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.
Acute hypoxic vasoconstriction and development of hypoxic pulmonary hypertension (PHTN) are unique properties of the pulmonary circulation. The pulmonary endothelium produces vasoactive factors, ...including nitric oxide (NO), that modify these phenomena. We tested the hypothesis that NO produced by endothelial nitric oxide synthase (eNOS) modulates pulmonary vascular responses to hypoxia using mice with targeted disruption of the eNOS gene (eNOS-/-). Marked PHTN was found in eNOS-/- mice raised in mild hypoxia when compared with either controls or eNOS-/- mice raised in conditions simulating sea level. We found an approximate twofold increase in partially and fully muscularized distal pulmonary arteries in eNOS-/- mice compared with controls. Consistent with vasoconstriction being the primary mechanism of PHTN, however, acute inhalation of 25 ppm NO resulted in normalization of RV pressure in eNOS-/- mice. In addition to studies of eNOS-/- mice, the dose-effect of eNOS was tested using heterozygous eNOS+/- mice. Although the lungs of eNOS+/- mice had 50% of normal eNOS protein, the response to hypoxia was indistinguishable from that of eNOS-/- mice. We conclude that eNOS-derived NO is an important modulator of the pulmonary vascular response to chronic hypoxia and that more than 50% of eNOS expression is required to maintain normal pulmonary vascular tone.
Objective: Inhaled nitric oxide therapy causes selective and sustained pulmonary vasodilation in patients with pulmonary hypertension; however, attempts to discontinue inhaled nitric oxide therapy ...may be complicated by abrupt life-threatening events. Dipyridamole, a cyclic guanosine monophosphate–specific phosphodiesterase inhibitor, blocks the hydrolysis of cyclic guanosine monophosphate in vascular smooth muscle cells.
Methods: We studied 23 consecutive children who were treated with inhaled nitric oxide because of clinically significant pulmonary hypertension after surgery for congenital heart disease. Inhaled nitric oxide therapy was withdrawn before and after dipyridamole treatment of children in whom sustained elevations of pulmonary artery pressure developed for over 30 minutes.
Results: In 7 of 23 children, inhaled nitric oxide withdrawal caused a 40% increase in pulmonary artery pressure, a 17% decrease in systemic venous oxygen saturation, and a 46% increase in the ratio of mean pulmonary artery pressure to aortic pressure. Compared with children who had no significant increase in pulmonary artery pressure, children who experienced the development of prolonged pulmonary hypertension after inhaled nitric oxide therapy withdrawal had higher mean pulmonary artery pressure immediately before inhaled nitric oxide withdrawal (22 ± 1 mm Hg versus 27 ± 2 mm Hg;
p = 0.04) and received inhaled nitric oxide for a longer duration (2 ± 1 days versus 4 ± 1 days;
p = 0.01). Dipyridamole therapy attenuated the rise in pulmonary artery pressure and fall in systemic venous oxygen saturation in all six patients studied with rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.
Conclusion: We conclude that dipyridamole therapy acutely attenuates the adverse hemodynamic effects of rapid withdrawal of inhaled nitric oxide therapy. Children with higher pulmonary artery pressure and who are treated with inhaled nitric oxide for a longer duration may be at increased risk for adverse hemodynamic effects of inhaled nitric oxide therapy withdrawal. We speculate that dipyridamole therapy may sustain elevations of smooth muscle cyclic guanosine monophosphate induced by inhaled nitric oxide and that phosphodiesterase activity contributes to acute pulmonary hypertension after inhaled nitric oxide withdrawal. (J Thorac Cardiovasc Surg 1998;115:875-82)
This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy.
Bosentan, an oral ...endothelin ETA/ETBreceptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children.
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.
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·m2to 15 ± 2 U·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.
These data suggest that bosentan, an oral endothelin ETA/ETBreceptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.
Inhaled NO improves oxygenation and decreases ECMO use in term newborns with PPHN. From the available information, a reasonable recommendation for a starting dose of iNO in the term infant is 20 ppm, ...with reductions in dose over time. Toxicity isapparent at 80 ppm, causing increases in methemoglobinemia and inspired ni trogen dioxide. High doses (<20 ppm) of iNO may also prolong bleeding time, but clinically significant increases in bleeding complications have not been reported in term newborns. The use of iNO in non-ECMO centers must be done cautiously, with arrange ments in place for transport to an ECMO center without interruption of iNO delivery in patients with suboptimal immediate responses. Finally, there is increasing evidence for the potential role of low-dose iNO (5 ppm) in premature newborns with hypoxemic respiratory failure. Low-dose iNO causes immediate improvement in oxygenation and may prove to be useful as a lung-specific anti-inflammatory therapy. However, clinical application should currently be limited to controlled trials that target outcomes of both safety and efficacy.
Pulmonary hypertension contributes significantly to morbidity and mortality in bronchopulmonary dysplasia (BPD), but little is known about the relative contribution of arterial tone, structural ...remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, we studied the acute effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) were 34 +/- 3 mm Hg and 0.42 +/- 0.07, respectively. In response to hypoxia, PAP and PVR/SVR increased by 50 +/- 8% and 82 +/- 14%, respectively (p < 0.01). Hyperoxia decreased PVR/SVR by 28 +/- 9% (p = 0.05). The addition of iNO treatment (20-40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 +/- 5% (p < 0.01) and 45 +/- 6% (p < 0.05) from baseline values, respectively, achieving near normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.
To examine the potential role of endothelium-derived relaxing factor (EDRF) in regulation of the perinatal pulmonary circulation, we studied the hemodynamic effects of a selective inhibitor of EDRF ...production, nitro-L-arginine (L-NA), on pulmonary vascular tone and dilator reactivity in the late-gestation ovine fetus and on the pulmonary vasodilation that normally occurs at birth. L-NA infusion decreased pulmonary blood flow from 78 +/- 8 to 65 +/- 6 ml/min (P less than 0.01) and increased pulmonary artery pressure from 48 +/- 2 to 54 +/- 3 mmHg (P less than 0.002, n = 8 animals). To study the selectivity of L-NA on vasodilator responses to endothelium-dependent (acetylcholine) and -independent (atrial natriuretic factor) stimuli, we measured responses to brief infusions of each dilator before and after L-NA treatment. Acetylcholine increased pulmonary blood flow during the control period but not after L-NA treatment. In contrast, L-NA had little effect on the vasodilator response to atrial natriuretic factor. To study the role of EDRF in the transition of the pulmonary circulation from fetal to neonatal conditions, we infused L-NA into the left pulmonary artery immediately before cesarean-section delivery. In comparison with control animals, the rise in pulmonary blood flow at 1 h after delivery was reduced in the L-NA-treated animals (331 +/- 28 in control vs. 185 +/- 16 ml/min in treated, P less than 0.001).
Objectives and background: To determine whether inhaled nitric oxide (iNO) therapy can attenuate the progression of lung disease in acute hypoxemic respiratory failure, we performed a multicenter, ...randomized, masked, controlled study of the effects of prolonged iNO therapy on oxygenation. We hypothesized that iNO therapy would improve oxygenation in an acute manner, slow the rate of decline in gas exchange, and decrease the number of patients who meet pre-established oxygenation failure criteria.
Study design: A total of 108 children (median age 2.5 years) with severe acute hypoxemic respiratory failure from 7 centers were enrolled. After consent was obtained, patients were randomized to treatment with iNO (10 ppm) or mechanical ventilation alone for at least 72 hours. Patients with an oxygenation index ≥40 for 3 hours or ≥25 for 6 hours were considered treatment failures and exited the study.
Results: Patient age, primary diagnosis, pediatric risk of mortality score, mode of ventilation, and median oxygenation index (35 ± 22 vs 30 ± 15; iNO vs control; mean ± SEM) were not different between groups at study entry. Comparisons of oxygenation indexes during the first 12 hours demonstrated an acute improvement in oxygenation in the iNO group at 4 hours (-10.2 vs -2.7, mean values;
P < .014) and at 12 hours (-9.2 vs -2.8;
P < .007). At 12 hours 36% of the control group met failure criteria in contrast with 16% in the iNO group (
P < .05). During prolonged therapy the failure rate was reduced in the iNO group in patients whose entry oxygenation index was ≥25 (
P < .04) and in immunocompromised patients (
P < .03).
Conclusions: We conclude that iNO causes an acute improvement in oxygenation in children with severe AHRF. Two subgroups (immunocompromised and an entry oxygen index ≥25) appear to have a more sustained improvement in oxygenation, and we speculate that these subgroups may benefit from prolonged therapy. (J Pediatr 1999;134:406-12)
To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old ...newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.
To determine the effects of inhaled NO (iNO) on pulmonary edema and lung inflammation in experimental hyaline membrane disease (HMD), we measured the effects of iNO on pulmonary hemodynamics, gas ...exchange, pulmonary edema, and lung myeloperoxidase (MPO) activity in extremely premature lambs (115 d of gestation, 0.78 term). In protocol 1, we measured the effects of iNO (20 ppm) on lung vascular endothelial permeability to 125I-labeled albumin (indexed to blood volume using 57Cr-tagged red blood cells) during 1 h (n = 10) and 3 h (n = 14) of conventional mechanical ventilation with FiO2 = 1.00. In comparison with controls, iNO improved pulmonary hemodynamics and gas exchange, but did not alter lung weight-to-dry weight ratio or vascular permeability to albumin after 1 or 3 h of mechanical ventilation. To determine whether low dose iNO (5 ppm) would decrease lung neutrophil accumulation in severe HMD, we measured lung MPO activity after 4 h of mechanical ventilation with or without iNO (protocol 2). Low dose iNO improved gas exchange during 4 h of mechanical ventilation (PaO2 at 4 h: 119 +/- 35 mm Hg iNO versus 41 +/- 7 mm Hg control, p < 0.05), and reduced MPO activity by 79% (p < 0.05). We conclude that low dose iNO increases pulmonary blood flow, without worsening pulmonary edema, and decreases lung neutrophil accumulation in severe experimental HMD. We speculate that in addition to its hemodynamic effects, low dose iNO decreases early neutrophil recruitment and may attenuate lung injury in severe HMD.
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