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1
D'Angio, Carl T., and Rita M. Ryan. "Animal models of bronchopulmonary dysplasia. The preterm and term rabbit models." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 12 (December 15, 2014): L959—L969. http://dx.doi.org/10.1152/ajplung.00228.2014.
Повний текст джерелаАнотація:
Bronchopulmonary dysplasia (BPD) is an important lung developmental pathophysiology that affects many premature infants each year. Newborn animal models employing both premature and term animals have been used over the years to study various components of BPD. This review describes some of the neonatal rabbit studies that have contributed to the understanding of BPD, including those using term newborn hyperoxia exposure models, premature hyperoxia models, and a term newborn hyperoxia model with recovery in moderate hyperoxia, all designed to emulate aspects of BPD in human infants. Some investigators perturbed these models to include exposure to neonatal infection/inflammation or postnatal malnutrition. The similarities to lung injury in human premature infants include an acute inflammatory response with the production of cytokines, chemokines, and growth factors that have been implicated in human disease, abnormal pulmonary function, disordered lung architecture, and alveolar simplification, development of fibrosis, and abnormal vascular growth factor expression. Neonatal rabbit models have the drawback of limited access to reagents as well as the lack of readily available transgenic models but, unlike smaller rodent models, are able to be manipulated easily and are significantly less expensive than larger animal models.
2
Mühlfeld, Christian, Henri Schulte, Johanna Christine Jansing, Costanza Casiraghi, Francesca Ricci, Chiara Catozzi, Matthias Ochs, Fabrizio Salomone, and Christina Brandenberger. "Design-Based Stereology of the Lung in the Hyperoxic Preterm Rabbit Model of Bronchopulmonary Dysplasia." Oxidative Medicine and Cellular Longevity 2021 (October 6, 2021): 1–12. http://dx.doi.org/10.1155/2021/4293279.
Повний текст джерелаАнотація:
Bronchopulmonary dysplasia (BPD) is a complex condition frequently occurring in preterm newborns, and different animal models are currently used to mimic the pathophysiology of BPD. The comparability of animal models depends on the availability of quantitative data obtained by minimally biased methods. Therefore, the aim of this study was to provide the first design-based stereological analysis of the lungs in the hyperoxia-based model of BPD in the preterm rabbit. Rabbit pups were obtained on gestation day 28 (three days before term) by cesarean section and exposed to normoxic (21% O2, n = 8 ) or hyperoxic (95% O2, n = 8 ) conditions. After seven days of exposure, lung function testing was performed, and lungs were taken for stereological analysis. In addition, the ratio between pulmonary arterial acceleration and ejection time (PAAT/PAET) was measured. Inspiratory capacity and static compliance were reduced whereas tissue elastance and resistance were increased in hyperoxic animals compared with normoxic controls. Hyperoxic animals showed signs of pulmonary hypertension indicated by the decreased PAAT/PAET ratio. In hyperoxic animals, the number of alveoli and the alveolar surface area were reduced by one-third or by approximately 50% of control values, respectively. However, neither the mean linear intercept length nor the mean alveolar volume was significantly different between both groups. Hyperoxic pups had thickened alveolar septa and intra-alveolar accumulation of edema fluid and inflammatory cells. Nonparenchymal blood vessels had thickened walls, enlarged perivascular space, and smaller lumen in hyperoxic rabbits in comparison with normoxic ones. In conclusion, the findings are in line with the pathological features of human BPD. The stereological data may serve as a reference to compare this model with BPD models in other species or future therapeutic interventions.
3
Dean, Jay B., Daniel K. Mulkey, Richard A. Henderson, Stephanie J. Potter, and Robert W. Putnam. "Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons." Journal of Applied Physiology 96, no. 2 (February 2004): 784–91. http://dx.doi.org/10.1152/japplphysiol.00892.2003.
Повний текст джерелаАнотація:
Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O2 receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O2 and reactive O2 species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O2 and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O2 has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO2 chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O2 and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed.
4
George, Caroline L. S., Giamila Fantuzzi, Stuart Bursten, Laura Leer, and Edward Abraham. "Effects of lisofylline on hyperoxia-induced lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 5 (May 1, 1999): L776—L785. http://dx.doi.org/10.1152/ajplung.1999.276.5.l776.
Повний текст джерелаАнотація:
Lisofylline [1-(5 R-hydroxyhexyl)-3,7-dimethylxanthine] decreases lipid peroxidation in vitro and in vivo suppresses proinflammatory cytokine expression in models of lung injury due to sepsis, blood loss, and oxidative damage. In the present experiments, we used a murine hyperoxia model to examine the effects of lisofylline on the activation of nuclear transcriptional regulatory factors [nuclear factor-κB and cAMP response element binding protein (CREB)], the expression of proinflammatory cytokines in the lungs, and the circulating levels of oxidized free fatty acids as well as on hyperoxia-induced lung injury and mortality. Treatment with lisofylline inhibited hyperoxia-associated increases in tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the lungs as well as decreased the levels of hyperoxia-induced serum-oxidized free fatty acids. Although hyperoxic exposure produced activation of both nuclear factor-κB and CREB in lung cell populations, only CREB activation was reduced in the mice treated with lisofylline. Lisofylline diminished hyperoxia-associated increases in lung wet-to-dry weight ratios and improved survival in animals exposed to hyperoxia. These results suggest that lisofylline ameliorates hyperoxia-induced lung injury and mortality through inhibiting CREB activation, membrane oxidation, and proinflammatory cytokine expression in the lungs.
5
Chen, Yin, Dong Wei, Jin Zhao, Xiangnan Xu, and Jingyu Chen. "Reduction of hyperoxic acute lung injury in mice by Formononetin." PLOS ONE 16, no. 1 (January 7, 2021): e0245050. http://dx.doi.org/10.1371/journal.pone.0245050.
Повний текст джерелаАнотація:
Background The antioxidant and anti-inflammatory features of Formononetin, an isoflavone constituent extracted from traditional Chinese medicine, have been reported. The present study investigated that whether Formononetin plays a benefit on hyperoxic ALI. Methods C57BL/6 mice were exposed to hyperoxia for 72 h to produce experimental hyperoxic ALI model. Formononetin or vehicle was administrated intraperitoneally. Samples from the lung were collected at 72 h post hyperoxia exposure for further study. Pulmonary microvascular endothelial cells isolated from the lung of C57BL/6 mice were used for in vitro study. Results Formononetin pretreatment notably attenuated hyperoxia-induced elevating pulmonary water content, upregulation of proinflammatory cytokine levels and increasing infiltration of neutrophil in the lung. Western blot analyses showed that Formononetin enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) which is a key transcription factor regulating the expression of heme oxygenase-1 (HO-1). Formononetin increased HO-1 expression and activity compared with vehicle-treated animals. Moreover, Formononetin reversed hyperoxia-caused the reduction of M2 macrophage polarization. However, pretreatment of a HO-1 inhibitor reduced the protective effect of Formononetin on hyperoxic ALI. Cell study showed that the Formononetin-induced upregulation of HO-1 was abolished when the Nrf2 was silenced. Conclusions Formononetin pretreatment reduces hyperoxia-induced ALI via Nrf2/HO-1-mediated antioxidant and anti-inflammatory effects.
6
Cheon, In Su, Youngmin Son, and Jie Sun. "An animal model of enhanced disease development following respiratory viral infection in children with chronic lung diseases." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 93.10. http://dx.doi.org/10.4049/jimmunol.204.supp.93.10.
Повний текст джерелаАнотація:
Abstract Infants born prematurely often develop chronic lung diseases including bronchopulmonary dysplasia (BPD). BPD is associated with greatly increased host susceptibility and severe disease development following respiratory viral infection. To this end, we have recently established a neonatal hyperoxia model respiratory viral infection in hosts with lung prematurity and BPD. Using this model, we observed that mice exposed with neonatal hyperoxia (80% oxygen, BPD hosts) developed enhanced diseases following influenza virus or respiratory syncytial virus (RSV) infection compared to those of influenza or RSV-infected control mice. We showed that neonatal hyperoxia leaded to modestly enhanced viral replication in the respiratory tract. Using nanostring immune gene profiling and multiplex cytokine analysis, we found that neonatal hyperoxia markedly enhanced immune-associated gene expression and the production of a number of proinflammatory cytokines and chemokines in the airway compared to those of control mice. Neonatal hyperoxia also increased the accumulation of multiple inflammatory innate cell types that were shown to be pathogenic during respiratory viral infections. Importantly, antiviral T, B cells and NK cells were similar in the lungs between infected neonatal hyperoxia-exposed and control mice, which are consistent with the similar viral clearance kinetics in those mice. Thus, we have successfully established a clinically-relevant mouse model of respiratory viral infection in BPD hosts. We expect to further uncover novel insights on the viral pathogenesis and host disease devlopment in this novel model of respiratory viral infection in hosts with chronic lung diseases.
7
Mowes, Anja, Beatriz E. de Jongh, Timothy Cox, Yan Zhu, and Thomas H. Shaffer. "A translational cellular model to study the impact of high-frequency oscillatory ventilation on human epithelial cell function." Journal of Applied Physiology 122, no. 1 (January 1, 2017): 198–205. http://dx.doi.org/10.1152/japplphysiol.00400.2016.
Повний текст джерелаАнотація:
High-frequency oscillatory ventilation (HFOV) has been proposed as gentle ventilation strategy to prevent lung injury in the preterm infant. High-frequency jet ventilation leads to dimensional and mechanical airway deformation in animal airway models, which is consistent with translational studies demonstrating the impact of oxygen and biophysical stresses on normal airway cellular function. There is an overall paucity of clinical and cellular data on the impact of HFOV on the conducting airway. We developed an innovative method to test the impact of the clinical HFO Ventilator (SensorMedics 3100A) on human epithelial cell function. In this translational model, we were able to study the differential effects of biophysical stress due to HFOV independently and in combination with hyperoxia on a direct cellular level of the conducting airway system. Additionally, we could demonstrate that hyperoxia and pressure by HFOV independently resulted in significant cell dysfunction and inflammation, while the combination of HFOV and hyperoxia had a synergistic effect, resulting in greater cell death. NEW & NOTEWORTHY Traditionally, large-animal models are used to analyze the impact of clinical ventilators on lung cellular function. In our dual-chamber model, we interface high-frequency oscillatory ventilation (HFOV) directly with airway cells to study the effects of HFOV independently and combined with hyperoxia. Therefore, it is possible to study the preclinical impact of interventional factors without the high cost of animal models, thus reducing staff, time, as well as animal sparing.
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Porzionato, Andrea, Patrizia Zaramella, Arben Dedja, Diego Guidolin, Kelly Van Wemmel, Veronica Macchi, Marcin Jurga, et al. "Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L6—L19. http://dx.doi.org/10.1152/ajplung.00109.2018.
Повний текст джерелаАнотація:
Mesenchymal stem cells (MSCs) prevent the onset of bronchopulmonary dysplasia (BPD) in animal models, an effect that seems to be mediated by their secreted extracellular vesicles (EVs). The aim of this study was to compare the protective effects of intratracheally (IT) administered MSCs versus MSC-EVs in a hyperoxia-induced rat model of BPD. At birth, rats were distributed as follows: animals raised in ambient air for 2 wk ( n = 10), and animals exposed to 60% oxygen for 2 wk and treated with IT-administered physiological solution ( n = 10), MSCs ( n = 10), or MSC-EVs ( n = 10) on postnatal days 3, 7, and 10. The sham-treated hyperoxia-exposed animals showed reductions in total surface area of alveolar air spaces, and total number of alveoli ( Nalv), and an increased mean alveolar volume (Valv). EVs prompted a significant increase in Nalv ( P < 0.01) and a significant decrease in Valv ( P < 0.05) compared with sham-treated animals, whereas MSCs only significantly improved Nalv ( P < 0.05). Small pulmonary vessels of the sham-treated hyperoxia-exposed rats also showed an increase in medial thickness, which only EVs succeeded in preventing significantly ( P < 0.05). In conclusion, both EVs and MSCs reduce hyperoxia-induced damage, with EVs obtaining better results in terms of alveolarization and lung vascularization parameters. This suggests that IT-administered EVs could be an effective approach to BPD treatment.
9
Berger, Jessica, and Vineet Bhandari. "Animal models of bronchopulmonary dysplasia. The term mouse models." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 12 (December 15, 2014): L936—L947. http://dx.doi.org/10.1152/ajplung.00159.2014.
Повний текст джерелаАнотація:
The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante- and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation-induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD.
10
Datta, Ankur, Gina A. Kim, Joann M. Taylor, Sylvia F. Gugino, Kathryn N. Farrow, Paul T. Schumacker, and Sara K. Berkelhamer. "Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 4 (August 15, 2015): L369—L377. http://dx.doi.org/10.1152/ajplung.00176.2014.
Повний текст джерелаАнотація:
Animal models demonstrate that exposure to supraphysiological oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in hyperoxia. We hypothesize that consequences of hyperoxia may also be developmentally regulated and mitochondrial reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of hyperoxia, neonatal mice were placed in 75% oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), during early postnatal hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of hyperoxia are developmentally regulated and decrease with age. Attenuated disease in mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted antioxidant therapy in the prevention or treatment of BPD.
11
Sopi, Ramadan B., Musa A. Haxhiu, Richard J. Martin, Ismail A. Dreshaj, Suneel Kamath, and Syed I. A. Zaidi. "Disruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchyma." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 4 (October 2007): L1029—L1036. http://dx.doi.org/10.1152/ajplung.00182.2007.
Повний текст джерелаАнотація:
Exposure of immature lungs to hyperoxia for prolonged periods contributes to neonatal lung injury and airway hyperreactivity. We studied the role of disrupted nitric oxide-guanosine 3′,5′-cyclic monophosphate (NO-cGMP) signaling in impairing the relaxant responses of lung tissue from hyperoxia-exposed rat pups. Pups were exposed to ≥95% O2 or room air for 7 days starting from days 1, 5, or 14. The animals were killed, lungs were removed, and 1-mm-thick lung parenchymal strips were prepared. Lung parenchymal strips of room air or hyperoxic pups were preconstricted using bethanechol and then graded electrical field stimulation (EFS) was applied to induce relaxation. EFS-induced relaxation of lung parenchymal strips was greater at 7 and 12 days than at 21 days in room air-exposed rat pups. Hyperoxic exposure significantly reduced relaxation at 7 and 12 days but not 21 days compared with room air exposure. NO synthase blockade with Nω-nitro-l-arginine methyl ester diminished relaxant responses in room air but not in hyperoxic pups at 12 days. After incubation with supplemental l-arginine, the relaxation response of hyperoxic strips was restored. cGMP, a key mediator of the NO signaling pathway, also decreased in strips from hyperoxic vs. room air pups and cGMP levels were restored after incubation with supplemental l-arginine. In addition, arginase activity was significantly increased in hyperoxic lung parenchymal strips compared with room air lung parenchymal strips. These data demonstrate disruption of NO-cGMP signaling in neonatal rat pups exposed to hyperoxia and show that bioavailability of the substrate l-arginine is implicated in the predisposition of this model to airway hyperreactivity.
12
Bigdeli, Mohammad Reza. "Neuroprotection Caused by Hyperoxia Preconditioning in Animal Stroke Models." Scientific World JOURNAL 11 (2011): 403–21. http://dx.doi.org/10.1100/tsw.2011.23.
Повний текст джерелаАнотація:
Ischemic tolerance induced by hyperoxia (HO) can protect against brain injury and neurodegenerative diseases. Although multiple studies demonstrate neuroprotection by HO, the exact mechanism(s) of HO neuroprotection has not been elucidated. Here, I first review related mechanisms of brain ischemia and then data evaluating the neuroprotective effects of HO in focal and global ischemic animal models. I clearly establish that the cerebrovascular, extracellular matrix, plasma membrane, endoplasmic reticulum, mitochondrial, and lysosomal reactions are critical in neuroprotection induced by HO in focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke. Neuroprotection induced by HO exhibits specific adaptation responses that involve a number of cellular and biochemical alterations, including metabolic homeostasis and reprogramming of gene expression. The changes in the metabolic pathways are generally short lived and reversible, while the consequences of gene expression are a long-term process and may lead to the permanent alteration in the pattern of gene expression. The neuroprotection provided by HO may have important clinical implications. Therefore, it is important to assess the benefits and risks of HO therapy in noninfarcted tissue.
13
Dudley, R. "Atmospheric oxygen, giant Paleozoic insects and the evolution of aerial locomotor performance." Journal of Experimental Biology 201, no. 8 (April 1, 1998): 1043–50. http://dx.doi.org/10.1242/jeb.201.8.1043.
Повний текст джерелаАнотація:
Uniformitarian approaches to the evolution of terrestrial locomotor physiology and animal flight performance have generally presupposed the constancy of atmospheric composition. Recent geophysical data as well as theoretical models suggest that, to the contrary, both oxygen and carbon dioxide concentrations have changed dramatically during defining periods of metazoan evolution. Hyperoxia in the late Paleozoic atmosphere may have physiologically enhanced the initial evolution of tetrapod locomotor energetics; a concurrently hyperdense atmosphere would have augmented aerodynamic force production in early flying insects. Multiple historical origins of vertebrate flight also correlate temporally with geological periods of increased oxygen concentration and atmospheric density. Arthropod as well as amphibian gigantism appear to have been facilitated by a hyperoxic Carboniferous atmosphere and were subsequently eliminated by a late Permian transition to hypoxia. For extant organisms, the transient, chronic and ontogenetic effects of exposure to hyperoxic gas mixtures are poorly understood relative to contemporary understanding of the physiology of oxygen deprivation. Experimentally, the biomechanical and physiological effects of hyperoxia on animal flight performance can be decoupled through the use of gas mixtures that vary in density and oxygen concentration. Such manipulations permit both paleophysiological simulation of ancestral locomotor performance and an analysis of maximal flight capacity in extant forms.
14
Tiboldi, Akos, Eva Hunyadi-Gulyas, Peter Wohlrab, Johannes A. Schmid, Klaus Markstaller, Klaus Ulrich Klein, and Verena Tretter. "Effects of Hyperoxia and Hyperoxic Oscillations on the Proteome of Murine Lung Microvascular Endothelium." Antioxidants 11, no. 12 (November 28, 2022): 2349. http://dx.doi.org/10.3390/antiox11122349.
Повний текст джерелаАнотація:
Patients presenting with insufficient tissue oxygenation and impaired lung function as in acute respiratory distress syndrome (ARDS) frequently require mechanical ventilation with supplemental oxygen. Despite the lung being used to experiencing the highest partial pressure of oxygen during healthy breathing, the organ is susceptible to oxygen-induced injury at supraphysiological concentrations. Hyperoxia-induced lung injury (HALI) has been regarded as a second hit to pre-existing lung injury and ventilator-induced lung injury (VILI) attributed to oxidative stress. The injured lung has a tendency to form atelectasis, a cyclic collapse and reopening of alveoli. The affected lung areas experience oxygen conditions that oscillate between hyperoxia and hypoxia rather than remaining in a constant hyperoxic state. Mechanisms of HALI have been investigated in many animal models previously. These studies provided insights into the effects of hyperoxia on the whole organism. However, cell type-specific responses have not been dissected in detail, but are necessary for a complete mechanistic understanding of ongoing pathological processes. In our study, we investigated the effects of constant and intermittent hyperoxia on the lung endothelium from a mouse by an in vitro proteomic approach. We demonstrate that these oxygen conditions have characteristic effects on the pulmonary endothelial proteome that underlie the physiological (patho)mechanisms.
15
Goss, Kara N., Anthony R. Cucci, Amanda J. Fisher, Marjorie Albrecht, Andrea Frump, Roziya Tursunova, Yong Gao, et al. "Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 8 (April 15, 2015): L797—L806. http://dx.doi.org/10.1152/ajplung.00276.2014.
Повний текст джерелаАнотація:
The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0–4 or 0–10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.
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García-Laorden, M. Isabel, Raquel Rodríguez-González, José L. Martín-Barrasa, Sonia García-Hernández, Ángela Ramos-Nuez, H. Celeste González-García, Jesús M. González-Martín, Robert M. Kacmarek, and Jesús Villar. "Systemic Effects Induced by Hyperoxia in a Preclinical Model of Intra-abdominal Sepsis." Mediators of Inflammation 2020 (October 15, 2020): 1–9. http://dx.doi.org/10.1155/2020/5101834.
Повний текст джерелаАнотація:
Supplemental oxygen is a supportive treatment in patients with sepsis to balance tissue oxygen delivery and demand in the tissues. However, hyperoxia may induce some pathological effects. We sought to assess organ damage associated with hyperoxia and its correlation with the production of reactive oxygen species (ROS) in a preclinical model of intra-abdominal sepsis. For this purpose, sepsis was induced in male, Sprague-Dawley rats by cecal ligation and puncture (CLP). We randomly assigned experimental animals to three groups: control (healthy animals), septic (CLP), and sham-septic (surgical intervention without CLP). At 18 h after CLP, septic ( n = 39 ), sham-septic ( n = 16 ), and healthy ( n = 24 ) animals were placed within a sealed Plexiglas cage and randomly distributed into four groups for continuous treatment with 21%, 40%, 60%, or 100% oxygen for 24 h. At the end of the experimental period, we evaluated serum levels of cytokines, organ damage biomarkers, histological examination of brain and lung tissue, and ROS production in each surviving animal. We found that high oxygen concentrations increased IL-6 and biomarkers of organ damage levels in septic animals, although no relevant histopathological lung or brain damage was observed. Healthy rats had an increase in IL-6 and aspartate aminotransferase at high oxygen concentration. IL-6 levels, but not ROS levels, are correlated with markers of organ damage. In our study, the use of high oxygen concentrations in a clinically relevant model of intra-abdominal sepsis was associated with enhanced inflammation and organ damage. These findings were unrelated to ROS release into circulation. Hyperoxia could exacerbate sepsis-induced inflammation, and it could be by itself detrimental. Our study highlights the need of developing safer thresholds for oxygen therapy.
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Spence, T. H., S. G. Jenkinson, K. H. Johnson, J. F. Collins, and R. A. Lawrence. "Effects of bacterial endotoxin on protecting copper-deficient rats from hyperoxia." Journal of Applied Physiology 61, no. 3 (September 1, 1986): 982–87. http://dx.doi.org/10.1152/jappl.1986.61.3.982.
Повний текст джерелаАнотація:
The administration of very low doses of bacterial endotoxin protects rats during exposure to hyperoxia and is associated with the induction of lung antioxidant enzyme activities. Copper-deficient rats have increased susceptibility to O2 toxicity, which may be related to their decreased lung superoxide dismutase activity (SOD) or decreased plasma ceruloplasmin concentrations. To determine whether endotoxin can protect against hyperoxia in this susceptible model, we exposed copper-deficient and control rats to a fractional inspiratory concentration of O2 greater than 0.95 for 96 h after pretreatment with 500 micrograms/kg of bacterial endotoxin or phosphate-buffered saline (PBS). Mortality in the copper-deficient and control rats given PBS and exposed to O2 for 96 h was 100%. Copper-deficient rats died significantly earlier during the exposure than controls. No mortality occurred in either group treated with endotoxin and hyperoxia despite the decreased activity of copper-dependent enzymes in the copper-deficient rats. Copper-deficient rats treated with endotoxin and exposed to hyperoxia did increase lung Cu-Zn-SOD activity, but activity remained below levels found in air-exposed controls. Mn-SOD activity was found to be induced above air-exposed controls in the copper-deficient rats treated with endotoxin and exposed to hyperoxia. Hyperoxic exposure resulted in a marked increase in plasma ceruloplasmin concentrations in the control rats, but no increases in ceruloplasmin occurred in the copper-deficient animals. Endotoxin protects copper-deficient rats from hyperoxia despite their decreased lung Cu-Zn-SOD activity, and decreased plasma ceruloplasmin.
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Morton, Ronald L., David Iklé, and Carl W. White. "Loss of lung mitochondrial aconitase activity due to hyperoxia in bronchopulmonary dysplasia in primates." American Journal of Physiology-Lung Cellular and Molecular Physiology 274, no. 1 (January 1, 1998): L127—L133. http://dx.doi.org/10.1152/ajplung.1998.274.1.l127.
Повний текст джерелаАнотація:
The premature primate exposed to hyperoxia provides a useful model of bronchopulmonary dysplasia. A critical target in hyperoxic injury is the mitochondrial matrix enzyme aconitase. We hypothesized that this enzyme’s activity would decline in the premature baboon lung during exposure to hyperoxia. Total aconitase activity was significantly decreased in the lungs of premature baboons of 140 days gestation with exposure to 100% oxygen for 6–10 days compared with as needed [pro re nada (PRN)] oxygen exposure and fetal controls ( P = 0.0001). In activity gels, lungs from 100% oxygen-exposed animals (6–10 days) showed a nearly complete loss of mitochondrial aconitase activity relative to lungs from animals exposed only to PRN oxygen. Decreased lung aconitase activity was not a nonspecific effect of hyperoxia, causing mitochondrial damage or loss, because the activity of the mitochondrial respiratory enzyme cytochrome oxidase was not different in lungs of 100% oxygen-exposed relative to PRN oxygen-exposed newborns. In 125-day-gestation premature primates (age 6–10 days), lung total aconitase activity was correlated with inspired oxygen tension ( r = 0.73 for fraction of inspired oxygen > 0.35), whereas, for animals of 140 days gestation, no such correlation was found. Thus the more premature animal’s lung was more susceptible to loss of aconitase.
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Vogel, Elizabeth R., Logan J. Manlove, Ine Kuipers, Michael A. Thompson, Yun-Hua Fang, Michelle R. Freeman, Rodney D. Britt, et al. "Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 317, no. 1 (July 1, 2019): L99—L108. http://dx.doi.org/10.1152/ajplung.00111.2018.
Повний текст джерелаАнотація:
Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.
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Pattappa, Girish, Jonas Krueckel, Ruth Schewior, Dustin Franke, Alexander Mench, Matthias Koch, Johannes Weber, et al. "Physioxia Expanded Bone Marrow Derived Mesenchymal Stem Cells Have Improved Cartilage Repair in an Early Osteoarthritic Focal Defect Model." Biology 9, no. 8 (August 17, 2020): 230. http://dx.doi.org/10.3390/biology9080230.
Повний текст джерелаАнотація:
Focal early osteoarthritis (OA) or degenerative lesions account for 60% of treated cartilage defects each year. The current cell-based regenerative treatments have an increased failure rate for treating degenerative lesions compared to traumatic defects. Mesenchymal stem cells (MSCs) are an alternative cell source for treating early OA defects, due to their greater chondrogenic potential, compared to early OA chondrocytes. Low oxygen tension or physioxia has been shown to enhance MSC chondrogenic matrix content and could improve functional outcomes of regenerative therapies. The present investigation sought to develop a focal early OA animal model to evaluate cartilage regeneration and hypothesized that physioxic MSCs improve in vivo cartilage repair in both, post-trauma and focal early OA defects. Using a rabbit model, a focal defect was created, that developed signs of focal early OA after six weeks. MSCs cultured under physioxia had significantly enhanced in vitro MSC chondrogenic GAG content under hyperoxia with or without the presence of interleukin-1β (IL-1β). In both post-traumatic and focal early OA defect models, physioxic MSC treatment demonstrated a significant improvement in cartilage repair score, compared to hyperoxic MSCs and respective control defects. Future investigations will seek to understand whether these results are replicated in large animal models and the underlying mechanisms involved in in vivo cartilage regeneration.
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Loi, Barbara, Costanza Casiraghi, Chiara Catozzi, Matteo Storti, Monica Lucattelli, Barbara Bartalesi, Nadya Yousef, Fabrizio Salomone, and Daniele De Luca. "Lung ultrasound features and relationships with respiratory mechanics of evolving BPD in preterm rabbits and human neonates." Journal of Applied Physiology 131, no. 3 (September 1, 2021): 895–904. http://dx.doi.org/10.1152/japplphysiol.00300.2021.
Повний текст джерелаАнотація:
We have reported that hyperoxia-exposed preterm rabbits and human preterm neonates with evolving BPD have the same lung ultrasound appearance, and that lung ultrasound can be fruitfully applied on this model with a brief training. The animal model and human neonates also presented the same relationship between semiquantitative ultrasound-assessed lung aeration and airway resistances. In conclusion, this animal model fairly reproduce evolving BPD as it is seen in clinical practice.
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Masood, Azhar, Man Yi, Mandy Lau, Rosetta Belcastro, Samuel Shek, Jingyi Pan, Crystal Kantores, et al. "Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 5 (November 2009): L920—L930. http://dx.doi.org/10.1152/ajplung.00139.2009.
Повний текст джерелаАнотація:
Permissive hypercapnia, achieved using low tidal volume ventilation, has been an effective protective strategy in patients with acute respiratory distress syndrome. To date, no such protective effect has been demonstrated for the chronic neonatal lung injury, bronchopulmonary dysplasia. The objective of our study was to determine whether evolving chronic neonatal lung injury, using a rat model, is resistant to the beneficial effects of hypercapnia or simply requires a less conservative approach to hypercapnia than that applied clinically to date. Neonatal rats inhaled air or 60% O2 for 14 days with or without 5.5% CO2. Lung parenchymal neutrophil and macrophage numbers were significantly increased by hyperoxia alone, which was associated with interstitial thickening and reduced secondary crest formation. The phagocyte influx, interstitial thickening, and impaired alveolar formation were significantly attenuated by concurrent hypercapnia. Hyperoxic pups that received 5.5% CO2 had a significant increase in alveolar number relative to air-exposed pups. Increased tyrosine nitration, a footprint for peroxynitrite-mediated reactions, arteriolar medial wall thickening, and both reduced small peripheral pulmonary vessel number and VEGF and angiopoietin-1 (Ang-1) expression, which were observed with hyperoxia, was attenuated by concurrent hypercapnia. We conclude that evolving chronic neonatal lung injury in a rat model is responsive to the beneficial effects of hypercapnia. Inhaled 5.5% CO2 provided a significant degree of protection against parenchymal and vascular injury in an animal model of chronic neonatal lung injury likely due, at least in part, to its inhibition of a phagocyte influx.
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Fujii, Yutaka. "Evaluation of Inflammation Caused by Cardiopulmonary Bypass in a Small Animal Model." Biology 9, no. 4 (April 20, 2020): 81. http://dx.doi.org/10.3390/biology9040081.
Повний текст джерелаАнотація:
Extracorporeal circulation (ECC) methods are being increasingly used for mechanical support of respiratory and cardio-circulatory failure. Especially, cardiopulmonary bypass (CPB) during cardiovascular surgery, sustenance of the patient’s life by providing an appropriate blood flow and oxygen supply to principal organs. On the other hand, systemic inflammatory responses in patients undergoing cardiovascular surgery supported by CPB contribute significantly to CPB-associated mortality and morbidity. Our previous research showed that CPB causes a systemic inflammatory response and organ damage in a small animal CPB model. We have been studying the effects of hyperoxia and blood plasma substitute on CPB. In this review, we present a study focusing on the systemic inflammatory response during CPB, along with our findings.
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Hainis, K. D., J. I. Sznajder, and D. E. Schraufnagel. "Lung lymphatics cast from the airspace." American Journal of Physiology-Lung Cellular and Molecular Physiology 267, no. 2 (August 1, 1994): L199—L205. http://dx.doi.org/10.1152/ajplung.1994.267.2.l199.
Повний текст джерелаАнотація:
Lymphatics are important in the resolution of pulmonary edema, but which lymphatics drain alveolar fluid and how they change during lung injury and edema is uncertain. To study this question 16 rats were exposed to 85% O2 for 7 days. At 0, 3, 7, and 14 days after removal from the hyperoxic chamber, the lungs of the rats were cast by instilling methyl methacrylate into the trachea. The lungs of four similar room-air breathing rats served as controls. Tissue was taken for light microscopy and the casts were examined for lymphatic filling with a scanning electron microscope. Rats exposed to hyperoxia had diffuse damage and extensive edema. On removal from hyperoxia (day 0), 29% of the rat bronchioles had saccular lymphatic casts around them and 6% of bronchioles were surrounded by these lymphatics. Twenty-five percent of bronchioles had conduit lymphatic casts. Fourteen percent of arteries had lymphatic casts around them. All were different from the rats kept in room air (P < 0.0001). Rats exposed to hyperoxia had lymphatics on the pleural surface, near alveoli and alveolar ducts, and around veins. The peribronchial and periarterial saccular lymphatics formed separate groups with communicating conduit lymphatics. The perivenous lymphatics had their own separate conduit lymphatics. Fourteen days after returning to ambient air, the lymphatics were similar to those of control animals. In this model, airway casting allows three-dimensional analysis of the lung lymphatics. It shows that lymphatic compartments expand during hyperoxic lung injury and that peribronchial and perivascular saccular lymphatics connect to conduit lymphatics of the bronchoalveolar bundle.
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Fracica, P. J., S. P. Caminiti, C. A. Piantadosi, F. G. Duhaylongsod, J. D. Crapo, and S. L. Young. "Natural surfactant and hyperoxic lung injury in primates. II. Morphometric analyses." Journal of Applied Physiology 76, no. 3 (March 1, 1994): 1002–10. http://dx.doi.org/10.1152/jappl.1994.76.3.1002.
Повний текст джерелаАнотація:
Diffuse lung injury is accompanied by low compliance and hypoxemia with histological evidence of endothelial and alveolar epithelial cell disruption. The histological effects of treatment of an acute diffuse lung injury with a natural surfactant product were evaluated in a primate model because surfactant function and content have been shown to be abnormal in diffuse lung injury in both animals and humans. Ten baboons were ventilated with 100% O2 for 96 h, and 5 were given an aerosol of natural porcine surfactant. Physiological and biochemical measurements of the effects of hyperoxia and surfactant treatment are presented in a companion paper. After O2 exposure, lungs were fixed and processed for quantitative electron microscopy. The responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. The hyperoxic animals treated with surfactant were compared with the untreated animals; the treatments altered neutrophil distribution, fibroblast proliferation, and changes in the volumes of type I epithelial cells and endothelial cells. Surfactant-treated animals also had decreased lamellar body volume density in type II epithelial cells and preservation of endothelial cell integrity. These changes suggest complex effects of natural surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction as well as significant interstitial inflammation and fibroblast proliferation. We conclude that natural surfactant treatment of hyperoxic lung injury in primates resulted in partial protection of epithelial and endothelial cells but also increased the accumulation of fibroblasts in the lung.
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Zhang, Duo, Heedoo Lee, Yong Cao, Charles S. Dela Cruz, and Yang Jin. "miR-185 mediates lung epithelial cell death after oxidative stress." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 7 (April 1, 2016): L700—L710. http://dx.doi.org/10.1152/ajplung.00392.2015.
Повний текст джерелаАнотація:
Lung epithelial cell death is a prominent feature involved in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Hyperoxia-induced ALI is an established animal model mimicking human ARDS. Small noncoding RNAs such as microRNAs (miRNAs) have potent physiological and pathological functions involving multiple disease processes. Emerging interests focus on the potential of miRNAs to serve as novel therapeutic targets and diagnostic biomarkers. We found that hyperoxia highly induces miR-185 and its precursor in human lung epithelial cells in a time-dependent manner, and this observation is confirmed using mouse primary lung epithelial cells. The hyperoxia-induced miR-185 is mediated by reactive oxygen species. Furthermore, histone deacetylase 4 (HDAC4) locates in the promoter region of miR-185. We found that hyperoxia suppresses HDAC4 specifically in a time-dependent manner and subsequently affects histone deacetylation, resulting in an elevated miR-185 transcription. Using MC1586, an inhibitor of class IIa HDACs, we showed that inhibition of class IIa HDACs upregulates the expression of miR-185, mimicking the effects of hyperoxia. Functionally, miR-185 promotes hyperoxia-induced lung epithelial cell death through inducing DNA damage. We confirmed functional roles of miR-185 using both the loss- and gain-of-function approaches. Moreover, multiple 14-3-3δ pathway proteins are highly attenuated by miR-185 in the presence of hyperoxia. Taken together, hyperoxia-induced miR-185 in lung epithelial cells contributes to oxidative stress-associated epithelial cell death through enhanced DNA damage and modulation of 14-3-3δ pathways.
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Simonson, Steven G., Karen E. Welty-Wolf, Yuh-Chin T. Huang, David E. Taylor, Stephen P. Kantrow, Martha S. Carraway, James D. Crapo, and Claude A. Piantadosi. "Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. I. Physiology and biochemistry." Journal of Applied Physiology 83, no. 2 (August 1, 1997): 550–58. http://dx.doi.org/10.1152/jappl.1997.83.2.550.
Повний текст джерелаАнотація:
Simonson, Steven G., Karen E. Welty-Wolf, Yuh-Chin T. Huang, David E. Taylor, Stephen P. Kantrow, Martha S. Carraway, James D. Crapo, and Claude A. Piantadosi. Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. I. Physiology and biochemistry. J. Appl. Physiol. 83(2): 550–558, 1997.—Prolonged hyperoxia causes lung injury and respiratory failure secondary to oxidative tissue damage mediated, in part, by the superoxide anion. We hypothesized that aerosol treatment with recombinant human manganese superoxide dismutase (rhMnSOD) would attenuate hyperoxic lung damage in primates. Adult baboons were anesthetized and ventilated with 100% oxygen for 96 h or until death. Six animals were treated with aerosolized rhMnSOD (3 mg ⋅ kg−1 ⋅ day−1in divided doses), and six control animals did not receive enzyme therapy. Physiological variables were recorded every 12 h, and ventilation-perfusion ratio relationships were evaluated by using the multiple inert-gas elimination technique. After the experiments, surfactant composition and lung edema were measured. We found that rhMnSOD significantly decreased pulmonary shunt fraction ( P < 0.01) and preserved arterial oxygenation ( P < 0.01) during hyperoxia. The rhMnSOD increased lung phospholipids, phosphatidylcholine and disaturated phosphatidylcholine, and decreased lung edema in this model. Testing of higher and lower doses of MnSOD (1 and 10 mg ⋅ kg−1 ⋅ day−1) in two other groups of baboons produced variable physiological protection, suggesting a “window” of effective dosage. We conclude that aerosolized MnSOD (3 mg ⋅ kg−1 ⋅ day−1) affords significant preservation of pulmonary gas exchange during hyperoxic lung injury.
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Lingappan, Krithika, Weiwu Jiang, Lihua Wang, and Bhagavatula Moorthy. "Sex-specific differences in neonatal hyperoxic lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no. 2 (August 1, 2016): L481—L493. http://dx.doi.org/10.1152/ajplung.00047.2016.
Повний текст джерелаАнотація:
Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by an arrest in lung development with marked impairment of alveolar septation and vascular development. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. In this investigation, we tested the hypothesis that male neonatal mice will be more susceptible to hyperoxic lung injury and will display larger arrest in lung alveolarization. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% FiO2, postnatal day (PND) 1–5] and euthanized on PND 7 and 21. Extent of alveolarization, pulmonary vascularization, inflammation, and modulation of the NF-κB pathway were determined and compared with room air controls. Macrophage and neutrophil infiltration was significantly increased in hyperoxia-exposed animals but was increased to a larger extent in males compared with females. Lung morphometry showed a higher mean linear intercept (MLI) and a lower radial alveolar count (RAC) and therefore greater arrest in lung development in male mice. This was accompanied by a significant decrease in the expression of markers of angiogenesis (PECAM1 and VEGFR2) in males after hyperoxia exposure compared with females. Interestingly, female mice showed increased activation of the NF-κB pathway in the lungs compared with males. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model. Elucidation of the sex-specific molecular mechanisms may aid in the development of novel individualized therapies to prevent/treat BPD.
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Shrestha, Amrit Kumar, Renuka T. Menon, Ahmed El-Saie, Roberto Barrios, Corey Reynolds, and Binoy Shivanna. "Interactive and independent effects of early lipopolysaccharide and hyperoxia exposure on developing murine lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 6 (December 1, 2020): L981—L996. http://dx.doi.org/10.1152/ajplung.00013.2020.
Повний текст джерелаАнотація:
Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a chronic infantile lung disease that lacks curative therapies. Infants with BPD-associated PH are often exposed to hyperoxia and additional insults such as sepsis that contribute to disease pathogenesis. Animal models that simulate these scenarios are necessary to develop effective therapies; therefore, we investigated whether lipopolysaccharide (LPS) and hyperoxia exposure during saccular lung development cooperatively induce experimental BPD-PH in mice. C57BL/6J mice were exposed to normoxia or 70% O2 (hyperoxia) during postnatal days (PNDs) 1–5 and intraperitoneally injected with varying LPS doses or a vehicle on PNDs 3–5. On PND 14, we performed morphometry, echocardiography, and gene and protein expression studies to determine the effects of hyperoxia and LPS on lung development, vascular remodeling and function, inflammation, oxidative stress, cell proliferation, and apoptosis. LPS and hyperoxia independently and cooperatively affected lung development, inflammation, and apoptosis. Growth rate and antioxidant enzyme expression were predominantly affected by LPS and hyperoxia, respectively, while cell proliferation and vascular remodeling and function were mainly affected by combined exposure to LPS and hyperoxia. Mice treated with lower LPS doses developed adaptive responses and hyperoxia exposure did not worsen their BPD phenotype, whereas those mice treated with higher LPS doses displayed the most severe BPD phenotype when exposed to hyperoxia and were the only group that developed PH. Collectively, our data suggest that an additional insult such as LPS may be necessary for models utilizing short-term exposure to moderate hyperoxia to recapitulate human BPD-PH.
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Porzionato, Andrea, Patrizia Zaramella, Arben Dedja, Diego Guidolin, Luca Bonadies, Veronica Macchi, Michela Pozzobon, et al. "Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia." American Journal of Physiology-Lung Cellular and Molecular Physiology 320, no. 5 (May 1, 2021): L688—L704. http://dx.doi.org/10.1152/ajplung.00148.2020.
Повний текст джерелаАнотація:
Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks ( n = 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution ( n = 10), or (c) MSC-EVs ( n = 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.
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Lozon, Tricia I., Alison J. Eastman, Gustavo Matute-Bello, Peter Chen, Teal S. Hallstrand, and William A. Altemeier. "PKR-dependent CHOP induction limits hyperoxia-induced lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 3 (March 2011): L422—L429. http://dx.doi.org/10.1152/ajplung.00166.2010.
Повний текст джерелаАнотація:
Supplemental O2is commonly employed in patients with respiratory failure; however, hyperoxia is also a potential contributor to lung injury. In animal models, hyperoxia causes oxidative stress in the lungs, resulting in increased inflammation, edema, and permeability. We hypothesized that oxidative stress from prolonged hyperoxia leads to endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) and induction of CCAAT enhancer-binding protein homologous protein (CHOP), a transcription factor associated with cell death in the setting of persistent ER stress. To test this hypothesis, we exposed the mouse lung epithelial cell line MLE-12 to 95% O2for 8–24 h and evaluated for evidence of UPR induction and CHOP induction. Hyperoxia caused increased CHOP expression without other evidence of UPR activation. Because CHOP expression is preceded by phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α), we evaluated the role of double-stranded RNA-activated protein kinase (PKR), a non-UPR-associated eIF2α kinase. Hyperoxia caused PKR phosphorylation, and RNA interference knockdown of PKR attenuated hyperoxia-induced CHOP expression. In vivo, hyperoxia induced PKR phosphorylation and CHOP expression in the lungs without other biochemical evidence for ER stress. Additionally, Ddit3−/−(CHOP-null) mice had increased lung edema and permeability, indicating a previously unknown protective role for CHOP after prolonged hyperoxia. We conclude that hyperoxia increases CHOP expression via an ER stress-independent, PKR-dependent pathway and that increased CHOP expression protects against hyperoxia-induced lung injury.
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Nunes, Irene, Rosemary D. Higgins, Lucia Zanetta, Peter Shamamian, and Stephen P. Goff. "C-Abl Is Required for the Development of Hyperoxia-Induced Retinopathy." Journal of Experimental Medicine 193, no. 12 (June 18, 2001): 1383–92. http://dx.doi.org/10.1084/jem.193.12.1383.
Повний текст джерелаАнотація:
The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl–deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.
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Ma. "Effects of Hyperoxia on Brain Tissue Oxygen Tension in Non-Sedated, Non- Anesthetized Arctic Ground Squirrels: An Animal Model of Hyperoxic Stress." American Journal of Animal and Veterinary Sciences 6, no. 1 (January 1, 2011): 7–17. http://dx.doi.org/10.3844/ajavsp.2011.7.17.
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Rodríguez-González, Raquel, José Luis Martín-Barrasa, Ángela Ramos-Nuez, Ana María Cañas-Pedrosa, María Teresa Martínez-Saavedra, Miguel Ángel García-Bello, Josefina López-Aguilar, et al. "Multiple System Organ Response Induced by Hyperoxia in a Clinically Relevant Animal Model of Sepsis." Shock 42, no. 2 (August 2014): 148–53. http://dx.doi.org/10.1097/shk.0000000000000189.
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Salaets, Thomas, André Gie, Julio Jimenez, Margo Aertgeerts, Olivier Gheysens, Greetje Vande Velde, Michel Koole, et al. "Local pulmonary drug delivery in the preterm rabbit: feasibility and efficacy of daily intratracheal injections." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 4 (April 1, 2019): L589—L597. http://dx.doi.org/10.1152/ajplung.00255.2018.
Повний текст джерелаАнотація:
Recent clinical trials in newborns have successfully used surfactant as a drug carrier for an active compound, to minimize systemic exposure. To investigate the translational potential of surfactant-compound mixtures and other local therapeutics, a relevant animal model is required in which intratracheal administration for maximal local deposition is technically possible and well tolerated. Preterm rabbit pups (born at 28 days of gestation) were exposed to either hyperoxia or normoxia and randomized to receive daily intratracheal surfactant, daily intratracheal saline, or no injections for 7 days. At day 7, the overall lung function and morphology were assessed. Efficacy in terms of distribution was assessed by micro-PET-CT on both day 0 and day 7. Lung function as well as parenchymal and vascular structure were altered by hyperoxia, thereby reproducing a phenotype reminiscent of bronchopulmonary dysplasia (BPD). Neither intratracheal surfactant nor saline affected the survival or the hyperoxia-induced BPD phenotype of the pups. Using PET-CT, we demonstrate that 82.5% of the injected radioactive tracer goes and remains in the lungs, with a decrease of only 4% after 150 min. Surfactant and saline can safely and effectively be administered in spontaneously breathing preterm rabbits. The described model and method enable researchers to evaluate intratracheal pharmacological interventions for the treatment of BPD.
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Ristescu, Anca Irina, Crina Elena Tiron, Adrian Tiron, and Ioana Grigoras. "Exploring Hyperoxia Effects in Cancer—From Perioperative Clinical Data to Potential Molecular Mechanisms." Biomedicines 9, no. 9 (September 13, 2021): 1213. http://dx.doi.org/10.3390/biomedicines9091213.
Повний текст джерелаАнотація:
Increased inspiratory oxygen concentration is constantly used during the perioperative period of cancer patients to prevent the potential development of hypoxemia and to provide an adequate oxygen transport to the organs, tissues and cells. Although the primary tumours are surgically removed, the effects of perioperative hyperoxia exposure on distal micro-metastases and on circulating cancer cells can potentially play a role in cancer progression or recurrence. In clinical trials, hyperoxia seems to increase the rate of postoperative complications and, by delaying postoperative recovery, it can alter the return to intended oncological treatment. The effects of supplemental oxygen on the long-term mortality of surgical cancer patients offer, at this point, conflicting results. In experimental studies, hyperoxia effects on cancer biology were explored following multiple pathways. In cancer cell cultures and animal models, hyperoxia increases the production of reactive oxygen species (ROS) and increases the oxidative stress. These can be followed by the induction of the expression of Brain-derived neurotrophic factor (BDNF) and other molecules involved in angiogenesis and by the promotion of various degrees of epithelial mesenchymal transition (EMT).
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Ozawa, Junichi, Kosuke Tanaka, Yukio Arai, Mitsuhiro Haga, Naoyuki Miyahara, Ai Miyamoto, Eri Nishimura, and Fumihiko Namba. "Thioredoxin-1 Ameliorates Oxygen-Induced Retinopathy in Newborn Mice Through Modulation of Proinflammatory and Angiogenic Factors." Antioxidants 11, no. 5 (April 30, 2022): 899. http://dx.doi.org/10.3390/antiox11050899.
Повний текст джерелаАнотація:
Oxygen-induced retinopathy (OIR) is an animal model for retinopathy of prematurity, which is a leading cause of blindness in children. Thioredoxin-1 (TRX) is a small redox protein that has cytoprotective and anti-inflammatory properties in response to oxidative stress. The purpose of this study was to determine the effect of TRX on OIR in newborn mice. From postnatal day 7, C57BL/6 wild type (WT) and TRX transgenic (TRX-Tg) mice were exposed to either 21% or 75% oxygen for 5 days. Avascular and neovascular regions of the retinas were investigated using fluorescence immunostaining. Fluorescein isothiocyanate-dextran and Hoechst staining were used to measure retinal vascular leakage. mRNA expression levels of proinflammatory and angiogenic factors were analyzed using quantitative polymerase chain reaction. Retinal histological changes were detected using immunohistochemistry. In room air, the WT mice developed well-organized retinas. In contrast, exposing WT newborn mice to hyperoxia hampered retinal development, increasing the retinal avascular and neovascular areas. After hyperoxia exposure, TRX-Tg mice had enhanced retinal avascularization compared with WT mice. TRX-Tg mice had lower retinal neovascularization and retinal permeability during recovery from hyperoxia compared with WT mice. In the early stages after hyperoxia exposure, VEGF-A and CXCL-2 expression levels decreased, while IL-6 expression levels increased in WT newborn mice. Conversely, no differences in gene expressions were observed in the TRX-Tg mouse retina. IGF-1 and Angpt1 levels did not decrease during recovery from hyperoxia in TRX-Tg newborn mice. As a result, overexpression of TRX improves OIR in newborn mice by modulating proinflammatory and angiogenic factors.
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Gelfand, Craig A., Reiko Sakurai, Ying Wang, Yitian Liu, Robert Segal, and Virender K. Rehan. "Inhaled vitamin A is more effective than intramuscular dosing in mitigating hyperoxia-induced lung injury in a neonatal rat model of bronchopulmonary dysplasia." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 3 (September 1, 2020): L576—L584. http://dx.doi.org/10.1152/ajplung.00266.2020.
Повний текст джерелаАнотація:
Prevention of bronchopulmonary dysplasia (BPD) in premature-birth babies continues to be an unmet medical need. Intramuscular vitamin A is currently employed in preterm neonates to prevent BPD but requires intramuscular injections in fragile neonates. We hypothesized that noninvasive inhaled delivery of vitamin A, targeted to lung, would be a more effective and tolerable strategy. We employed our well-established hyperoxia-injury neonatal rat model, exposing newborn rats to 7 days of constant extreme (95% O2) hyperoxia, comparing vitamin A dosed every 48 h via either aerosol inhalation or intramuscular injection with normoxic untreated healthy animals and vehicle-inhalation hyperoxia groups as positive and negative controls, respectively. Separately, similar vitamin A dosing of normoxia-dwelling animals was performed. Analyses after day 7 included characterization of alveolar histomorphology and protein biomarkers of alveolar maturation [surfactant protein C (SP-C), peroxisome proliferator-activated receptor (PPAR) γ, cholinephosphate cytidylyl transferase, vascular endothelial growth factor and its receptor, FLK-1, and retinoid X receptors (RXR-α, -β, and -γ], apoptosis (Bcl2 and Bax) key injury repair pathway data including protein markers (ALK-5 and β-catenin) and neutrophil infiltration, and serum vitamin A levels. Compared with intramuscular dosing, inhaled vitamin A significantly enhanced biomarkers of alveolar maturation, mitigated hyperoxia-induced lung damage, and enhanced surfactant protein levels, suggesting that it may be more efficacious in preventing BPD in extremely premature infants than the traditionally used IM dosing regimen. We speculate lung-targeted inhaled vitamin A may also be an effective therapy against other lung damaging conditions leading to BPD or, more generally, to acute lung injury.
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Mižíková, Ivana, Jordi Ruiz-Camp, Heiko Steenbock, Alicia Madurga, István Vadász, Susanne Herold, Konstantin Mayer, Werner Seeger, Jürgen Brinckmann, and Rory E. Morty. "Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 11 (June 1, 2015): L1145—L1158. http://dx.doi.org/10.1152/ajplung.00039.2015.
Повний текст джерелаАнотація:
Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia.
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Domm, William, Min Yee, Ravi S. Misra, Robert Gelein, Aitor Nogales, Luis Martinez-Sobrido, and Michael A. O’Reilly. "Oxygen-dependent changes in lung development do not affect epithelial infection with influenza A virus." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 5 (November 1, 2017): L940—L949. http://dx.doi.org/10.1152/ajplung.00203.2017.
Повний текст джерелаАнотація:
Infants born prematurely often require supplemental oxygen, which contributes to aberrant lung development and increased pulmonary morbidity following a respiratory viral infection. We have been using a mouse model to understand how early-life hyperoxia affects the adult lung response to influenza A virus (IAV) infection. Prior studies showed how neonatal hyperoxia (100% oxygen) increased sensitivity of adult mice to infection with IAV [IAV (A/Hong Kong/X31) H3N2] as defined by persistent inflammation, pulmonary fibrosis, and mortality. Since neonatal hyperoxia alters lung structure, we used a novel fluorescence-expressing reporter strain of H1N1 IAV [A/Puerto Rico/8/34 mCherry (PR8-mCherry)] to evaluate whether it also altered early infection of the respiratory epithelium. Like Hong Kong/X31, neonatal hyperoxia increased morbidity and mortality of adult mice infected with PR8-mCherry. Whole lung imaging and histology suggested a modest increase in mCherry expression in adult mice exposed to neonatal hyperoxia compared with room air-exposed animals. However, this did not reflect an increase in airway or alveolar epithelial infection when mCherry-positive cells were identified and quantified by flow cytometry. Instead, a modest increase in the number of CD45-positive macrophages expressing mCherry was detected. While neonatal hyperoxia does not alter early epithelial infection with IAV, it may increase the activity of macrophages toward infected cells, thereby enhancing early epithelial injury.
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Branch, Craig A., Min-Hui Cui, Nicholas Branch, and Seetharama Acharya. "Cerebral Perfusion Patterns in Transgenic Murine Models of Sickle Cell Disease As Seen By MRI Is Reflective of Their Anemia Profile and Parallels the Human Disease." Blood 126, no. 23 (December 3, 2015): 968. http://dx.doi.org/10.1182/blood.v126.23.968.968.
Повний текст джерелаАнотація:
Abstract Background: Sickle cell disease is an anemia disorder of the red blood cell in which hemoglobin S (HbS) undergoes polymerization and sickling under low-oxygenation conditions, leading to vaso-occlusive events. Major frequent neurological complications of SCD include ischemia and stroke leading to cognitive deficits and morbidity. Clinical observations have done little to identify the causes of stroke in SCD. Animal models of SCD, and in particular transgenic models have been useful in understanding the microvascular phenomena leading to vasculopathy. Polymerization and consequent sickling of red blood cells (RBC) under oxygen stress conditions likely result in sludging of blood and consequent vasoocclusion, at least in peripheral post-capillary tissues. Most animal studies suggest that the primary site for interaction of RBC's carrying HbSreside in the venous vasculature, yet large arterial stroke remains a significant occurrence in clinical SCD, where suggested risk factors include elevated carotid blood velocity and turbulence, cerebral blood flow asymmetry, loss of cerebrovascular reactivity and cerebral hyperemia. In particular, human cerebral hyperemia appears to be a frequent and significant finding, presumably a compensatory response to the SCD anemia. We sought to determine how closely Tg animal models of SCD mimic the cerebral findings associated with human SCD. Several models have been developed, including the NY1DD model which does not exhibit anemia, but in which sickling only occurs following a period of hypoxia, the S+S Antilles (SSAnt) model which suffers mild anemia and sickling under normal conditions, and the Berkley (BERK) which exhibits severe anemia, sickling and early mortality. We used MRI to evaluate these SCD models and compared the findings to those of WT animals. Methods: NY1DD (n=11, 2.6± 0.8 mo, HCT=0.47± 0.04), SSAnt (n=11, 3.3 ± 1.2 mo, HCT=0.43± 0.04), BERK (n=11 at 3 mo, n=5 at 10 mo, HCT=0.33± 0.03) and WT (C57bl, n=5 at 10 mo, n=4) were studied in accord with PHS and AALAC guidelines. Anesthetized (isoflurane) animals were studied with a 9.4 T MRI (Agilent, Inc., CA). MRI included assessment of perfusion (FAIR-ASL), fMRI (BOLD response to a period of hyperoxia), Diffusion Tensor Imaging (DTI), and structural imaging. Results: No differences were observed in CBF, BRHO or MD between young and old animals. Cerebral blood flow increased with severity of anemia-with BERK CBF higher than WT, NY1DD or SSAnt CBF (P < 0.0001). NY1DD and SSAnt CBF were not different, but both were higher than WT CBF (p < 0.001). Bold Response to hyperoxia indicated that BERK animals suffered the greatest oxygen debt, while NY1DD and SSAnt were not significantly worse than WT under normoxia conditions. Mean tissue diffusivity (obtained from DTI), a marker for edema and inflammation, was elevated only in BERK mice compared to WT mice (p < 0.05), while fractional anisotropy was not different between groups. Conclusion: As the degree of anemia worsens, CBF increases presumably to compensate for lower hemoglobin and reduced oxygen carrying capacity. In BERK mice, this increase in CBF is inadequate to compensate for reduced oxygen delivery, and this is indicated by an increase in the BOLD response to hyperoxia (BRHO measure). SSAnt and NY1DD animals both exhibited elevated CBF, but their BRHO was not significantly different from WT animals. This suggests that their increase in CBF was adequate to compensate for sickle induced vasoocclusion and/or mild anemia under normal oxygenation conditions. Our findings suggest that the BERK mouse may be the best model for evaluating therapeutics directed at treating the chronic anemia associated with human SCD, and for evaluating therapeutics aimed at remedying hypoxia induced oxygen radical damage. However, NY1DD or SSAnt may be better models for studying experimentally induced sickle crisis (extended durations of hypoxia), as BERK mice are to fragile to survive such perturbations. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Monteiro Rodrigues, Luis, Henrique Nazaré Silva, Hugo Ferreira, and Alain-Pierre Gadeau. "Characterizing Vascular Dysfunction in Genetically Modified Mice through the Hyperoxia Model." International Journal of Molecular Sciences 20, no. 9 (May 2, 2019): 2178. http://dx.doi.org/10.3390/ijms20092178.
Повний текст джерелаАнотація:
Modelling is essential for a better understanding of microcirculatory pathophysiology. In this study we tested our hyperoxia-mouse model with healthy and non-healthy mice. Animals (n = 41) were divided in groups—a control group, with 8 C57/BL6 non-transgenic male mice, a diabetic group (DB), with 8 C57BLKsJ-db/db obese diabetic mice and the corresponding internal controls of 8 age-matched C57BLKsJ-db/+ mice, and a cardiac hypertrophy group (CH), with 9 FVB/NJ cα-MHC-NHE-1 transgenic mice prone to develop cardiac failure and 8 age-matched internal controls. After anesthesia, perfusion data was collected by laser Doppler flowmetry (LDF) during rest (Phase 1), hyperoxia (Phase 2), and recovery (Phase 3) and compared. The LDF wavelet transform components analysis (WA) has shown that cardiorespiratory, myogenic, and endothelial components acted as main markers. In DB group, db/+ animals behave as the Control group, but WA already demonstrated significant differences for myogenic and endothelial components. Noteworthy was the increase of the sympathetic components in the db/db set, as in the cardiac overexpressing NHE1 transgenic animals, reported as a main component of these pathophysiological processes. Our model confirms that flow motion has a universal nature. The LDF component’s WA provides a deeper look into vascular pathophysiology reinforcing the model’s reproducibility, robustness, and discriminative capacities.
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Lejeune, P., J. L. Vachiery, J. M. De Smet, M. Leeman, S. Brimioulle, M. Delcroix, C. Melot, and R. Naeije. "PEEP inhibits hypoxic pulmonary vasoconstriction in dogs." Journal of Applied Physiology 70, no. 4 (April 1, 1991): 1867–73. http://dx.doi.org/10.1152/jappl.1991.70.4.1867.
Повний текст джерелаАнотація:
The effects of an increase in alveolar pressure on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We therefore studied the effects of positive end-expiratory pressure (PEEP) on pulmonary hemodynamics in 13 pentobarbital-anesthetized dogs ventilated alternately in hyperoxia [inspired O2 fraction (FIO2) 0.4] and in hypoxia (FIO2 0.1). In this intact animal model, HPV was defined as the gradient between hypoxic and hyperoxic transmural (tm) mean pulmonary arterial pressure [Ppa(tm)] at any level of cardiac index (Q). Ppa(tm)/Q plots were constructed with mean transmural left atrial pressure [Pla(tm)] kept constant at approximately 6 mmHg (n = 5 dogs), and Ppa(tm)/PEEP plots were constructed with Q kept constant approximately 2.8 l.min-1.m-2 and Pla(tm) kept constant approximately 8 mmHg (n = 8 dogs). Q was manipulated using a femoral arteriovenous bypass and a balloon catheter in the inferior vena cava. Pla(tm) was held constant by a balloon catheter placed by left thoracotomy in the left atrium. Increasing PEEP, from 0 to 12 Torr by 2-Torr increments, at constant Q and Pla(tm), increased Ppa(tm) from 14 +/- 1 (SE) to 19 +/- 1 mmHg in hyperoxia but did not affect Ppa(tm) (from 22 +/- 2 to 23 +/- 1 mmHg) in hypoxia. Both hypoxia and PEEP, at constant Pla(tm), increased Ppa(tm) over the whole range of Q studied, from 1 to 5 l/min, but more at the highest than at the lowest Q and without change in extrapolated pressure intercepts. Adding PEEP to hypoxia did not affect Ppa(tm) at all levels of Q.(ABSTRACT TRUNCATED AT 250 WORDS)
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Chen, Chung-Ming, Hsiu-Chu Chou, Yu-Chen S. H. Yang, Emily Chia-Yu Su, and Yun-Ru Liu. "Predicting Hyperoxia-Induced Lung Injury from Associated Intestinal and Lung Dysbiosis in Neonatal Mice." Neonatology 118, no. 2 (2021): 163–73. http://dx.doi.org/10.1159/000513553.
Повний текст джерелаАнотація:
<b><i>Background:</i></b> Preclinical studies have demonstrated that hyperoxia disrupts the intestinal barrier, changes the intestinal bacterial composition, and injures the lungs of newborn animals. <b><i>Objectives:</i></b> The aim of the study was to investigate the effects of hyperoxia on the lung and intestinal microbiota and the communication between intestinal and lung microbiota and to develop a predictive model for the identification of hyperoxia-induced lung injury from intestinal and lung microbiota based on machine learning algorithms in neonatal mice. <b><i>Methods:</i></b> Neonatal C57BL/6N mice were reared in either room air or hyperoxia (85% O<sub>2</sub>) from postnatal days 1–7. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract for 16S ribosomal RNA gene sequencing. Tissue from the right lung and terminal ileum were harvested for Western blot and histology analysis. <b><i>Results:</i></b> Hyperoxia induced intestinal injury, decreased intestinal tight junction expression, and impaired lung alveolarization and angiogenesis in neonatal mice. Hyperoxia also altered intestinal and lung microbiota and promoted bacterial translocation from the intestine to the lung as evidenced by the presence of intestinal bacteria in the lungs of hyperoxia-exposed neonatal mice. The relative abundance of these bacterial taxa was significantly positively correlated with the increased lung cytokines. <b><i>Conclusions:</i></b> Neonatal hyperoxia induced intestinal and lung dysbiosis and promoted bacterial translocation from the intestine to the lung. Further studies are needed to clarify the pathophysiology of bacterial translocation to the lung.
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Hall, Aaron A., Colin Young, Michael Bodo, and Richard T. Mahon. "Vigabatrin prevents seizure in swine subjected to hyperbaric hyperoxia." Journal of Applied Physiology 115, no. 6 (September 15, 2013): 861–67. http://dx.doi.org/10.1152/japplphysiol.00221.2013.
Повний текст джерелаАнотація:
Oxygen is the most widely used therapeutic strategy to prevent and treat decompression sickness (DCS). Oxygen prebreathe (OPB) eliminated DCS in 20-kg swine after rapid decompression from saturation at 60 feet of seawater (fsw). However, hyperbaric oxygen (HBO) has risks. As oxygen partial pressure increases, so do its toxic effects. Central nervous system (CNS) oxygen toxicity is the most severe side effect, manifesting as seizure. An adjunctive therapeutic is needed to extend OPB strategies to deeper depths and prevent/delay seizure onset. The Food and Drug Administration-approved anti-epileptic vigabatrin has prevented HBO-induced seizures in rats up to 132 fsw. This study aimed to confirm the rat findings in a higher animal model and determine whether acute high-dose vigabatrin evokes retinotoxicity symptoms seen with chronic use clinically in humans. Vigabatrin dose escalation studies were conducted 20-kg swine exposed to HBO at 132 or 165 fsw. The saline group had seizure latencies of 7 and 11 min at 165 and 132 fsw, respectively. Vigabatrin at 180 mg/kg significantly increased latency (13 and 27 min at 165 and 132 fsw, respectively); 250 mg/kg abolished seizure activity at all depths. Functional electroretinogram and histology of the retinas showed no signs of retinal toxicity in any of the vigabatrin=treated animals. In the 250 mg/kg group there was no evidence of CNS oxygen toxicity; however, pulmonary oxygen toxicity limited HBO exposure. Together, the findings from this study show that vigabatrin therapy is efficacious at preventing CNS oxygen toxicity in swine, and a single dose is not acutely associated with retinotoxicity.
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Gie, Andre G., Yannick Regin, Thomas Salaets, Costanza Casiraghi, Fabrizio Salomone, Jan Deprest, Jeroen Vanoirbeek, and Jaan Toelen. "Intratracheal budesonide/surfactant attenuates hyperoxia-induced lung injury in preterm rabbits." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 6 (December 1, 2020): L949—L956. http://dx.doi.org/10.1152/ajplung.00162.2020.
Повний текст джерелаАнотація:
Recent clinical trials have shown improvements in neonatal outcomes after intratracheal administration of a combination of budesonide/surfactant (ITBS) in infants at risk of bronchopulmonary dysplasia. However, the effect of ITBS on lung function and alveolar structure is not known. We aimed to determine the effect of ITBS on lung function, parenchymal structure, and inflammatory cytokine expression in a relevant preterm animal model for bronchopulmonary dysplasia. Premature neonatal rabbits were administered a single dose of ITBS on the day of delivery and exposed to 95% oxygen. Following 7 days of hyperoxia, in vivo forced oscillation and pressure-volume maneuvers were performed to examine pulmonary function. Histological and molecular analysis was performed to assess alveolar and extracellular matrix (ECM) morphology, along with gene expression of connective tissue growth factor (CTGF), IL-8, and CCL-2. ITBS attenuated the functional effect of hyperoxia-induced lung injury and limited the change to respiratory system impedance, measured using the forced oscillation technique. Treatment effects were most obvious in the small airways, with significant effects on small airway resistance and small airway reactance. In addition, ITBS mitigated the decrease in inspiratory capacity and static compliance. ITBS restricted alveolar septal thickening without altering the mean linear intercept and mitigated hyperoxia-induced remodeling of the ECM. These structural changes were associated with improved inspiratory capacity and lung compliance. Gene expression of CTGF, IL-8, and CCL-2 was significantly downregulated in the lung. Treatment with ITBS shortly after delivery attenuated the functional and structural consequences of hyperoxia-induced lung injury to day 7 of life in the preterm rabbit.
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Zhang, Liang, Li-Jie Yuan, Shuang Zhao, Yu Shan, Hong-Min Wu, and Xin-Dong Xue. "The role of placenta growth factor in the hyperoxia-induced acute lung injury in an animal model." Cell Biochemistry and Function 33, no. 1 (December 16, 2014): 44–49. http://dx.doi.org/10.1002/cbf.3085.
Повний текст джерела
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Olave, Nelida, Charitharth Vivek Lal, Brian Halloran, Vineet Bhandari, and Namasivayam Ambalavanan. "Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 4 (October 1, 2018): L535—L544. http://dx.doi.org/10.1152/ajplung.00125.2017.
Повний текст джерелаАнотація:
Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg−1·day−1, nimesulide (selective COX-2 antagonist) 100 mg·kg−1·day−1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.
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Ferrari, Michele, Isha H. Jain, Olga Goldberger, Emanuele Rezoagli, Robrecht Thoonen, Kai-Hung Cheng, David E. Sosnovik, Marielle Scherrer-Crosbie, Vamsi K. Mootha, and Warren M. Zapol. "Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome." Proceedings of the National Academy of Sciences 114, no. 21 (May 8, 2017): E4241—E4250. http://dx.doi.org/10.1073/pnas.1621511114.
Повний текст джерелаАнотація:
The most common pediatric mitochondrial disease is Leigh syndrome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at ≈60 d of age. We previously reported that continuously breathing normobaric 11% O2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated survival curves and organ pathology in Ndufs4 KO mice exposed to hypoxia or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as continuous normobaric 17% O2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O2 in mice with late-stage encephalopathy reverses their established neurological disease, evidenced by improved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hypoxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials.
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Wood, Thomas, Daniel Moralejo, Kylie Corry, Jessica M. Snyder, Christopher Traudt, Chad Curtis, Elizabeth Nance, Pratik Parikh, and Sandra E. Juul. "A Ferret Model of Encephalopathy of Prematurity." Developmental Neuroscience 40, no. 5-6 (2018): 475–89. http://dx.doi.org/10.1159/000498968.
Повний текст джерелаАнотація:
There is an ongoing need for relevant animal models in which to test therapeutic interventions for infants with neurological sequelae of prematurity. The ferret is an attractive model species as it has a gyrified brain with a white-to-gray matter ratio similar to that in the human brain. A model of encephalopathy of prematurity was developed in postnatal day 10 (P10) ferret kits, considered to be developmentally equivalent to infants of 24–26 weeks’ gestation. Cross-fostered P10 ferret kits received 5 mg/kg of lipopolysaccharide (LPS) before undergoing consecutive hypoxia-hyperoxia-hypoxia (60 min at 9%, 120 min at 60%, and 30 min at 9%). Control animals received saline vehicle followed by normoxia. The development of basic reflexes (negative geotaxis, cliff aversion, and righting) as well as gait coordination on an automated catwalk were assessed between P28 and P70, followed by ex vivo magnetic resonance imaging (MRI) and immunohistochemical analysis. Compared to controls, injured animals had slower overall reflex development between P28 and P40, as well as smaller hind-paw areas consistent with “toe walking” at P42. Injured animals also displayed significantly greater lateral movement during CatWalk assessment as a result of reduced gait coordination. Ex vivo MRI showed widespread white-matter hyperintensity on T2-weighted imaging as well as altered connectivity patterns. This coincided with white-matter dysmaturation characterized by increased intensity of myelin basic protein staining, white-matter thinning, and loss of oligodendrocyte transcription factor 2 (OLIG2)-positive cells. These results suggest both pathological and motor deficits consistent with premature white-matter injury. This newborn ferret model can therefore provide an additional platform to assess potential therapies before translation to human clinical trials.