inflammation, and apoptosis were measured. In parallel experiments, rabbits were cannulated for cardiopulmonary bypass (CPB). Following cardioplegic arrest and aortic cross-clamp removal, hearts were reperfused under normoxic or hyperoxic conditions. Left ventricular developed pressure and contractility (LV +dP/dt) were recorded, and blood samples and heart tissues were collected for measurement of OS, inflammation, and cardiac injury. Results showed that H9c2 cells exposed to hyperoxic reoxygenation showed significant increases in OS, inflammation, and apoptosis compared to normoxic reoxygenation. Following CPB and 2-hour hyperoxic reperfusion, LV +dP/dt and left ventricular developed pressure were significantly decreased compared with pre-CPB values (to 36 ± 21%, P = 0.002; and 53 ± 20%, P = 0.02, respectively), associated with significant increases in all plasma and tissue biomarkers for OS, inflammation, and myocardial injury. In contrast, LV +dP/dt was relatively well preserved under normoxic reperfusion conditions (to 70 ± 14% after 2-hour reperfusion), and was associated with an attenuated myocardial OS, inflammatory, apoptotic, and injury response compared to the hyperoxia group (eg, cTn-I: 5.9 ± 1.5 vs 20.2 ± 7.6 ng/mL, respectively, P < 0.0001). Overall, in both in vitro and in vivo experiments, normoxic reperfusion/reoxygenation was associated with less robust OS, inflammation, apoptosis, and myocardial injury compared with hyperoxic reperfusion/reoxygenation. These results suggest that hyperoxia should be avoided to minimize myocardial OS, inflammation, and ventricular dysfunction after CPB.


Assuntos
Apoptose , Hiperóxia/prevenção & controle , Mediadores da Inflamação/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Reperfusão Miocárdica/métodos , Miócitos Cardíacos/patologia , Estresse Oxidativo , Oxigênio/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Ponte Cardiopulmonar , Linhagem Celular , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Masculino , Reperfusão Miocárdica/efeitos adversos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/toxicidade , Coelhos , Ratos , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda , Pressão Ventricular
10.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L144-L156, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382766

RESUMO

Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. The role of miRNAs in mediating sex biases in BPD is understudied. Analysis of the pulmonary transcriptome revealed that a large percentage of angiogenesis-related differentially expressed genes are miR-30a targets. We tested the hypothesis that there is differential expression of miR-30a in vivo and in vitro in neonatal human pulmonary microvascular endothelial cells (HPMECs) upon exposure to hyperoxia. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% fraction of inspired oxygen (FiO2), postnatal day ( PND) 1-5] and euthanized on PND 7 and 21. HPMECs (18-24-wk gestation donors) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. miR-30a expression was increased in both males and females in the acute phase ( PND 7) after hyperoxia exposure. However, at PND 21 (recovery phase), female mice showed significantly higher miR-30a expression in the lungs compared with male mice. Female HPMECs showed greater expression of miR-30a in vitro upon exposure to hyperoxia. Delta-like ligand 4 (Dll4) was an miR-30a target in HPMECs and showed sex-specific differential expression. miR-30a increased angiogenic sprouting in vitro in female HPMECs. Lastly, we show decreased expression of miR-30a and increased expression of DLL4 in human BPD lung samples compared with controls. These results support the hypothesis that miR-30a could, in part, contribute to the sex-specific molecular mechanisms in play that lead to the sexual dimorphism in BPD.


Assuntos
Displasia Broncopulmonar/metabolismo , Regulação da Expressão Gênica , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , MicroRNAs/biossíntese , Caracteres Sexuais , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Hiperóxia/patologia , Lesão Pulmonar/patologia , Masculino , Camundongos
11.
Am J Respir Cell Mol Biol ; 61(1): 51-60, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30508396

RESUMO

Supplemental O2 (hyperoxia; 30-90% O2) is a necessary intervention for premature infants, but it contributes to development of neonatal and pediatric asthma, necessitating better understanding of contributory mechanisms in hyperoxia-induced changes to airway structure and function. In adults, environmental stressors promote formation of senescent cells that secrete factors (senescence-associated secretory phenotype), which can be inflammatory and have paracrine effects that enhance chronic lung diseases. Hyperoxia-induced changes in airway structure and function are mediated in part by effects on airway smooth muscle (ASM). In the present study, using human fetal ASM cells as a model of prematurity, we ascertained the effects of clinically relevant moderate hyperoxia (40% O2) on cellular senescence. Fetal ASM exposed to 40% O2 for 7 days exhibited elevated concentrations of senescence-associated markers, including ß-galactosidase; cell cycle checkpoint proteins p16, p21, and p-p53; and the DNA damage marker p-γH2A.X (phosphorylated γ-histone family member X). The combination of dasatinib and quercetin, compounds known to eliminate senescent cells (senolytics), reduced the number of hyperoxia-exposed ß-galactosidase-, p21-, p16-, and p-γH2A.X-positive ASM cells. The senescence-associated secretory phenotype profile of hyperoxia-exposed cells included both profibrotic and proinflammatory mediators. Naive ASM exposed to media from hyperoxia-exposed senescent cells exhibited increased collagen and fibronectin and higher contractility. Our data show that induction of cellular senescence by hyperoxia leads to secretion of inflammatory factors and has a functional effect on naive ASM. Cellular senescence in the airway may thus contribute to pediatric airway disease in the context of sequelae of preterm birth.


Assuntos
Senescência Celular , Feto/patologia , Hiperóxia/patologia , Pulmão/embriologia , Miócitos de Músculo Liso/patologia , Biomarcadores/metabolismo , Ciclo Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Citocinas/metabolismo , Dano ao DNA , Dasatinibe/farmacologia , Etoposídeo/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Miócitos de Músculo Liso/efeitos dos fármacos , Fenótipo , Quercetina/farmacologia
12.
Int. j. morphol ; 36(4): 1310-1315, Dec. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-975701

RESUMO

Exposure to normobaric hyperoxia (NH) is known to increase the production of reactive oxygen species (ROS) by mitochondria. The present study was designed to examine mitochondrial ultrastructure morphological changes in the cortical brainin relation to glutathione peroxidase (GPX) activity and free radicals (FR) productions in brain tissue during hyperoxia exposure. The experimental groups were exposed to NH for 24 and 48 h continuously. Following the exposure periods, animals were sacrificed and cortical tissues were divided randomly into two parts; the first part was processed for the ultrastructural examination and the second was homogenized for GPX and FR determinations. Analysis of variance (ANOVA) showed that the main effects of O2 exposure periods were significant (p<0.05) for GPX and FR. Pair-wise means comparisons showed that NH elevated the average (+SE) GPX activity significantly (p<0.05) from the baseline control value of 5670.99+556.34 to13748.42+283.04 and 15134.19+1529.26 U/L with increasing length of NH exposure period from 24 to 48 h, respectively. Similarly, FR production was increased significantly (p<0.05) to 169.73+10.31 and 185.33+21.87, above baseline control of 105.27+5.25 Unit. Ultrastructure examination showed that O2 breathing for 48 h resulted in giant and swelled mitochondria associated with diluted inner membrane and damaged cristae. These mitochondria pathological alterations were associated with damages of myelin, axonal and cellular organelles. Normobaric-hyperoxia inducts mitochondria oxidative stress (MOS) and the subsequent rise of ROS causes variety of ultrastructure morphological pathological alterations in the organelles of cortical brain cells.


Se sabe que la exposición a la hiperoxia normobárica (HN) aumenta la producción de especies reactivas de oxígeno (ERO) por parte de las mitocondrias. El estudio se diseñó para examinar los cambios morfológicos de la ultraestructura mitocondrial en la corteza cerebral con la actividad de la glutatión peroxidasa (GPX) y la producción de radicales libres (RL) en el tejido cerebral durante la exposición a la hiperoxia. Los grupos experimentales fueron expuestos a HN durante 24 y 48 h continuamente. Tras los períodos de exposición, los animales se sacrificaron y los tejidos corticales se dividieron aleatoriamente en dos partes; la primera parte se procesó para el examen ultraestructural y la segunda se homogeneizó para las determinaciones de GPX y RL. El análisis de varianza (ANOVA) mostró que los efectos principales de los períodos de exposición al O2 fueron significativos (p <0,05) para GPX y RL. Las comparaciones de medias por pares mostraron que la HN elevó la actividad promedio de GPX (+ SE) significativamente (p <0,05) desde el valor de control de línea base de 5670,99 + 556,34 a 13748,42 + 283,04 y 15134,19 + 1529,26 U / L con una mayor duración del período de exposición a HN de 24 a 48 h, respectivamente. De manera similar, la producción de RL se incrementó significativamente (p <0,05) a 169,73 + 10,31 y 185,33 + 21,87, por encima del control de referencia de 105,27 + 5,25 unidades. El examen de la ultraestructura mostró que la respiración de O2 durante 48 h dio lugar a mitocondrias gigantes e hinchadas asociadas con la membrana interna diluida y las crestas dañadas. Estas alteraciones patológicas de las mitocondrias se asociaron con daños de mielina, axones y organelos celulares. La hiperoxia normobárica induce el estrés oxidativo mitocondrial (MOS) y el posterior aumento de las ERO provoca una variedad de alteraciones patológicas y morfológicas en los organelos de las células cerebrales corticales.


Assuntos
Animais , Ratos , Córtex Cerebral/ultraestrutura , Hiperóxia/patologia , Mitocôndrias/patologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Análise de Variância , Espécies Reativas de Oxigênio , Ratos Wistar , Espécies Reativas de Nitrogênio , Glutationa Peroxidase/metabolismo , Mitocôndrias/ultraestrutura
13.
Respir Res ; 19(1): 229, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30463566

RESUMO

BACKGROUND: Hyperoxia is a frequently employed therapy for prematurely born infants, induces lung injury and contributes to development of bronchopulmonary dysplasia (BPD). BPD is characterized by decreased cellular proliferation, cellular migration, and failure of injury repair systems. Actin binding proteins (ABPs) such as VASP, cofilin1, and profilin1 regulate cell proliferation and migration via modulation of actin dynamics. Lung mesenchymal stem cells (L-MSCs) initiate repair processes by proliferating, migrating, and localizing to sites of injury. These processes have not been extensively explored in hyperoxia induced lung injury and repair. METHODS: ABPs and CD146+ L-MSCs were analyzed by immunofluorescence in human lung autopsy tissues from infants with and without BPD and by western blot in lung tissue homogenates obtained from our murine model of newborn hyperoxic lung injury. RESULTS: Decreased F-actin content, ratio of VASPpS157/VASPpS239, and profilin 1 expression were observed in human lung tissues but this same pattern was not observed in lungs from hyperoxia-exposed newborn mice. Increases in cofilin1 expression were observed in both human and mouse tissues at 7d indicating a dysregulation in actin dynamics which may be related to altered growth. CD146 levels were elevated in human and newborn mice tissues (7d). CONCLUSION: Altered phosphorylation of VASP and expression of profilin 1 and cofilin 1 in human tissues indicate that the pathophysiology of BPD involves dysregulation of actin binding proteins. Lack of similar changes in a mouse model of hyperoxia exposure imply that disruption in actin binding protein expression may be linked to interventions or morbidities other than hyperoxia alone.


Assuntos
Displasia Broncopulmonar/metabolismo , Moléculas de Adesão Celular/metabolismo , Cofilina 1/biossíntese , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Profilinas/biossíntese , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Cofilina 1/genética , Feminino , Expressão Gênica , Humanos , Hiperóxia/patologia , Recém-Nascido , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C3H , Fosforilação/fisiologia , Gravidez , Profilinas/genética , Distribuição Aleatória
14.
PLoS One ; 13(10): e0206311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356317

RESUMO

Formyl peptide receptor 1 (FPR1) has been shown to be a key regulator of inflammation. However, its role in bronchopulmonary dysplasia (BPD) has not been delineated yet. We investigated whether FPR1 plays a pivotal role in regulating lung inflammation and injuries, and whether intratracheally transplanted mesenchymal stem cells (MSCs) attenuate hyperoxic lung inflammation and injuries by down-regulating FPR1. Newborn wild type (WT) or FPR1 knockout (FPR1-/-) C57/BL6 mice were randomly exposed to 80% oxygen or room air for 14 days. At postnatal day (P) 5, 2×10(5) MSCs were intratracheally transplanted. At P14, mice were sacrificed for histopathological and morphometric analyses. Hyperoxia significantly increased lung neutrophils, macrophages, and TUNEL-positive cells, while impairing alveolarization and angiogenesis, along with a significant increase in FPR1 mRNA levels in WT mice. The hyperoxia-induced lung inflammation and lung injuries were significantly attenuated, with the reduced mRNA level of FPR1, in WT mice with MSC transplantation and in FPR1-/- mice, irrespective of MSCs transplantation. However, only MSC transplantation, but not the FPR1 knockout, significantly attenuated the hyperoxia-induced increase in TUNEL-positive cells. Our findings indicate that FPR1 play a critical role in regulating lung inflammation and injuries in BPD, and MSCs attenuate hyperoxic lung inflammation and injuries, but not apoptosis, with down regulating, but not direct inhibiting FPR1.


Assuntos
Hiperóxia/patologia , Pulmão/patologia , Transplante de Células-Tronco Mesenquimais , Receptores de Formil Peptídeo/genética , Traqueia/transplante , Animais , Lesão Pulmonar/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Receptores de Formil Peptídeo/metabolismo , Transdução de Sinais
15.
Elife ; 72018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30178747

RESUMO

Pdgfra-expressing (Pdgfra+) cells have been implicated as progenitors in many mesenchymal tissues. To determine lineage potential, we generated PdgfrartTA knockin mice using CRISPR/Cas9. During lung maturation, counter to a prior study reporting that Pdgfra+ cells give rise equally to myofibroblasts and lipofibroblasts, lineage tracing using PdgfrartTA;tetO-cre mice indicated that ~95% of the lineaged cells are myofibroblasts. Genetic ablation of Pdgfra+ cells using PdgfrartTA-driven diphtheria toxin (DTA) led to alveolar simplification, demonstrating that these cells are essential for building the gas exchange surface area. In the adult bleomycin model of lung fibrosis, lineaged cells increased to contribute to pathological myofibroblasts. In contrast, in a neonatal hyperoxia model of bronchopulmonary dysplasia (BPD), lineaged cells decreased and do not substantially contribute to pathological myofibroblasts. Our findings revealed complexity in the behavior of the Pdgfra-lineaged cells as exemplified by their distinct contributions to myofibroblasts in normal maturation, BPD and adult fibrosis.


Assuntos
Linhagem da Célula , Pulmão/crescimento & desenvolvimento , Pulmão/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Bleomicina , Sistemas CRISPR-Cas/genética , Proliferação de Células , Modelos Animais de Doenças , Deleção de Genes , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/metabolismo , Recombinação Homóloga/genética , Hiperóxia/patologia , Pulmão/metabolismo , Camundongos Transgênicos , Fibrose Pulmonar/patologia , Análise de Célula Única
16.
Trans Am Clin Climatol Assoc ; 129: 195-201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30166714

RESUMO

In premature neonates, hyperoxic exposure contributes to lung injury characterized by simplified alveolarization and arrested vascularization. These are the hallmarks of bronchopulmonary dysplasia, a disease with long-term consequences on pulmonary and neurodevelopmental function. Lung vascular development and endothelial cell signals are synergistically important for normal alveolarization. It has been shown that metabolism of nutrients such as glucose, fatty acid, and glutamine is key in controlling proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses, which contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia. Recent studies show that metabolic reprogramming occurs in vitro in cells and in vivo in animal models and more importantly in patients with bronchopulmonary dysplasia, suggesting that metabolic dysregulation may participate in the pathogenesis and progression of these diseases. Although endothelial cells rely mainly on glycolysis for bioenergetics, they have the metabolic flexibility to maintain cell function under stress or nutrient deprivation. Others have shown that hyperoxia decreases glycolysis and oxidative phosphorylation in epithelial cells. Nevertheless, endothelial cells show enhanced mitochondrial fatty acid use after exposure to hyperoxia. This may serve to preserve endothelial cell proliferation and alveolarization, and thereby mitigate neonatal hyperoxic lung injury.


Assuntos
Displasia Broncopulmonar/metabolismo , Células Endoteliais/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Lesão Pulmonar/metabolismo , Pulmão/metabolismo , Mitocôndrias/metabolismo , Regeneração , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/fisiopatologia , Proliferação de Células , Células Endoteliais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Idade Gestacional , Humanos , Hiperóxia/complicações , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Nascimento Prematuro , Fatores de Risco
17.
Biochem Biophys Res Commun ; 503(4): 2653-2658, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30093115

RESUMO

Mesenchymal stromal cell (MSC) derived exosomes mediate tissue protection and regeneration in many injuries and diseases by modulating cell protein production, protecting from apoptosis, inhibiting inflammation, and increasing angiogenesis. In the present study, daily intraperitoneal injection of MSC-derived exosomes protected alveolarization and angiogenesis in a newborn rat model of bronchopulmonary dysplasia (BPD) induced by 14 days of neonatal hyperoxia exposure (85% O2). Exosome treatment during hyperoxia prevented disruption of alveolar growth, increased small blood vessel number, and inhibited right heart hypertrophy at P14, P21, and P56. In vitro, exosomes significantly increased tube-like network formation by HUVEC, in part through a VEGF mediated mechanism. In summary, daily intraperitoneal injection of exosomes increased blood vessel number and size in the lung through pro-angiogenic mechanisms. MSC-derived exosomes therefore have both anti-inflammatory and pro-angiogenic mechanism to protect the lung from hyperoxia induced lung and heart disease associated with BPD.


Assuntos
Displasia Broncopulmonar/prevenção & controle , Cardiomegalia/prevenção & controle , Exossomos/fisiologia , Hiperóxia/prevenção & controle , Células-Tronco Mesenquimais/química , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Animais Recém-Nascidos , Células da Medula Óssea/química , Células da Medula Óssea/citologia , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Modelos Animais de Doenças , Exossomos/transplante , Feminino , Regulação da Expressão Gênica , Hiperóxia/genética , Hiperóxia/metabolismo , Hiperóxia/patologia , Injeções Intraperitoneais , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica/genética , Oxigênio/toxicidade , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/agonistas , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Biochem Biophys Res Commun ; 503(4): 2792-2799, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30100069

RESUMO

Retinopathy of prematurity (ROP) is an eye disease that causes blindness due to delayed vascular growth, retinal ischemia, and resulting abnormal angiogenesis. Nonselective ß-antagonist propranolol is in clinical trials for the treatment of ROP due to its effect of reducing VEGF expression and inhibiting retinal angiogenesis in oxygen-induced ROP models (OIR), but the mechanism by which propranolol acts on ROP vessels is still unclear. In the present study, we have focused on the effect of propranolol on pericyte survival and vascular permeability. We demonstrated that propranolol increases pericyte apoptosis more sensitively than endothelial cells (ECs), thereby weakening EC tight junctions to increase endothelial permeability in co-cultures of pericytes and ECs. Mechanistically, pericyte apoptosis by propranolol was due to the inhibition of Akt signaling pathway. We also demonstrated that propranolol increases pericyte loss and vascular permeability of retinal vessels in a mouse model of OIR. These results suggest that propranolol may be negative for blood vessels in retinas of OIR, and that the efficacy of propranolol for the treatment of ROP needs to be more thoroughly verified.


Assuntos
Apoptose/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Hiperóxia/induzido quimicamente , Propranolol/farmacologia , Retinopatia da Prematuridade/induzido quimicamente , Vasodilatadores/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperóxia/genética , Hiperóxia/metabolismo , Hiperóxia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/administração & dosagem , Pericitos/citologia , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/genética , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinopatia da Prematuridade/genética , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/ultraestrutura , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Pediatr Pulmonol ; 53(8): 1053-1066, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29893049

RESUMO

AIM: Autophagy is a common process during development. Abnormal autophagy can impact cell apoptosis. Previous studies have shown that apoptosis is present during bronchopulmonary dysplasia (BPD). However, there is no consensus on the level of coexisting autophagy. This study was designed to investigate the role of autophagy and the effects of autophagy inducers in a BPD model. METHOD: A total of 100 newborn Sprague-Dawley rats were randomly assigned to model and control groups. BPD models were established by hyperoxic induction(FiO2 0.80). Some of them were treated with autophagy-inducing agents. RESULT: As compared to the control group, more autophagic bodies were found within Type II alveolar epithelial cells (AT-II cells) under transmission electron microscopy (TEM) in the model group at 3 d . These autophagic bodies were also accompanied by apoptotic bodies and expression of both bodies peaked at 7 d. As shown by TdT-mediated dUTP nick end labeling (TUNEL), there were more apoptotic cells in the model group than in the control group. Protein expression levels of LC3B-II, p62, Lamp1, and cleaved Caspase-3 increased with increased hyperoxic exposure time. No significant differences were observed in the mRNA expression levels of LC3B, p62, and Lamp1. After introducing an autophagy inducer, either rapamycin or lithium chloride, the radial alveolar count (RAC) value of BPD model group increased as compared with placebo group, the thickness of alveolar septum decreased, while apoptosis decreased. CONCLUSION: Reduced autophagy resulting from blocked autophagy flow may be a key link in the pathogenesis of BPD. By enhancing repressed autophagy, apoptosis could be reduced and alveolar development improved.


Assuntos
Células Epiteliais Alveolares/metabolismo , Apoptose/fisiologia , Autofagia/fisiologia , Displasia Broncopulmonar/metabolismo , Hiperóxia/metabolismo , Pulmão/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/patologia , Recém-Nascido , Pulmão/patologia , Ratos , Ratos Sprague-Dawley
20.
Respir Res ; 19(1): 114, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884181

RESUMO

BACKGROUND: Exposure to high levels of oxygen (hyperoxia) after birth leads to lung injury. Our aims were to investigate the modulation of myeloid cell sub-populations and the reduction of fibrosis in the lungs following administration of human mesenchymal stem cells (hMSC) to neonatal mice exposed to hyperoxia. METHOD: Newborn mice were exposed to 90% O2 (hyperoxia) or 21% O2 (normoxia) from postnatal days 0-4. A sub-group of hyperoxia mice were injected intratracheally with 2.5X105 hMSCs. Using flow cytometry we assessed pulmonary immune cells at postnatal days 0, 4, 7 and 14. The following markers were chosen to identify these cells: CD45+ (leukocytes), Ly6C+Ly6G+ (granulocytes), CD11b+CD11c+ (macrophages); macrophage polarisation was assessed by F4/80 and CD206 expression. hMSCs expressing enhanced green fluorescent protein (eGFP) and firefly luciferase (fluc) were administered via the trachea at day 4. Lung macrophages in all groups were profiled using next generation sequencing (NGS) to assess alterations in macrophage phenotype. Pulmonary collagen deposition and morphometry were assessed at days 14 and 56 respectively. RESULTS: At day 4, hyperoxia increased the number of pulmonary Ly6C+Ly6G+ granulocytes and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. At days 7 and 14, hyperoxia increased numbers of CD45+ leukocytes, CD11b+CD11c+ alveolar macrophages and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. hMSCs administration ameliorated these effects of hyperoxia, notably reducing numbers of CD11b+CD11c+ and F4/80lowCD206low macrophages; in contrast, F4/80highCD206high macrophages were increased. Genes characteristic of anti-inflammatory 'M2' macrophages (Arg1, Stat6, Retnla, Mrc1, Il27ra, Chil3, and Il12b) were up-regulated, and pro-inflammatory 'M1' macrophages (Cd86, Stat1, Socs3, Slamf1, Tnf, Fcgr1, Il12b, Il6, Il1b, and Il27ra) were downregulated in isolated lung macrophages from hyperoxia-exposed mice administered hMSCs, compared to mice without hMSCs. Hydroxyproline assay at day 14 showed that the 2-fold increase in lung collagen following hyperoxia was reduced to control levels in mice administered hMSCs. By day 56 (early adulthood), hMSC administration had attenuated structural changes in hyperoxia-exposed lungs. CONCLUSIONS: Our findings suggest that hMSCs reduce neonatal lung injury caused by hyperoxia by modulation of macrophage phenotype. Not only did our cell-based therapy using hMSC induce structural repair, it limited the progression of pulmonary fibrosis.


Assuntos
Hiperóxia/metabolismo , Hiperóxia/terapia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/terapia , Macrófagos Alveolares/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células Mieloides/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Hiperóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/patologia , Macrófagos Alveolares/patologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/patologia , Gravidez , Resultado do Tratamento
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