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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O2). Prolonged exposure to NO/O2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO +/- O2. Exposure to NO and O2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-kappaB activity. Cells lacking functional NF-kappaB p65 subunit were more sensitive to NO/O2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-kappaB and susceptibility to the cytotoxicity of NO/O2. Despite the reduced NF-kappaB activity in cells exposed to NO +/- O2, IkappaBalpha was degraded, suggesting that pathways regulating the steady-state levels of IkappaB were not involved. However, exposure to NO/O2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-kappaB p65 subunit. These results suggest that NO/O2-induced apoptosis occurs by suppressing NF-kappaB activity.
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PMID:Suppression of nuclear factor-kappa B activity by nitric oxide and hyperoxia in oxygen-resistant cells. 1221 28

Neonatal rats exposed to 60% O(2) for 14 days develop lung changes compatible with human bronchopulmonary dysplasia and pulmonary hypertension. Our aim was to evaluate and compare the newborn and adult rat pulmonary vascular and airway smooth muscle force generation and relaxation potential after exposure to 60% O(2) for 14 days. Vascular and airway intrapulmonary rings 100 microm in diameter were mounted on a myograph and bathed in Krebs-Henseleit solution bubbled with air- 6% CO(2) at 37 degrees C. Significant age-dependent changes in intrapulmonary arteries and their neighboring airway muscle properties were observed. Whereas hyperoxia enhanced force in neonatal vascular and airway muscle, the opposite was seen in adult samples. No changes in endothelium-dependent vascular relaxation were observed at either age, but the dose response to an endothelium-independent NO donor was altered. In the newborn experimental animals, the relaxation was reduced, whereas, in their adult counterparts, it was enhanced. After O(2) exposure, the bronchial muscle relaxation response to epithelium-dependent and -independent stimulation was not altered in either age group, whereas the epithelium-dependent response was decreased only in the adult. The antioxidant Trolox, or an endothelin-A and -B receptor antagonist, reversed the vascular and airway muscle's hyperoxia-induced changes. We conclude that chronic O(2) exposure in the newborn rat results in enhanced lung vascular and airway muscle contraction potential via a mechanism involving reactive oxygen species and the endothelin pathway. The present findings also suggest that the newborn is more susceptible to airway hyperresponsiveness after chronic O(2) exposure.
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PMID:Chronic O2 exposure enhances vascular and airway smooth muscle contraction in the newborn but not adult rat. 1256 76

Exogenous or inhaled NO (iNO) has been successfully used, as a selective pulmonary vasodilator, in a wide variety of clinical situations especially in the management of persistent pulmonary hypertension in the newborn. A better understanding of the role of endogenous and exogenous NO in the lungs of surfactant-deficient animals exposed to hyperoxia could result in novel strategies for the better management of RDS in premature babies with the ultimate aim to decrease chronic lung disease in these infants. This review will focus on the effects of NO, when used in combination with hyperoxia, on lung injury; information on the effects on cell culture systems and animal models will be used to highlight the unique responses of the developing lung. Most of the data from cell culture systems and adult animal models of hyperoxia-induced lung injury suggests that endogenous NO has a protective role. In the newborn animal, endogenous NO appeared to be harmful, had no effect or was protective in hyperoxia-induced lung injury. The data are conflicting on the issue of whether exogenous NO is protective or damaging in the presence of hyperoxia on lung cells and animal models. Despite the variability in the studies, it would appear that low dose exogenous NO for short duration is beneficial in hyperoxic lung injury in adult and newborn animals. In the human newborn, use of iNO in infants< 34 weeks of gestation should be considered experimental, pending results of ongoing trials.
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PMID:The role of nitric oxide in hyperoxia-induced injury to the developing lung. 1270 92

We used a prematurely born rat/hyperoxia model of bronchopulmonary dysplasia (BPD) to test whether keratinocyte growth factor (KGF) treatment would protect against the development of several serious (cardio-)pulmonary complications of early life exposure to hyperoxia. KGF significantly protected against hyperoxic lethality (13-day survival rate = 50/64 (78%) for the O(2)-KGF vs. 29/66 (44%) for the O(2)-saline group, p < 0.001). Although KGF failed to protect against hyperoxic inhibition of normal postnatal alveoli formation and early pulmonary fibrosis, KGF consistently had a significant protective/preventive effect against the development of pulmonary hypertension during hyperoxia as reflected in comparative right ventricular hypertrophy: mean increase = +35% above normal for the O(2)-saline group vs. +3% for the O(2)-KGF premature rat group (p < 0.01).
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PMID:Protective effect of keratinocyte growth factor against lung abnormalities associated with hyperoxia in prematurely born rats. 1274 56

During the fetal period, blood is oxygenated through the placenta, and most of the cardiac output bypasses the lung through the ductus arteriosus. At birth, pulmonary vascular resistance falls with the initiation of ventilation. Coincidentally, the ductus arteriosus constricts. Endothelin-1 (ET-1) appears to play an important role during that transition period and postnatally. ET-1 can dramatically increase resistance in the placental microcirculation and may be involved in blood flow redistribution with hypoxia. At birth, the increase in oxygen tension is important in triggering ductus vasoconstriction. It is proposed that oxygen triggers closure of the ductus arteriosus by activating a specific, cytochrome P450-linked reaction, which in turn stimulates the synthesis of ET-1. On the neonatal heart, ET-1 has a positive chronotropic but negative inotropic effect. In the newborn piglet and the fetal lamb, both term and preterm, ET-1 causes a potent, long-lasting pulmonary vasoconstriction. Furthermore, a transient dilator response has been identified, and it is ascribed to nitric oxide formation. ET receptors are abundant in the piglet pulmonary vasculature. They are predominantly of the ETA constrictor subtype, though ETB2 constrictor receptors may also be present in certain species. The dilator response is linked to the ETB1 receptor, and the number of ETB1 receptors is reduced in hypoxia-induced pulmonary hypertension. ET-1 appears to be a causative agent in the pathogenesis of hypoxia- and hyperoxia-induced pulmonary hypertension as demonstrated by reversal of hemodynamic and morphological changes with treatment with an ETA receptor antagonist. Findings are amenable to practical applications in the management of infants with pulmonary hypertension or requiring persistent patency of the ductus arteriosus.
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PMID:Endothelin in the perinatal circulation. 1283 75

Chronic oxygen exposure in the newborn rat results in lung isoprostane formation, which may contribute to the pulmonary hypertension evident in this animal model. The purpose of this study was to investigate the pulmonary arterial smooth muscle responses to 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2a)) in newborn rats exposed to 60% O2 for 14 days. Because, in the adult rat, 8-iso-PGF(2alpha) may have a relaxant effect, mediated by nitric oxide (NO), we also sought to evaluate the pulmonary arterial NO synthase (NOS) protein content and NO release in the newborn exposed to chronic hyperoxia. Compared with air-exposed control animals, 8-iso-PGF(2a) induced a significantly greater force (P < 0.01) and reduced (P < 0.01) relaxation of precontracted pulmonary arteries in the 60% O2-treated animals. These changes were reproduced in control pulmonary arteries by NOS blockade by using NG-nitro-L-arginine methyl ester. Pulmonary arterial endothelial NOS was unaltered, but the inducible NOS protein content was significantly decreased (P < 0.01) in the experimental group. Pulmonary (P < 0.05) and aortic (P < 0.01) tissue ex vivo NO accumulation was significantly reduced in the 60% O2-treated animals. We speculate that impaired pulmonary vascular tissue NO metabolism after chronic O2 exposure potentiates 8-iso-PGF(2alpha)-induced vasoconstriction in the newborn rat, thus contributing to pulmonary hypertension.
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PMID:Chronic O2 exposure in the newborn rat results in decreased pulmonary arterial nitric oxide release and altered smooth muscle response to isoprostane. 1456 64

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.
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PMID:Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. 1518 2

We hypothesized that inhaled nitric oxide (iNO), a selective vasodilator for pulmonary hypertension, may exacerbate hyperoxia-related lung inflammatory injury by alteration of phosphatidylcholine (PC) synthesis in mature lungs. Healthy adult rats were allocated to 4 groups and exposed to: 95% oxygen, or 20ppm iNO, or both (ONO), or room air, all for 48h. (3)H-choline chloride was injected i.v. at 10min, 8, 16, and 24h prior to the end of 48h exposure and the animal lungs were processed. In oxygen group, oxidative damage and inflammation were significantly induced compared to the room air group. In ONO group there were significantly elevated glutathione, attenuated malondialdehyde, myeloperoxidase, and wet-to-dry lung weight ratio in lung parenchyma, decreased white cell counts and vascular-to-alveolar leakage of albumin in bronchoalveolar lavage fluid. In both oxygen and ONO groups both total phospholipids and surfactant protein-A were significantly increased compared with the room air group. Newly synthesized (3)H-PC was low in the lungs of NO group but high over time in both oxygen and ONO groups. Morphologically, lung injury was mild in ONO, but moderate in both oxygen and NO groups. We conclude that iNO alleviated oxidative damage and inflammation, and reduced alveolar leakage in hyperoxic injury of the mature lungs. Hyperoxia enhanced production of surfactant, whereas iNO did not attenuate this effect.
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PMID:Inhaled nitric oxide attenuates hyperoxic and inflammatory injury without alteration of phosphatidylcholine synthesis in rat lungs. 1648 Sep 8

Studies have shown the importance of heart rate variability alterations as a marker of neurohumoral dysregulation and haemodynamic derangements in experimental heart failure. Other studies have also revealed the importance of enhanced sympathetic nerve traffic and chemoreflex dysregulation in patients with pulmonary hypertension. Furthermore, the lack of favorable effects of beta mimetic agents on long term survival in heart failure patients may implicate an absence of sympathoinhibition, possibly related to a sensitization of the peripheral chemoreceptors. Sympathetic hyperactivity is however reduced by cardiac resynchronisation therapy. Last, a comparison of sympathetic nerve traffic during normoxia and hyperoxia in heart transplant recipients, essential hypertensive patients and control subjects has revealed that transplantation does not normalize peripheral chemoreflex hyperactivity and hypersensitivity. This mechanism contributes to blood pressure elevation and exercise hyperpnea in cardiac transplant recipients.
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PMID:[Physiopathology of heart failure: experimental model and therapeutic effects]. 1728 2

The pulmonary vascular endothelial cell plays a crucial role in the regulation of the pulmonary vascular tone and in the maintenance of the barrier function and integrity of the alveolar-capillary membrane. It also plays a major role in coagulation, fibrinolysis, and angiogenesis and participates in inflammatory reactions. Vascular endothelial growth factor (VEGF) is a central growth and survival factor for the endothelial cell. Particularly high levels of VEGF are expressed in the lungs, reflecting the critical role of VEGF for lung development and structural integrity of the adult lung. Vascular endothelial growth factor exerts a variety of physiological and pathophysiological actions in the lung. Recent evidence suggests its involvement in the pathogenesis of lung diseases such as bronchopulmonary dysplasia, acute lung injury, emphysema, and pulmonary hypertension. To summarize the critical effects of VEGF on the pulmonary endothelial cell in the pathogenesis of these diseases, the purposes of this review are to (1) discuss the biological activities and intracellular signaling pathways of VEGF in the lung; (2) summarize the regulatory mechanisms involved in VEGF expression; (3)address the effects of VEGF on endothelial cells in hyperoxia-induced and other forms of lung injury; (4) highlight the endothelial effects of VEGF in the pathogenesis of emphysema; and (5) explore the role of VEGF in the pathogenesis of pulmonary arterial hypertension.
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PMID:The critical role of vascular endothelial growth factor in pulmonary vascular remodeling after lung injury. 1751 May 98


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