Role of the LRP1-pPyk2-MMP9 pathway in hyperoxia-induced lung injury in neonatal rats / 中国当代儿科杂志

OBJECTIVES@#To study the role of the low-density lipoprotein receptor-related protein 1 (LRP1)-proline-rich tyrosine kinase 2 phosphorylation (pPyk2)-matrix metalloproteinases 9 (MMP9) pathway in hyperoxia-induced lung injury in neonatal rats.@*METHODS@#A total of 16 neonatal rats were randomly placed in chambers containing room air (air group) or 95% medical oxygen (hyperoxia group) immediately after birth, with 8 rats in each group. All of the rats were sacrificed on day 8 of life. Hematoxylin and eosin staining was used to observe the pathological changes of lung tissue. ELISA was used to measure the levels of soluble LRP1 (sLRP1) and MMP9 in serum and bronchoalveolar lavage fluid (BALF). Western blot was used to measure the protein expression levels of LRP1, MMP9, Pyk2, and pPyk2 in lung tissue. RT-PCR was used to measure the mRNA expression levels of LRP1 and MMP9 in lung tissue.@*RESULTS@#The hyperoxia group had significantly higher levels of sLRP1 and MMP9 in serum and BALF than the air group (@*CONCLUSIONS@#The activation of the LRP1-pPyk2-MMP9 pathway is enhanced in hyperoxia-induced lung injury in neonatal rats, which may be involved in the pathogenesis of bronchopulmonary dysplasia.

Protective effect of adrenomedullin on hyperoxia-induced lung injury / 中国当代儿科杂志

OBJECTIVES@#To study the role of adrenomedullin (ADM) in hyperoxia-induced lung injury by examining the effect of ADM on the expression of calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein 2 (RAMP2), extracellular signal-regulated kinase (ERK), and protein kinase B (PKB) in human pulmonary microvascular endothelial cells (HPMECs) under different experimental conditions.@*METHODS@#HPMECs were randomly divided into an air group and a hyperoxia group (@*RESULTS@#Compared with the air group, the hyperoxia group had significant increases in the mRNA and protein expression levels of ADM, CRLR, RAMP2, ERK1/2, and PKB (@*CONCLUSIONS@#ERK1/2 and PKB may be the downstream targets of the ADM signaling pathway. ADM mediates the ERK/PKB signaling pathway by regulating CRLR/RAMP2 and participates in the protection of hyperoxia-induced lung injury.

Anti-placental growth factor antibody ameliorates hyperoxia-mediated impairment of lung development in neonatal rats

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.

Pulmonary oxidative stress in diabetic rats exposed to hyperoxia

Abstract Purpose: To evaluate the pulmonary oxidative stress in diabetic rats exposed to hyperoxia for 90 minutes. Methods: Forty male Wistar rats were divided into four groups, each one containing 10 animals, according to the oxygen concentration to which they were exposed: 21%, 50%, 75% and 100% (hyperoxia). In each group five animals were randomly induced to diabetes by means of at a dose of 55 mg/kg of streptozotocin (STZ). Results: Seventy two hours after diabetes induction, a significant difference was seen in blood glucose in the experimental groups in comparison with the control. In the experimental groups a significant difference was observed in the concentration of malondialdehyde (MDA) in lung tissue and blood plasma (p<0.05), except the 50% group. In the control group, significant differences in the MDA concentration in plasma and lung tissue were also observed (p<0.05), except the 75% group. The MDA concentration in lung tissue in comparison with the diabetic and non-diabetic groups showed a significant difference in the 21% group; however, no difference was seen in the 75 and 100% groups. Conclusion: In diabetic animals high oxygen concentrations (75 and 100%) do not appear to exert deleterious effects on lipid peroxidation in lung tissue.

Granulocyte Colony Stimulating Factor Attenuates Hyperoxia-Induced Lung Injury by Down-Modulating Inflammatory Responses in Neonatal Rats

PURPOSE: Granulocyte colony stimulating factor (G-CSF) has been known to increase neutrophil production and have anti-inflammatory properties, but the effect of G-CSF on pulmonary system is in controversy. We investigated whether G-CSF treatment could attenuate hyperoxia-induced lung injury, and whether this protective effect is mediated by the down-modulation of inflammatory responses in a neonatal rat model. MATERIALS AND METHODS: Newborn Sprague-Dawley rats (Orient Co., Seoul, Korea) were subjected to 14 days of hyperoxia (90% oxygen) beginning within 10 h after birth. G-CSF (20 microg/kg) was administered intraperitoneally on the fourth, fifth, and sixth postnatal days. RESULTS: This treatment significantly improved hyperoxia-induced reduction in body weight gain and lung pathology such as increased mean linear intercept, mean alveolar volume, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling positive cells. Hyperoxia-induced activation of nicotinamide adenine dinucleotide phosphate oxidase, which is responsible for superoxide anion production, as evidenced by upregulation and membrane translocation of p67phox was significantly attenuated after G-CSF treatment, as were inflammatory responses such as increased myeloperoxidase activity and mRNA expression of transforming growth factor-beta. However, the attenuation of other proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 was not significant. CONCLUSION: In sum, G-CSF treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.

Effect of postnatal malnutrition on hyperoxia-induced newborn lung development

Several factors are associated with bronchopulmonary dysplasia. Among them, hyperoxia and lung immaturity are considered to be fundamental; however, the effect of malnutrition is unknown. Our objective was to evaluate the effects of 7 days of postnatal malnutrition and hyperoxia on lung weight, volume, water content, and pulmonary morphometry of premature rabbits. After csection, 28-day-old New Zealand white rabbits were randomized into four groups: control diet and room air (CA, N = 17), control diet and ¡Ý95% O2 (CH, N = 17), malnutrition and room air (MA, N = 18), and malnutrition and ¡Ý95% O2 (MH, N = 18). Malnutrition was defined as a 30% reduction of all the nutrients provided in the control diet. Treatments were maintained for 7 days, after which histological and morphometric analyses were conducted. Lung slices were stained with hematoxylin-eosin, modified orcein-resorcin or picrosirius. The results of morphometric analysis indicated that postnatal malnutrition decreased lung weight (CA: 0.83 ¡À 0.19; CH: 0.96 ¡À 0.28; MA: 0.65 ¡À 0.17; MH: 0.79 ¡À 0.22 g) and water content, as well as the number of alveoli (CA: 12.43 ¡À 3.07; CH: 8.85 ¡À 1.46; MA: 7.33 ¡À 0.88; MH: 6.36 ¡À 1.53 x 10-3/mm) and elastic and collagen fibers. Hyperoxia reduced the number of alveoli and increased septal thickening and the mean linear intercept. The reduction of alveolar number, collagen and elastic fibers was intensified when malnutrition and hyperoxia were associated. These data suggest that dietary restriction enhances the magnitude of hyperoxia-induced alveolar growth arrest and lung parenchymal remodeling. It is interesting to consider the important influence of postnatal nutrition upon lung development and ronchopulmonary dysplasia.

cardiovascular changes induced by inspired oxygen fraction in patients undergoing on-pump coronay artery surgery

The inspiratory gas during open heart surgery with on-pump technique usually consists of 100% oxygen without any N2O because the risks of bubble embolism during these procedures. We sought to establish whether the cardiovascular effects of increased FiO2 are also present in cardiac surgery patients. The present study was a randomized double- blind clinical trial on sixty adult patients [40-70 years] with the cardiac ejection fraction [EF] of more than 40% and ASA II or III undergoing elective on pump coronary artery bypass. They received either a mixture of 50% O2 with 50% air [case group=30] or 100% oxygen [control group=30] throughout the anesthesia. Data were analyzed by SPSS software using t-test and Q-square as well as non parametric tests wherever appropriate. The mean values of systolic, diastolic and mean blood pressure as well as HR and CI were similar in the case and control groups [p>0.05] at all times of measurement. The mean PaO2 was significantly higher in the control group [p<0.05]. The mean pH was statistically higher in the control group but not clinically noticeable. The control group required more inotropic drug support than the case group [16 vs. 8 patients respectively]. Likewise, the mean venous pressure was higher in the control group compared with the case group. Exposing patients during and after coronary artery surgery to hyperoxia induced significant hemodynamic changes which required more extensive studies with invasive CI measurements and larger groups

Intratracheal Administration of Endotoxin Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

PURPOSE: This study was undertaken to determine the effects of intratracheal administration of endotoxin on hyperoxia-induced lung injury in neonatal rats. MATERIALS AND METHODS: Newborn Sprague Dawley rat pups were divided into four experimental groups: normoxia control (NC), normoxia with endotoxin treatment (NE), hyperoxia control (HC), and hyperoxia with endotoxin treatment (HE) groups. In HC and HE, rat pups were subjected to 14 days of hyperoxia (> 95% oxygen) within 12 hours after birth. In endotoxin treated group (NE and HE), Escherichia coli endotoxin (0.5microgram in 0.03mL of saline) was given intratracheally at the 1st, 3rd and 5th postnatal day. Radial alveolar count (RAC), mean linear intercept (MLI), RAC/MLI ratios, and degree of fibrosis were measured to assess the changes in lung morphology. RESULTS: During the research period, survival rates in both HC and HE were notably reduced 7 days after endotoxin was administered, but body weight gain was considerably reduced only in HC. On day 14, significant arrest in alveolarization, as evidenced by the decrease of RAC and RAC/MLI ratio and increase of MLI as well as increased fibrosis, were noted in HC. Although slight but significant arrest in alveolarization and increased fibrosis score were observed in NE compared to NC, the hyperoxia-induced lung damage observed in HC was significantly improved in HE. CONCLUSION: This study suggests that intratracheal administration of endotoxin significantly attenuated hyperoxia-induced lung injury in neonatal rats.

Hiperóxia e risco aumentado de displasia broncopulmonar em prematuros / Hyperoxia and greater risk for bronchopulmonary dysplasia in preterm infants

Objetivo: estudar a associação entre hiperóxia e hipocapnia precoces e displasia broncopulmonar )DBP) em recém-nascidos pré-termo (RNPT) de muito baixo peso. Métodos: estudo retrospectivo com 181 RNPT admitidos na Unidade de Terapia Intensiva Neonatal (Unineo) da Maternidade de Santa Fé, em Belo Horizonte (MG), entre agosto de 1995 a agosto de 2004. Foram incluídos neonatos com idade gestacional <37 semanas e peso ao nascer <1.500g, submetidos à ventilação mecânica nas primeiras 72 horas de vida. Analisou-se, por meio de análise multivariada, a presença de associação entre DBP e as variáveis: hiperóxia (PaO2>80 mmHg) e hipocapnia (PaCO2<30 mmHg) entre seis e 72 horas de vida, idade gestacional, relação peso/IG, Apgar no primeiro e quinto minutos, uso de surfactante, uso de corticosteróides no período pré-natal e antibioticoterapia após o quinto dia de vida. Resultados: na população estudada, a idade gestacional foi <=30 semanas em 138(76 por cento) neonatos, 59(33 por cento) eram pequenos para a idade gestacional, 85(47 por cento) do sexo masculino; 122(67 por cento) receberam surfactante e 105(58 por cento) receberam antibioticoterapia após o quinto dia de vida. A média e a mediana foram respectivamente, para a PaO2, 87,4 e 80 mmHg e, para a PaCO2, 34,6 e 33 mmHg, entre seis e 72 horas de vida. A DBP ocorreu em 38(21 por cento) dos 181 RNPT e em 28(42 por cento) dos 67 RNPT com peso ao nascer <1.000 g. A análise multivariada confirmou a associação entre DBP e hiperóxia (p=0,011), peso ao nascer<1.000 g(p<0,001) e antibioticoterapia após o quinto dia (p<0,001). Conclusões: A DBP se associou à hiperóxia, no período neonatal precoce, ao peso mais baixo ao nascer e aos fatores inflamatórios.

Coelhos prematuros expostos à hiperoxia prolongada: um modelo para o estudo da displasia broncopulmonar / Preterm rabbits exposed to prolongued hyperoxia as a model for the study of bronchopulmonary dysplasia

Os modelos experimentais para o estudo da displasia broncopulmonar(DBP) são caros e de difícil manipulação. Com o objetivo de desenvolver um novo modelo animal, coelhos prematuros de 28 dias de gestação foram expostos ao oxigênio ³95 por cento por 7 ou 11 dias e comparados com animais mantidos em ar ambiente. O efeito da hiperoxia sobre o pulmão foi avaliado através de medidas de peso, volume, intecepto linear médio(Lm), área de superfície interna, número dos alvéolos, espessura do septo alveolar, proporção de água, fibras elásticas e colágenas. A exposição prolongada ao oxigênio ocasionou o bloqueio do crescimento e desenvolvimento pulmonar, com hipoalveolização, aumento do LM, maior espessamento septal e desorganização das fibras, reproduzindo as lesões características da DBP humana /The experimental models used for the study of bronchopulmonary dysplasia (BPD) are expensive and difficult to be handled. In order to develop a new animal model, 28 days gestation preterm rabbits were exposed to ³95 per cent oxygen for 7 or 11 days, and compared to room air. Hyperoxia effect was evalueted through body weight, lung volume, mean linear intercepts (MLI), internal gas-exchange surface area, alveoli number and septal thickness, water proportion, elastic and colagen fiber deposition. Oxygen exposure in premature rabbits arrested lung growth and development, reducing alveoli number, increasing MLI and alveolar septal thickening and disorganizating fibers deposition; reproducing the major histological BPD findings described in humans...

Radicales libres: bioquímica y sistemas antioxidantes: implicancia en la patología neonatal / Free radicals: biochemistry and antioxidants: their implication in newborn pathology

Los radicales libres del oxígeno se forman continuamente en el organismo por el metabolismo normal, siendo eliminados por las defensas antioxidantes. Cuando, son producidos en exceso pueden ocasionar una lesión tisular, por cuyo motivo han sido implicados en muchas enfermedades. En esta revisión se dan algunas nociones de la química de estos compuestos, se resume el mecanismo de su producción y el papel desempeñado por los iones de los metales de transición. Se insiste también sobre la importancia de la defensa antioxidante, cuya función es prevenir la oxidación, ya sea eliminando las especies reactivas del oxígeno tales como el radical superóxido, el radical hidroxilo o el peróxido de hidrógeno, o previniendo su formación. Los efectos deletéreos de estos compuestos se pueden observar en diversas patologías del adulto y del niño. El recién nacido, sobre todo pretérmino, es especialmente vulnerable, dado que nace con una protección insuficiente contra los radicales libres del oxígeno. En este sentido se analiza el papel desempeñado por los radicales libres en las siguientes afecciones: encefalopatía hipóxico-isquémica, enterocolitis necrotizante, broncodisplasia pulmonar, retinopatía del prematuro y hemorragia intraventricular. También se señala la importancia de la lipoperoxidación en la administración intravenosa de una emulsión de lípidos