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Biomedical subjects

Steven H Abman

Publications and source records attributed to Steven H Abman.

At least 19 recordsLinked to original sources
PubMed2007

Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia.

Hyperoxia disrupts vascular and alveolar growth of the developing lung and contributes to the development of bronchopulmonary dysplasia (BPD). Endothelial progenitor cells (EPC) have been implicated in repair of the vasculature, but their role in lung vascular development is unknown. Since disruption of vascular growth impairs lung structure, we hypothesized that neonatal hyperoxia impairs EPC mobilization and homing to the lung, contributing to abnormalities in lung structure. Neonatal mice (1-day-old) were exposed to 80% O(2) at Denver's altitude (= 65% at sea level) or room air for 10 days. Adult mice were also exposed for comparison. Blood, lung, and bone marrow were harvested after hyperoxia. Hyperoxia decreased pulmonary vascular density by 72% in neonatal but not adult mice. In contrast to the adult, hyperoxia simplified distal lung structure neonatal mice. Moderate hyperoxia reduced EPCs (CD45-/Sca-1+/CD133+/VEGFR-2+) in the blood (55%; P < 0.03), bone marrow (48%; P < 0.01), and lungs (66%; P < 0.01) of neonatal mice. EPCs increased in bone marrow (2.5-fold; P < 0.01) and lungs (2-fold; P < 0.03) of hyperoxia-exposed adult mice. VEGF, nitric oxide (NO), and erythropoietin (Epo) contribute to mobilization and homing of EPCs. Lung VEGF, VEGF receptor-2, endothelial NO synthase, and Epo receptor expression were reduced by hyperoxia in neonatal but not adult mice. We conclude that moderate hyperoxia decreases vessel density, impairs lung structure, and reduces EPCs in the circulation, bone marrow, and lung of neonatal mice but increases EPCs in adults. This developmental difference may contribute to the increased susceptibility of the developing lung to hyperoxia and may contribute to impaired lung vascular and alveolar growth in BPD.

Aging↗
PubMed2006

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Administration, Inhalation↗
PubMed2006

Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia.

Recent studies suggest that VEGF may worsen pulmonary edema during acute lung injury (ALI), but, paradoxically, impaired VEGF signaling contributes to decreased lung growth during recovery from ALI due to neonatal hyperoxia. To examine the diverse roles of VEGF in the pathogenesis of and recovery from hyperoxia-induced ALI, we hypothesized that exogenous recombinant human VEGF (rhVEGF) treatment during early neonatal hyperoxic lung injury may increase pulmonary edema but would improve late lung structure during recovery. Sprague-Dawley rat pups were placed in a hyperoxia chamber (inspired O(2) fraction 0.9) for postnatal days 2-14. Pups were randomized to daily intramuscular injections of rhVEGF(165) (20 microg/kg) or saline (controls). On postnatal day 14, rats were placed in room air for a 7-day recovery period. At postnatal days 3, 14, and 21, rats were killed for studies, which included body weight and wet-to-dry lung weight ratio, morphometric analysis [including radial alveolar counts (RAC), mean linear intercepts (MLI), and vessel density], and lung endothelial NO synthase (eNOS) protein content by Western blot analysis. Compared with room air controls, hyperoxia increased pulmonary edema by histology and wet-to-dry lung weight ratios at postnatal day 3, which resolved by day 14. Although treatment with rhVEGF did not increase edema in control rats, rhVEGF increased wet-to-dry weight ratios in hyperoxia-exposed rats at postnatal days 3 and 14 (P < 0.01). Compared with room air controls, hyperoxia decreased RAC and increased MLI at postnatal days 14 and 21. Treatment with VEGF resulted in increased RAC by 181% and decreased MLI by 55% on postnatal day 14 in the hyperoxia group (P < 0.01). On postnatal day 21, RAC was increased by 176% and MLI was decreased by 58% in the hyperoxia group treated with VEGF. rhVEGF treatment during hyperoxia increased eNOS protein on postnatal day 3 by threefold (P < 0.05). We conclude that rhVEGF treatment during hyperoxia-induced ALI transiently increases pulmonary edema but improves lung structure during late recovery. We speculate that VEGF has diverse roles in hyperoxia-induced neonatal lung injury, contributing to lung edema during the acute stage of ALI but promoting repair of the lung during recovery.

Animals↗
PubMed2006

Rho kinase activation maintains high pulmonary vascular resistance in the ovine fetal lung.

Mechanisms that maintain high pulmonary vascular resistance (PVR) in the fetal lung are poorly understood. Activation of the Rho kinase signal transduction pathway, which promotes actin-myosin interaction in vascular smooth muscle cells, is increased in the pulmonary circulation of adult animals with experimental pulmonary hypertension. However, the role of Rho kinase has not been studied in the fetal lung. We hypothesized that activation of Rho kinase contributes to elevated PVR in the fetus. To address this hypothesis, we studied the pulmonary hemodynamic effects of brief (10 min) intrapulmonary infusions of two specific Rho kinase inhibitors, Y-27632 (15-500 microg) and HA-1077 (500 microg), in chronically prepared late-gestation fetal lambs (n = 9). Y-27632 caused potent, dose-dependent pulmonary vasodilation, lowering PVR from 0.67 +/- 0.18 to 0.16 +/- 0.02 mmHg x ml(-1) x min(-1) (P < 0.01) at the highest dose tested without lowering systemic arterial pressure. Despite brief infusions, Y-27632-induced pulmonary vasodilation was sustained for 50 min. HA-1077 caused a similar fall in PVR, from 0.39 +/- 0.03 to 0.19 +/- 0.03 (P < 0.05). To study nitric oxide (NO)-Rho kinase interactions in the fetal lung, we tested the effect of Rho kinase inhibition on pulmonary vasoconstriction caused by inhibition of endogenous NO production with nitro-L-arginine (L-NA; 15-30 mg), a selective NO synthase antagonist. L-NA increased PVR by 127 +/- 73% above baseline under control conditions, but this vasoconstrictor response was completely prevented by treatment with Y-27632 (P < 0.05). We conclude that the Rho kinase signal transduction pathway maintains high PVR in the normal fetal lung and that activation of the Rho kinase pathway mediates pulmonary vasoconstriction after NO synthase inhibition. We speculate that Rho kinase plays an essential role in the normal fetal pulmonary circulation and that Rho kinase inhibitors may provide novel therapy for neonatal pulmonary hypertension.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is a chronic lung disease that affects premature babies and contributes to their morbidity and mortality. Improved survival of very immature infants has led to increased numbers of infants with this disorder. This increase puts a heavy burden on health resources since these infants need frequent re-admission to hospital in the first 2 years after birth and, even as adolescents, have lung-function abnormalities and persistent respiratory symptoms. Unlike the original description of the disease in 1967, premature infants can develop chronic oxygen dependency without severe, acute respiratory distress; this "new bronchopulmonary dysplasia" could be the result of impaired postnatal lung growth. Whether such infants subsequently have catch-up lung growth, especially if given corticosteroids postnatally, is unknown. No safe and effective preventive therapy has been identified, but promising new treatments directed either at reducing lung injury or improving lung growth are under study.

Antioxidants↗
PubMed2006

BAY 41-2272, a direct activator of soluble guanylate cyclase, reduces right ventricular hypertrophy and prevents pulmonary vascular remodeling during chronic hypoxia in neonatal rats.

Exposure to hypoxia during the first weeks of life in newborn rats decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). BAY 41-2272 is a novel direct activator of soluble guanylate cyclase independent of nitric oxide, effective as an acute pulmonary vasodilator in an animal model of persistent pulmonary hypertension of the newborn, but whether prolonged BAY 41-2272 therapy is effective in the setting of chronic PH is unknown. We hypothesize that BAY 41-2272 would prevent PH induced by chronic exposure to neonatal hypoxia. At 2 days of age, newborn rats were randomly exposed to hypoxia (FiO2, 0.12) or room air, and received daily intramuscular treatment with BAY 41-2272 (1 mg/kg) or saline. After 2 weeks, rats were killed for assessment of right ventricular hypertrophy (RVH), wall thickness of small pulmonary arteries, vessels density, radial alveolar counts and mean linear intercepts. In comparison with control, hypoxia increased RVH and artery wall thickness, reduced vessels density, decreased radial alveolar counts and increased mean linear intercepts. In comparison with hypoxic controls, prolonged BAY 41-2272 treatment during chronic hypoxia reduced RVH (0.67 +/- 0.03 vs. 0.52 +/- 0.05; p < 0.05), and attenuated artery wall thickness (48.2 +/- 2.8% vs. 35.7 +/- 4.1 microm; p < 0.01). However, BAY 41-2272 did not change vessels density, radial alveolar counts or mean linear intercepts. We conclude that BAY 41-2272 prevents the vascular structural effects of PH and reduces RVH but does not protect from hypoxia-induced inhibition of alveolarization and vessel growth. We speculate that BAY 41-2272 may provide a new therapy for chronic PH.

Animals↗
PubMed2006

Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia.

We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS-/-) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide (NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS-/- mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS-/- mice during recovery. Mice (1 day old) from heterozygous (eNOS+/-) parents were placed in hypobaric hypoxia (Fi(O2) = 0.16). After 10 days, pups were to recovered in room air (HR group) or inhaled NO (10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS-/- mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient (eNOS+/+) mice (increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS+/- was not different from eNOS+/+. Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS-/- mice that completely restored normal lung structure. eNOS+/- mice (HR group) had a 2.5-fold increase in lung vascular endothelial growth factor (VEGFR)-2 protein compared with eNOS+/+ (P < 0.05). eNOS-/- mice (HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS-/- (HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS-/- mice.

Administration, Inhalation↗
PubMed2006

Nitric oxide augments fetal pulmonary artery endothelial cell angiogenesis in vitro.

Growth and development of the lung normally occur in the low oxygen environment of the fetus. The role of this low oxygen environment on fetal lung endothelial cell growth and function is unknown. We hypothesized that low oxygen tension during fetal life enhances pulmonary artery endothelial cell (PAEC) growth and function and that nitric oxide (NO) production modulates fetal PAEC responses to low oxygen tension. To test this hypothesis, we compared the effects of fetal (3%) and room air (RA) oxygen tension on fetal PAEC growth, proliferation, tube formation, and migration in the presence and absence of the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine (LNA), and an NO donor, S-nitroso-N-acetylpenicillamine (SNAP). Compared with fetal PAEC grown in RA, 3% O(2) increased tube formation by over twofold (P < 0.01). LNA treatment reduced tube formation in 3% O(2) but had no affect on tube formation in RA. Treatment with SNAP increased tube formation during RA exposure to levels observed in 3% O(2). Exposure to 3% O(2) for 48 h attenuated cell number (by 56%), and treatment with LNA reduced PAEC growth by 44% in both RA and 3% O(2). We conclude that low oxygen tension enhances fetal PAEC tube formation and that NO is essential for normal PAEC growth, migration, and tube formation. Furthermore, we conclude that in fetal cells exposed to the relative hyperoxia of RA, 21% O(2), NO overcomes the inhibitory effects of the increased oxygen, allowing normal PAEC angiogenesis and branching. We speculate that NO production maintains intrauterine lung vascular growth and development during exposure to low O(2) in the normal fetus. We further speculate that NO is essential for pulmonary angiogenesis in fetal animal exposed to increased oxygen tension of RA and that impaired endothelial NO production may contribute to the abnormalities of angiogenesis see in infants with bronchopulmonary dysplasia.

Animals↗
PubMed2006

Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease.

Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.

Adult↗
PubMed2005

Effects of long-term bosentan in children with pulmonary arterial hypertension.

OBJECTIVES: This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children. METHODS: In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health Organization (WHO) functional class, and safety data were collected. RESULTS: At the cutoff date, 68 patients (79%) were still treated with bosentan, 13 (15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients (n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg, p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at one and two years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.

Adolescent↗
PubMed2005

Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep.

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Superoxide dismutase improves gas exchange and pulmonary hemodynamics in premature lambs.

RATIONALE: Oxidant stress may increase the severity of respiratory distress syndrome (RDS) after premature birth by altering vasoreactivity and increasing lung edema, but the acute effects of superoxide dismutase (SOD) treatment on gas exchange, lung compliance (CL), and pulmonary vascular resistance in premature animals with RDS are unknown. OBJECTIVE: We studied the effects of intratracheal recombinant human SOD treatment (rhSOD) on gas exchange, CL, and pulmonary hemodynamics in 46 premature lambs with RDS. METHODS: After C-section delivery, lambs were randomly assigned to treatment with SOD (2.5-10 mg/kg) with or without inhaled nitric oxide (iNO, 5 ppm), and mechanically ventilated for 4 hours. At the end of the study, pressure-volume curves and wet-dry lung weights were measured to assess CL and edema, respectively. MAIN RESULTS: Despite an initial rise in Pa(O(2)), Pa(O(2)) in control animals progressively declined over the 4-hour treatment period (Pa(O(2)) = 25.0 +/- 7.5 mm Hg at 4 hours). In comparison with control animals, early treatment with SOD at 5 and 10 mg/kg improved Pa(O(2)) at 4 hours (167 +/- 44 and 269 +/- 33 mm Hg, respectively; p < 0.05 vs. control), but did not decrease lung edema or improve CL. In contrast, late treatment with SOD did not improve Pa(O(2)). Treatment with iNO increased Pa(O(2)) (196 +/- 22 vs. 25 +/- 8 mm Hg, control animals; p < 0.01), but the response to iNO was not augmented by combined therapy (SOD + iNO). After 4 hours of ventilation with FI(O(2)) = 1.00, rhSOD treatment lowered pulmonary vascular resistance compared with control animals. CONCLUSIONS: Early intratracheal rhSOD treatment improves oxygenation in premature lambs with RDS and prevents the development of pulmonary hypertension.

Administration, Inhalation↗
PubMed2005

Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats.

VEGF signaling inhibition decreases alveolar and vessel growth in the developing lung, suggesting that impaired VEGF signaling may contribute to decreased lung growth in bronchopulmonary dysplasia (BPD). Whether VEGF treatment improves lung structure in experimental models of BPD is unknown. The objective was to determine whether VEGF treatment enhances alveolarization in infant rats after hyperoxia. Two-day-old Sprague-Dawley rats were placed into hyperoxia or room air (RA) for 12 days. At 14 days, rats received daily treatment with rhVEGF-165 or saline. On day 22, rats were killed. Tissue was collected. Morphometrics was assessed by radial alveolar counts (RAC), mean linear intercepts (MLI), and skeletonization. Compared with RA controls, hyperoxia decreased RAC (6.1 +/- 0.4 vs. 11.3 +/- 0.4, P < 0.0001), increased MLI (59.2 +/- 1.8 vs. 44.0 +/- 0.8, P < 0.0001), decreased nodal point density (447 +/- 14 vs. 503 +/- 12, P < 0.0004), and decreased vessel density (11.7 +/- 0.3 vs. 18.9 +/- 0.3, P < 0.001), which persisted despite RA recovery. Compared with hyperoxic controls, rhVEGF treatment after hyperoxia increased RAC (11.8 +/- 0.5, P < 0.0001), decreased MLI (42.2 +/- 1.2, P < 0.0001), increased nodal point density (502 +/- 7, P < 0.0005), and increased vessel density (23.2 +/- 0.4, P < 0.001). Exposure of neonatal rats to hyperoxia impairs alveolarization and vessel density, which persists despite RA recovery. rhVEGF treatment during recovery enhanced vessel growth and alveolarization. We speculate that lung structure abnormalities after hyperoxia may be partly due to impaired VEGF signaling.

Animals↗
PubMed2005

Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats.

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGF-dependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (Fio(2)), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia.

Animals↗
PubMed2005

rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep.

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.

Animals↗
PubMed2005

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation.

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl-12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 +/- 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 +/- 12% vs. 2 +/- 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension.

Amides↗
PubMed2005

Inhaled nitric oxide therapy in children.

Inhaled nitric oxide therapy improves oxygenation and reduces the need for treatment with extracorporeal membrane oxygenation in term newborns with hypoxaemic respiratory failure and persistent pulmonary hypertension. In this review, we summarise the current status of iNO therapy in the newborn and the potential role of iNO in other paediatric populations.

Child↗