摘要:

Ligation of the ductus arteriosusin uteroproduces fetal and neonatal pulmonary hypertension and alterations in the hemodynamic responses to nitric oxide and endothelin-1 in fetal and newborn lambs. To determine whether fetal pulmonary hypertension alters the expression of the genes of the nitric oxide and endothelin-1 pathways, seven fetal lambs (123-126-d gestation) underwent ligation of the ductus arteriosus. Near-term (138-139-d gestation), total lung RNA, and protein were prepared from control and ductal ligation fetal lambs for RNase protection assays and Western blotting. Ligation of the ductus arteriosus was associated with decreased expression of endothelial nitric oxide synthase mRNA and protein, and the α1and the β1subunits of soluble guanylate cyclase protein; and with increased expression of phosphodiesterase V mRNA. Ligation of the ductus arteriosus was also associated with increased expression of preproendothelin-1 mRNA and with decreased expression of endothelin B receptor (ETB) mRNA. These results suggest that there is coordinated regulation of genes of the nitric oxide pathway, which would decrease nitric oxide and cGMP concentration, thereby decreasing pulmonary vasodilator activity. There is also coordinated regulation of genes of the endothelin-1 pathway, which would increase endothelin-1 concentration and limit ETBreceptor activation, thereby increasing pulmonary vasoconstrictor activity. These alterations in gene expression would increase fetal pulmonary vascular resistance, contributing to the development of pulmonary hypertension after birth.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Nitric oxide (NO) relaxes vascular smooth muscle by increasing the intracellular concentration of cGMP. In the pulmonary circulation, cGMP is inactivated by specific phosphodiesterases (PDE5). Dipyridamole, a clinically approved drug, has inhibitory activity against PDE5 and has been reported to augment the response to inhaled NO in persistent pulmonary hypertension of the newborn (PPHN). We wished to determine whether dipyridamole alone, or in combination with NO, can be used to treat a newborn lamb model of PPHN. In newborn lambs with PPHN, dipyridamole infused at 0.02 mg/kg/min for 45 min alone, or in combination with 5 ppm of inhaled NO for the final 15 min, significantly decreased pulmonary and systemic blood pressure, decreased pulmonary vascular resistance, and increased pulmonary blood flow. There was no significant difference between the pulmonary vascular effects of 5 ppm NO alone compared with the effects of NO combined with dipyridamole. In control lambs, the 45-min infusion of dipyridamole did not change pulmonary pressure whereas systemic pressure decreased by 28 ± 3%. These systemic effects in control lambs persisted 90 min after discontinuing the dipyridamole infusion. Systemic arteries isolated from both control and PPHN lambs were significantly more sensitive to dipyridamole than pulmonary arteries. We conclude that dipyridamole has significant hemodynamic effects in both the pulmonary and systemic circulations of newborn lambs with pulmonary hypertension as well as in the systemic circulation of newborn control lambs. The pronounced effects of dipyridamole on the systemic circulation limits its utility as an adjunct to inhaled NO in the treatment of PPHN.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Severe perinatal aspiration of meconium is frequently complicated by unsuccessful neonatal adaptation with associated pulmonary hypertension. This vascular complication is supposedly related to pulmonary release of vasoconstrictory agents, including metabolites of arachidonic acid. Thus, to investigate the role of prostanoids on these meconium-induced circulatory changes in the lungs, the hemodynamic response to meconium instillation was studied in acetylsalicylic acid-pretreated juvenile pigs. Twelve 10-wk-old pigs with adapted lung circulation received 3 mL/kg of 65 mg/mL human meconium via the endotracheal tube. Six of them were medicated with 10 mg/kg acetylsalicylic acid 30 min before meconium insufflation. Hemodynamic parameters and urinary excretion of stable metabolites of thromboxane A2and prostacyclin were measured serially for 6 h after the insult. Meconium administration induced a biphasic increase in mean pulmonary artery pressure and pulmonary vascular resistance, and a rapid rise in urinary levels of prostanoid metabolites. Acetylsalicylic acid pretreatment prevented the initial (0-1 h) pulmonary hypertensive response and increase in prostanoid excretion. During the second phase (1-6 h), acetylsalicylic acid did not attenuate the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance nor did it affect the longitudinal distribution of the pulmonary resistances. Our results thus show that in adapted porcine lungs, arachidonic acid metabolites contribute to the early hypertensive response, but have only minor effects during the second phase vascular hypertension.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The immediate effect on the pulmonary circulation of reoxygenation with either room air or 100% O2was studied in newborn piglets. Hypoxemia was induced by ventilation with 8% O2until base excess was <-20 mmol/L or mean arterial blood pressure was <20 mm Hg. Reoxygenation was performed with either room air (n= 9) or 100% O2(n= 9). Mean pulmonary artery pressure increased during hypoxemia (p= 0.012). After 5 min of reoxygenation, pulmonary artery pressure increased further from 24 ± 2 mm Hg at the end of hypoxemia to 35 ± 3 mm Hg (p= 0.0077versusbaseline) in the room air group and from 27 ± 3 mm Hg at the end of hypoxemia to 30 ± 2 mm Hg (p= 0.011versusbaseline) in the O2group (NS between groups). Pulmonary vascular resistance index increased (p= 0.0005) during hypoxemia. During early reoxygenation pulmonary vascular resistance index decreased rapidly to values comparable to baseline within 5 min of reoxygenation in both groups (NS between groups). Plasma endothelin-1 (ET-1) decreased during hypoxemia from 1.5 ± 0.1 ng/L at baseline to 1.2 ± 0.1 ng/L at the end of hypoxemia (p= 0.003). After 30 min of reoxygenation plasma ET-1 increased to 1.8 ± 0.3 and 1.5 ± 0.2 ng/L in the room air and O2groups, respectively (p= 0.0077 in each groupversusend hypoxemia; NS between groups). We conclude that hypoxemic pulmonary hypertension and plasma ET-1 normalizes as quickly when reoxygenation is performed with room air as with 100% O2in this hypoxia model with newborn piglets.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Many of the signaling pathways regulating fetal lung mesenchymal cell proliferation are mediated by the Shc intracellular signaling proteins. Shc is expressed as three isoforms: 52 kD and 46 kD proteins (Shc 52 and Shc 46, respectively) translated from the same mRNA, and a 66 kD form (Shc 66) translated from a separate mRNA. Shc 52 is an activator of Ras and mitogen-activated protein kinase, whereas Shc 66 antagonizes Ras activation. The function of Shc 46 is unclear. We hypothesized that the Shc isoforms are differentially regulated during fetal mouse lung morphogenesis. Relative Shc 66 and Shc 46 protein expression are high until parturition (term = 18.5 d), when a dramatic decrease begins; by postconceptual d 20, relative Shc 66 and Shc 46 expression have fallen by 75 and 69%, respectively. A similar pattern of decreasing Shc 66 mRNA expression in the peripartum period was detected by reverse transcription and competitive polymerase chain reaction during the same period. By isoform-specific immunohistochemistry, Shc 66 is widely distributed in the embryonic lung but becomes restricted to the bronchial smooth muscle and overlying epithelia, periarterial smooth muscle, and the interlobar pleura late in gestation. After parturition, Shc 66 is virtually absent from the lung. All three Shc isoforms are phosphorylated by epidermal growth factor stimulation in fetal lung mesenchymal cells, indicating that Shc 66 is functional in these cells. These data indicate that Shc isoforms are differentially regulated during lung development.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Although surfactants containing only lipids and surfactant protein C (SP-C) or SP-C analogs can be effective for the treatment of surfactant deficiency in animal models, there is no information concerning the alveolar or lung clearance of SP-C. Because the other lipid and protein components of surfactant are cleared very slowly from the preterm lung, we hypothesized that SP-C also would be cleared slowly. Therefore, we compared the losses of iodinated native SP-C (nSP-C) and recombinant SP-C analog (rSP-C, phenylalanines in positions 4 and 5 and isoleucine in position 32 of the human sequence) to [14C] dipalmitoylphos-phatidylcholine (DPPC) after airway administration at birth of trace or treatment doses of surfactant given to preterm lambs. In preterm lambs given trace doses at 134-136 d gestation, alveolar [14C]DPPC and [125I]rSP-C decreased to 14.7% recovery for DPPC and 8.3% recovery for rSP-C after 2 h ventilation. There was no loss of [14C]DPPC from the total lungs (alveolar wash + lung tissue), and approximately 20% of the [125I]rSP-C was lost from the lungs. For 128 d gestational age lambs treated with 100-mg/kg doses of surfactants containing nSP-C or 2% of rSP-C, the alveolar and total lung recoveries for [125I]nSP-C or [125I]rSP-C were equivalent to that of [14C]DPPC after 5 h ventilation. These results demonstrate that nSP-C and rSP-C have alveolar clearances and accumulations into preterm lung tissue that are similar to those of DPPC.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We previously established that increased hyaluronan synthesis in ductus arteriosus (DA) compared with aorta (Ao) endothelial cells (EC) from early gestation fetal lambs (100-d, term = 145 d) is transforming growth factor-β (TGF-β)-dependent. We now address whether this is associated with tissue-specific and developmentally up-regulated expression of TGF-β1in the 100-d DA EC. Immunoprecipitation revealed TGF-β synthesis doubled in DAversusAo EC from 100-d gestation lambs (p< 0.05). In 138-d DA EC, TGF-β protein levels were reduced (p< 0.05) and comparable to those in Ao cells. Western immunoblotting with a β1isoform-specific antibody confirmed these differences as being related to TGF-β1. Northern blot analysis demonstrated that TGF-β1mRNA levels were slightly but not significantly increased in 100-d DA compared with Ao EC, despite its short half-life in DA (9.5 h)versusAo EC (20 h). TGF-β1mRNA levels were reduced in 138-d DA and Ao EC (p< 0.05), and the mRNA half-life was comparable in DA (9 h)versusAo (13 h). Nuclear run-on analysis confirmed increased TGF-β1mRNA transcription in 100-d DAversusAo and 138-d DA EC. Thus, up-regulated TGF-β1expression in 100-d DA compared with Ao cells is due to increased transcription and translation of a relatively unstable mRNA, and its down-regulation in 138-d DA and Ao EC is related to reduced mRNA transcription and stability, respectively.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Diabetes mellitus is characterized by microangiopathy and increased angiogenic response in various organs. Basic fibroblast growth factor (bFGF) as well as vascular endothelial growth factor (VEGF) are both angiogenic and are involved in vascular endothelial cell growth. The purpose of this study was to determine serum levels of bFGF and VEGF, in children and adolescents (youngsters) with type 1 diabetes mellitus, and correlate them with parameters reflecting the severity of the disease. Forty diabetic youngsters without clinical evidence of complications were compared with 30 healthy control subjects (mean age ± SD, 14.3 ± 3.6 and 13.8 ± 3.6 y, respectively). Diabetes duration and metabolic control (expressed by glycosylated Hb) were (mean ± SD) 6.2 ± 3.8 y and 9.6 ± 1.8%, respectively. bFGF and VEGF (pg/mL) were measured in serum samples by enzyme immunoassays, and both were not significantly different between the type 1 diabetes mellitus and the control group (p= 0.952 andp= 0.559, respectively). Restricting the analysis to the type 1 diabetes mellitus group, neither the duration nor the metabolic control of the disease showed any correlation with bFGF and VEGF serum levels, whereas a significantly positive correlation was found between the two examined angiogenic factors both in the diabetic (r= 0.3464,p= 0.025) and the control group (r= 0.4619,p= 0.0013). In conclusion, serum levels of bFGF and VEGF were not found to vary significantly in diabetic youngsters in relation to controls and had no correlation with the duration and metabolic control of the disease. Nevertheless, a positive correlation was found between these two angiogenic factors both in the type 1 diabetes mellitus and the control group.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We hypothesized that antenatal exposure to glucocorticoids influences subsequent pulsatile cortisol (F) secretion in premature neonates. To test this hypothesis, blood was sampled for plasma F determinationviaindwelling arterial lines at 15-min intervals for 6 h in 26 clinically stable neonates whose gestational ages were 25-33 wk. Deconvolution analysis was used to characterize F secretion and elimination. Pulsatile F secretion was observed in all neonates. Deconvolution estimates in eight neonates exposed to antenatal glucocorticoids (ANG group) were compared with those of 18 neonates not or only remotely exposed to ANG (No/RG group). The median amplitude of the F secretory burst of the ANG group was significantly less than that of the No/RG group [4.3 nmol/Lv·min and 9.2 nmol/Lv·min, respectively;p= 0.026 (Lvis liter of F distribution volume)]. The number and duration of F secretory bursts was similar for both groups: 5 bursts per 6 h, and 23versus16 min. By univariate linear regression analysis, mean arterial blood pressure correlated positively with F secretory burst frequency and F production rate (p= 0.0035,r= 0.55 andp= 0.0067,r= 0.52, respectively). We propose that ANG treatment modulates the amplitude of pulsatile F secretion in premature neonates.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Human growth is a nonlinear process with marked variation in growth rate during the short-term. It is not known how long-term height gain or stature is influenced by short-term changes in height and weight. This study has addressed these issues by using thrice weekly height and weight measurements during 1 year in 43 normal prepubertal children (aged 5.7-7.7 y) to construct individual height and weight velocity curves by regression analysis. The former were comprised of 3 to 6 growth spurts separated by stasis, whereas the latter were characterized by 2 to 5 periods of weight gain separated by periods of weight loss. Stepwise regression analysis to determine characteristics of these curves that influence stature and growth showed that height SD score was correlated to the mean absolute weight velocity amplitude (+), the mean lenght of height velocity peaks (-), and the number of periods of weight gain (-) (r2= 38%). In contrast, change in height SD score (Δheight SD score) was correlated to the number (+) and mean amplitude (+) of the periods of weight gain and the mean height velocity peak amplitude (+) (r2= 44%). Examination of changes in height relative to weight during the year in the whole group revealed that height increased relative to weight in autumn and spring, whereas the reverse occurred during the winter months. We conclude that1) both height and weight velocities during 1 year show a biphasic pattern,2) there is seasonal variation in the short-term change in height relative to weight, and3) prepubertal stature and the amount grown through the year are related to short-term changes in height and weight. Our data indicate that large but infrequent changes in weight with growth spurts of short duration are found in tall children. Good growth during the year was related to large but frequent gains in weight and large individual spurts in height.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID