Prostaglandin concentrations in ovine maternal and fetal tissues at late gestation

Maternal and fetal sheep organs were measured for their concentrations of prostaglandins (PG) E2, F2 alpha, 13,14-dihydro-15-keto PGF2 alpha (PGFM), 6-keto PGF1 alpha (hydrolysis produce of PGI2), and 6-keto PGE1 (enzymatic product of PGI2) by radioimmunoassay at day 131 of pregnancy (0.90 gestation). It was observed that the concentrations of PGFM were greater (p less than 0.01) in maternal endometrium than in any other maternal tissue or any other PG measured in endometrium. The lowest concentrations of PG in maternal tissues were in the myometrium, while PGE2 and 6-keto PGF1 alpha were present in maternal lungs in high concentrations. Fetal prostaglandin concentrations were high in the chorioallantois, fetal portion of the cotyledons and amnion, while they were very low in the kidney, liver, and lung. Fetal lung concentrations were lower than maternal lung concentrations (p less than 0.01) for all PG measured. In fetal aorta and ductus arteriosus, 6-keto PGF1 alpha concentrations were significantly greater (p less than 0.05) than all other measured PG, while in umbilical artery and vein 6-keto PGF1 alpha levels were equal to PGE2 levels. 6-Keto PGE1 concentrations were consistently among the lowest in all tissues measured. These results suggest that the endometrium may serve as a metabolic barrier to PG diffusing from the chorioallantois to the myometrium, that the capacity of pulmonary tissue to produce PG may increase with age, that the fetal membranes and cotyledons may be one major source of circulating PG in the fetus, and that 6-keto PGF1 alpha is the major metabolite of PGI2 in ovine tissues.     

Maternally administered dexamethasone at 0.7 of gestation suppresses maternal and fetal pituitary and adrenal responses to hypoxemia in sheep

Women who are at risk of preterm delivery are treated with antenatal steroids to facilitate fetal lung maturation. During this period, there is a potential for fetal or maternal hypoxemia to occur. Fetal responses to hypoxemia in sheep are well documented. However, less is known regarding maternal responses to hypoxemia. Therefore, we determined the effects of dexamethasone (DM) on maternal and fetal responses to hypoxemia in sheep. Ewes received four i.m. injections of DM or saline at 12-h intervals beginning at 103 d of gestation. Samples for ACTH, cortisol, and glucose were collected at 0900 h. At 105 d of gestation, hypoxemia was induced for 1 h by maternal nitrogen gas inhalation. Samples for ACTH, cortisol, and glucose were collected at 15-min intervals before, during, and after the hypoxemia challenge. Fluorescent microspheres were administered to the mother and the fetus before and during hypoxemia to measure organ perfusion. DM suppressed basal fetal and maternal cortisol and ACTH concentrations but increased glucose levels. DM also increased fetal but not maternal blood pressure. In control subjects, hypoxemia elevated fetal and maternal cortisol and ACTH concentrations. These responses were obliterated by DM. Hypoxemia increased blood pressure in DM-exposed fetuses but not in control subjects. In addition, hypoxemia decreased fetal adrenal vascular resistance in saline but not DM fetuses or ewes from either treatment group. In summary, maternal administration of a low dose of DM at 0.7 of gestation suppresses maternal and fetal adrenal function and changes fetal responses to hypoxemic stress to resemble those observed later in gestation.     

盐酸氨溴索和倍他米松对大鼠胎肺形态发育影响的对比研究

目的 探讨产前注射盐酸氨溴索和倍他米松对大鼠胎肺形态发育的影响.方法 12只孕鼠随机分成4组:盐酸氨溴索组、倍他米松1d组、3d组及对照组,每组3只大鼠.盐酸氨溴索组、倍他米松3d组从妊娠第16天起分别腹腔注射3d盐酸氨溴索100mg/(kg·d)、倍他米松O.2mg/(kg·d);倍他米松1d组在妊娠第16、17天注射生理盐水,第18天注射倍他米松0.2mg/(kg·d);对照组在同样时间连续3d注射生理盐水.在妊娠第19天将孕鼠处死后立即剖腹取仔鼠,每只孕鼠取6只胎鼠肺组织,通过光镜观察、图像分析及电镜技术比较2种药物、不同疗程对孕鼠的胎仔肺组织形态结构影响.结果 光镜下各治疗组与对照组相比肺泡间隔薄(P<0.001),呼吸膜周径及肺泡表面积均增大(P相似文献   

Prostaglandin E1, E2, and F2 alpha in human milk and plasma.

Concentrations of prostaglandin E1, E2, and F2 alpha (PGE1, PGE2, and PGF2 alpha) were determined in milk and plasma from mothers of 9 preterm and 11 term infants. The concentration of PGE1 in milk was similar to that in plasma, and the concentrations of PGE2 and PGF2 alpha were approximately 1.2-2 times higher than those in plasma. However, no significant differences in the levels of PGE1, PGE2, and PGF2 alpha were observed between the foremilk and hindmilk, among the colostrum, transitional milk, and mature milk, and between preterm and term milk. Further studies have to be performed to confirm that the stable levels of PGE1, PGE2, and PGF2 alpha in human milk found in this study play an important role in the gastrointestinal function of infants.     

Enzyme induction in neonates after fetal exposure to antiepileptic drugs

The 13C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to 13C-AP breath tests, neonates have a very low capacity to eliminate 13CO2, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs 13C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerably stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, 13C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by 13C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between 13C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the 13C breath test data will transport very different informations about enzyme induction in these neonates.     

Continuous Nasogastric Infusion of Prostaglandin E2 in Ductus-Dependent Congenital Heart Disease

Prostaglandin E2 (PGE2) was infused continuously through a nasogastric gavage tube in four infants with pulmonary atresia. The drug was given at a rate of 12.5–160 µg/kg/h. The duration of therapy was 7–123 days. The effects and side effects seen by this method were similar to those seen in the conventional multiple dose regimen. This method was an effective and simple way of maintaining the ductus arteriosus open, especially for a long period of time.     

Prostaglandin E2 administration in infants with ductus-dependent cyanotic congenital heart disease

Prostaglandin E₂ was administered to 22 newborns with ductus-dependent cyanotic congenital heart disease. Twelve patients had pulmonary atresia and ten simple dextrotransposition of the great arteries. Patients were classified into two groups: group 1 (n=11) received prostaglandin E₂ by the intravenous route (dose: 0.01–0.05 g/kg per min); group 2 (n=11) received prostaglandin E₂ by the oral route (dose: 35–65 g/kg per 1–4 h). Treatment lasted for 1–90 days. All infants except one of group 2 showed a significant (>10 Torr) increase in PaO₂ following PGE₂ administration. The mean increase in PaO₂ was higher (P<0.01) in group 1 (21.8±1.7, Torr) than in group 2 (15.8±1.5, Torr). PaO₂ fell significantly (P<0.01) in five patients of group 1 who continued treatment orally with satisfactory (>30 Torr) levels in four of them. Severe side effects were observed only in group 1. The data show that similarly to prostaglandin E₁ infusions, prostaglandin E₂, given i.v. or orally, is useful in the management of infants with ductus-dependent cyanotic congenital heart disease. Oral prostaglandin E₂, administration is less effective than i.v. infusions, but can be used for long-term, therapy being more convenient and causing minimal morbidity.Presented at the IX European Congress of Perinatal Medicine, Dublin, Ireland, 1984     

Different expression of surfactant protein B mature peptide and proprotein at 21 weeks'' gestation in human fetal pulmonary epithelial cells

AIM: The aim of this study is to evaluate the maturation of pulmonary epithelial cells in human fetal lungs at 21 weeks' gestation. METHODS: Eight fetuses at 21 weeks' gestation were evaluated. The maturation of pulmonary epithelial cells was assessed by immunohistochemical examination for surfactant proteins and by electron microscopy. RESULTS: Surfactant protein B mature peptide was detected slightly in the epithelial lining of the bronchioles, but was totally absent in the terminal airways. Surfactant protein B proprotein was clearly detected in the epithelial lining of both bronchioles and terminal airways. Transmission electron microscopy of terminal airway cells showed abundant glycogen granules and few intracellular organelles. CONCLUSIONS: The production of mature surfactant protein B in terminal airways is scarce at 21 weeks' gestation, which is associated with the immature mechanism of proprotein processing in the cytoplasm.     

Transforming growth factor-alpha gene expression in late-gestation fetal rat lung.

Transforming growth factor-alpha (TGF-alpha) is a structural homologue of epidermal growth factor and competes for binding on a common transmembrane protein receptor/kinase. Although TGF-alpha appears to be more important than epidermal growth factor in embryogenesis and mammalian organogenesis, there is little information regarding its expression in developing lung. Accordingly, we measured levels of immunoreactive TGF-alpha and its gene expression in late-term fetal rat lung during the transition from the canalicular (19-20 d) to the saccular (21 d) stage. We report that at 19 d gestation intrapulmonary levels of TGF-alpha were 1.4 +/- 0.3 pmol/mg protein as determined by RIA, but had decreased by 50% at 21 d. To determine if the TGF-alpha gene is expressed in lung, RNA isolated from fetal rat lung was reverse transcribed, and a 302-bp fragment corresponding to a portion of the TGF-alpha gene was amplified by polymerase chain reaction. Southern blot hybridization with a 32P-labeled 2.3-kb EcoRI fragment of rat TGF-alpha cDNA clone showed a pattern of declining expression during late gestation. Therefore, fetal rat lung expresses TGF-alpha, as is evidenced by the synthesis of both the message and the protein. Because levels of protein were highest in the period of canalicular lung development when the respiratory acinus is formed and vascularized, a potential role for this intrapulmonary growth factor in pulmonary remodeling is suggested.     

Prostaglandin E2 attenuates hyperoxia-induced injury in cultured rabbit tracheal epithelial cells.

We assessed the kinetics of hyperoxia-induced prostaglandin E2 (PGE2) production by cultured rabbit tracheal epithelial (TE) cells with different inherent capacities to generate PGE2 and the role of endogenous PGE2 production in protecting these cells from hyperoxic injury. Rabbit TE cells grown to confluence with or without lipid supplements [0.1% Excyte III (Miles-Pentex) and 1 microM arachidonic acid] were exposed for 2 h to control (5% CO2/air) or hyperoxic (5% CO2/90% O2) atmospheres at a gas-fluid interface. Serial cell culture effluents collected during exposure were analyzed for PGE2 by enzyme-linked immunoassay. Basal PGE2 production by lipid-supplemented cells was approximately 3-fold greater than that by unsupplemented cultures (p less than 0.01). In lipid-supplemented cells, PGE2 production doubled after 15 min of hyperoxic exposure (p less than 0.05) and then declined to approximately 50% of initial levels, whereas exposure to 5% CO2/air did not significantly change PGE2 production. In unsupplemented cells, neither control nor hyperoxic exposure altered PGE2 production. Hyperoxia-exposed TE cells had decreased ability to convert 10 microM exogenous arachidonic acid to PGE2, suggesting hyperoxia-induced inhibition of the enzymes involved in PGE2 synthesis. Lipid-supplemented cells were less susceptible to hyperoxic injury than unsupplemented monolayers, as evidenced by increased viability (trypan blue exclusion) and decreased generation of lipid peroxides (thiobarbituric acid reactive substances). Addition of exogenous PGE2 to unsupplemented cultures at concentrations that were produced by lipid-supplemented cells (2 ng/mL every 15 min) during hyperoxic exposure eliminated these differences in hyperoxia-induced lipid peroxidation and cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cited2在肺发育成熟过程中的作用

转录共激活因子Cited2(cAMP反应元件结合蛋白/p300结合转化激活因子,含谷氨酸和天冬氮酸丰富羧基末端域)是转录激活因子家族中的新成员,通过乙酰化组蛋白和p300同源蛋白质来控制其他转录因子的活性,从而调控相关基因表达,其活性异常可引起一些疾病.Cited2生物学功能与胚胎发育有着密切联系.肺的发育成熟程度对新生儿尤其是早产儿的存活率有着重要影响.近10年来,Cited2对肺发育成熟影响的研究得到了重视,然而二者之间的相互作用和基因调节的关系目前尚不是很清楚.     

Altered lung development after prenatal nicotine exposure in young lambs

There is compelling evidence that prenatal nicotine exposure permanently alters lung development and airway function. The aim of this study was to determine how prenatal nicotine exposure alters proximal and distal airway function. Thirteen lambs were continuously exposed during the last fetal trimester to low-dose nicotine (LN) and 12 to a moderate dose (MN) (maternal s.c. dose: 0.5 and 1.5 mg/kg/d, respectively). Ten lambs served as controls (C). Proximal airway function was measured by lung mechanics. A multiple-breath N2 washout technique was used to measure lung volume (functional residual capacity) and efficiency of gas mixing in distal airways, i.e. terminal respiratory units (moment ratio and nitrogen clearance). In comparison with C, both LN and MN had significantly reduced specific airway conductance to the same extent at a median study age of 12, 25, and 51 d, indicating signs of proximal airway obstruction. Distal airway function showed significant improvement in LN. Ventilation and functional residual capacity were unaffected. In summary, prenatal nicotine exposure induced airway obstruction in proximal airways and improved gas mixing in distal airways, possibly reflecting restriction in proximal airway growth and accelerated maturation of the acinar part of the lung, respectively. We speculate that prenatal nicotine exposure has a disparate impact on airway development and function. The effect on the distal airways seemed to be inversely related to dose, which was not the case in the large airways. The altered airway function persisted during the study period, indicating that the effects of prenatal nicotine exposure might be permanent.     

High expression of pulmonary proteinase-activated receptor 2 in acute and chronic lung injury in preterm infants

Proteinase-activated receptor 2 (PAR(2)), a G-protein-coupled receptor activated by serine proteinases such as trypsin, has been suggested to play an important role in inflammatory and fibroproliferative processes. In preterm infants, the development of bronchopulmonary dysplasia (BPD) is characterized by early pulmonary inflammation and subsequent interstitial fibrosis. High pulmonary trypsin-2 has been shown to be associated with the development of BPD. We studied the expression and distribution of PAR(2) and trypsin-2 by immunohistochemistry in autopsy lung specimens of fetuses (n = 10), of preterm infants who died of acute or prolonged respiratory distress syndrome (RDS) (n = 8 and n = 7, respectively) or BPD (n = 6), and of newborn infants without lung disease (n = 5) who served as controls. In prolonged RDS and BPD, PAR(2) immunoreactivity was significantly higher in bronchial epithelium when compared with infants without pulmonary pathology (p < 0.05 and p < 0.005, respectively). In alveolar epithelium, expression of PAR(2) was elevated in prolonged RDS when compared with newborn infants without pulmonary pathology (p < 0.05). Moreover, strong expression of PAR(2) was detected in myofibroblasts of thickened and fibrotic alveolar walls in prolonged RDS or BPD. Trypsin-2 was co-localized with PAR(2) in bronchoalveolar epithelium. These findings suggest that PAR(2), possibly activated by trypsin-2, may participate in inflammation and fibroproliferation associated with progression of RDS toward BPD in preterm infants.     

Pressure-volume relationship and fluid content in fetal rabbit lung after beta-receptor-stimulating drugs

A considerable interest has been focused on the effects of various drugs on fetal and neonatal pulmonary maturation and adaptation. In the present study, we have investigated the effects of the selective beta1- and beta2-receptor-stimulating agents prenalterol and terbutalilne on the pressure-volume relationship and fluid content in fetal rabbit lung at 28 days of gestation. Pressure-volume recordings during deflation showed significantly increased lung volumes at equivalent transpulmonary pressures in terbutaline-treated fetuses as compared to controls. No such effect was noted after prenalterol. In the control animals, wet lung weight/body weight ratio decreased to a steady state level 60 min after birth, indicating a rapid dehydration of the lungs. This dehydration was present at delivery after terbutaline and prenalterol treatment. The amount of fluid collected from the airways was also reduced after terbutaline and prenalterol treatment. The present results indicate facilitated neonatal respiratory adaptation after especially terbutaline treatment. Possible mechanisms behind these effects are discussed.     

mRNA D(2) dopaminergic receptor expression after hypoxia-ischemia in rat immature brain

Previous studies have shown a reduction of dopaminergic D(2) receptors (D(2)R) in the striatum after hypoxia-ischemia in newborn rats. We show here an early and transient reduction of mRNA D(2)R in nonatrophic brains following hypoxia-ischemia. The left carotid artery of P7 rats was ligated followed by hypoxia for 2 h. The rats were sacrificed after 24 h, 48 h and 14 days. D(2)R mRNA was studied by in situ hybridization, the cell number by conventional histology, and neuronal and astrocyte differentiation by immunohistochemistry. A 20% reduction of striatal mRNA D(2)R occurred 24 h after hypoxia-ischemia, whereas no reduction was observed after 48 h and 14 days. There were no differences in total cell number and in the expression of neuronal (MAP-1, MAP-2) and astrocyte (GFAP) markers between both brain hemispheres nor between control and hypoxia-ischemia animals. The early decrease in mRNA D(2)R could explain the delayed reduced D(2)R after neonatal hypoxia-ischemia.