Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness.
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PMID:Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway. 2495 74

Supplemental oxygen after premature birth results in aberrant airway, alveolar, and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia, and development of wheeze and asthma, pulmonary hypertension, and chronic obstructive pulmonary disease in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway has significant beneficial effects on disease development in animal models, so far this could not be translated to the clinic. Oxidative stress reduces the NO-sGC-cGMP pathway by oxidizing heme-bound sGC, resulting in inactivation or degradation of sGC. Reduced sGC activity and/or expression is associated with pathology due to premature birth, oxidative stress-induced lung injury, including impaired alveolar maturation, smooth muscle cell (SMC) proliferation and contraction, impaired airway relaxation and vasodilation, inflammation, pulmonary hypertension, right ventricular hypertrophy, and an aggravated response toward hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca(2+) responses were significantly elevated in hyperoxia-exposed fetal human airway SMCs compared with normoxic controls and that this hyperoxia-induced increase in the response was strongly reduced by NO-independent stimulation and activation of sGC. These recent studies highlight the therapeutic potential of sGC modulators in the treatment of preterm infants for respiratory distress with supplemental oxygen. Such treatment is aimed at improving aberrant alveolar and vascular development of the neonatal lung and preventing the development of wheezing and asthma in survivors of premature birth. In addition, these studies highlight the suitability of fetal human airway SMCs as a translational model for pathological airway changes in the neonate.
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PMID:Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease. 2643 73

Although it is necessary and part of standard practice, supplemental oxygen (40-90% O2) or hyperoxia is a significant contributing factor to development of bronchopulmonary dysplasia, persistent pulmonary hypertension, recurrent wheezing, and asthma in preterm infants. This chapter discusses hyperoxia and the role of redox signaling in the context of neonatal lung growth and disease. Here, we discuss how hyperoxia promotes dysfunction in the airway and the known redox-mediated mechanisms that are important for postnatal vascular and alveolar development. Whether in the airway or alveoli, redox pathways are important and greatly influence the neonatal lung.
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PMID:Effects of Hyperoxia on the Developing Airway and Pulmonary Vasculature. 2904 87

Longer term respiratory morbidity is a frequent concern for former preterm infants. Increased airway reactivity and wheezing disorders are extremely common in this population, both in infants who meet diagnostic criteria for bronchopulmonary dysplasia [BPD], and in the absence of this diagnosis. It is, therefore, imperative to gain a better understanding of normal and abnormal postnatal development of the immature airway. Airway hyperreactivity may be secondary to abnormal bronchoalveolar attachments in the face of parenchymal lung injury, or secondary to an imbalance between constrictor and dilator neural pathways. Finally, the airway itself may undergo functional and/or structural changes, including increased airway smooth muscle mass, and changes in airway extracellular matrix which may, in turn, modulate downstream signaling pathways to hyperoxia or pressure exposed vulnerable airways.
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PMID:Vulnerability of the developing airway. 3138 14

Hyperoxia (HO)-induced lung injury contributes to bronchopulmonary dysplasia (BPD) in preterm newborns. Intractable wheezing seen in BPD survivors is associated with airway remodeling (AWRM). Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling promotes HO-mediated neonatal BPD; however, its role in the sequela of AWRM is not known. We noted an increased concentration of S1P in tracheal aspirates of neonatal infants with severe BPD, and earlier, demonstrated that Sphk1-/- mice showed protection against HO-induced BPD. The role of SPHK1/S1P in promoting AWRM following exposure of neonates to HO was investigated in a murine model. Therapy using PF543, the specific SPHK1 inhibitor, during neonatal HO reduced alveolar simplification followed by reduced AWRM in adult mice. This was associated with reduced airway hyperreactivity to intravenous methacholine. Neonatal HO exposure was associated with increased expression of SPHK1 in lung tissue of adult mice, which was reduced with PF543 therapy in the neonatal stage. This was accompanied by amelioration of HO-induced reduction of E-cadherin in airway epithelium. This may be suggestive of arrested partial epithelial mesenchymal transition (EMT) induced by HO. In vitro studies using human primary airway epithelial cells (HAEpCs) showed that SPHK1 inhibition or deletion restored HO-induced reduction in E-cadherin and reduced formation of mitochondrial reactive oxygen species (mtROS). Blocking mtROS with MitoTempo attenuated HO-induced partial EMT of HAEpCs. These results collectively support a therapeutic role for PF543 in preventing HO-induced BPD in neonates and the long-term sequela of AWRM, thus conferring a long-term protection resulting in improved lung development and function.
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PMID:Neonatal therapy with PF543, a sphingosine kinase 1 inhibitor, ameliorates hyperoxia-induced airway remodeling in a murine model of bronchopulmonary dysplasia. 3269 51