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Journal articles on the topic 'Hypoxia'
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1
Khaytsev, Nikolay Valentinovich, Andrey Glebovich Vasilyev, and Aleksandr Petrovich Trashkov. "THE EFFECT OF ADVANCE HYPOXIC TRAINING UPON TISSUE OXYGEN TENSION IN THE TUMOR DURING AQUTE HYPOXIA OF DIFFERENT TYPES." Pediatrician (St. Petersburg) 4, no. 1 (January 15, 2013): 74–77. http://dx.doi.org/10.17816/ped4174-77.
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The tumors of rats who had not been acclimated to hypoxia subjected to acute hypoxic hypoxia (altitude chamber) as well as blood hypoxia (carbon monoxide) decreased tissue oxygen tension while histotoxic hypoxia (NaCN) on the contrary increased tissue oxygen tension. The tumor acclimated to hypoxia seems to select compensatory mechanisms mostly associated with increased tissue oxygen tension thus taking advantage of lower extent of tissue oxygen tension when subject to acute hypoxic hypoxia than in femoral muscle. All types of acute hypoxias caused a decrease of tissue oxygen tension in the malignancy.
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Resta, T. C., J. M. Resta, and B. R. Walker. "Role of endogenous opioids and serotonin in the hemodynamic response to hemorrhage during hypoxia." American Journal of Physiology-Heart and Circulatory Physiology 269, no. 5 (November 1, 1995): H1597—H1606. http://dx.doi.org/10.1152/ajpheart.1995.269.5.h1597.
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Previous studies from our laboratory indicate that acute but not chronic hypoxia decreases the hemorrhage volume required to elicit reflex hypotension. Furthermore, chronically hypoxic animals exhibit an elevated hypotensive threshold during both normoxia and hypoxia compared with control animals. Because reports suggest that opioid and serotonergic mechanisms may be involved in mediating the sympathoinhibition that occurs with hemorrhage, we hypothesized that opioid and/or serotonergic systems are stimulated during hemorrhage under conditions of acute hypoxia and suppressed after chronic exposure to hypoxia and are thus responsible for the altered cardiovascular responses to hemorrhage under each condition. Control and chronically hypoxi rats were administered either the opioid receptor antagonist naltrexone (1 mg/kg), the selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) serotonergic receptor antagonist MDL-72222 (0.5 mg/kg), or their respective vehicles intravenously before hemorrhage was initiated during normoxia or hypoxia (FIO2 = 0.12). In control animals, pretreatment with naltrexone increased the hemorrhage was initiated volume required to achieve hypotension in hypoxic but not normoxic conditions. Naltrexone had no effect on hypotensive threshold in chronically hypoxic animals under conditions of either normoxia or hypoxia. In addition, MDL-72222 had no effect on hypotensive threshold in either control or chronically hypoxic animals in either normoxic or hypoxic conditions. We conclude that endogenous opioids may contribute to the reflex hypotension that occurs during hypoxic hemorrhage in control rats, while no such involvement is evident in chronically hypoxic animals. Furthermore, peripheral 5-HT3 receptors are not likely involved in this response during either normoxic or hypoxic hemorrhage in control or chronically hypoxic rats.
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Voronina, Tatiana A. "The role of hypoxia in stroke and convulsive states. Antihypoxants." Reviews on Clinical Pharmacology and Drug Therapy 14, no. 1 (March 15, 2016): 63–70. http://dx.doi.org/10.17816/rcf14163-70.
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The review deals with the main types of hypoxia and the reasons leading to its development, discusses the development of mechanisms of hypoxiа. Particular attention is paid to brain hypoxia and its role in the development of strokes and convulsive states. The features of the application of antihypoxants and antioxidants at different hypoxic conditions including stroke and seizures are discussed.
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Lowry, T. F., H. V. Forster, M. J. Korducki, A. L. Forster, and M. A. Forster. "Comparison of ventilatory responses to sustained reduction in arterial oxygen tension vs. content in awake ponies." Journal of Applied Physiology 76, no. 5 (May 1, 1994): 2147–53. http://dx.doi.org/10.1152/jappl.1994.76.5.2147.
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To gain insight into central and peripheral contributions to changes in breathing during hypoxia, we compared effects on breathing of reducing inspired PO2 (hypoxic hypoxia) with reducing arterial O2 content (CaO2) through elevation of carboxy-hemoglobin (COHb) (CO hypoxia). Twelve awake ponies were studied during 1 h of breathing room air followed by 6 h when COHb was increased to 25% and CaO2 was decreased by 17%. When COHb was increased, arterial PCO2 (PaCO2) increased gradually to 1.3 Torr above (P < 0.05) control level between 30 and 45 min of CO exposure. Pulmonary ventilation (VE) decreased (P = 0.09) approximately 1 liter the first 30 min of CO exposure. After approximately 45 min, PaCO2 began to decrease, steadily reaching 1.5 Torr below (P < 0.05) control level by 4.5 h of CO hypoxia. VE did not change significantly after 30 min of elevated COHb. Eight ponies were also studied during 5 h of hypoxic hypoxia (arterial PO2 approximately 40 Torr). PaCO2 decreased 5 Torr (P < 0.05) within 5 min of hypoxia and decreased another 4 Torr (P < 0.05) between 30 min and 5 h of hypoxia consistent with hypoxic ventilatory acclimatization. VE increased (P < 0.05) within 3 min of hypoxic hypoxia but then decreased (P < 0.05; VE roll off) toward control and did not increase significantly with acclimatization. Because CO and hypoxic hypoxia both decrease brain oxygenation but only hypoxic hypoxia increases carotid chemoreceptor activity, we conclude that initial hypoventilation with CO hypoxia and VE roll off with hypoxic hypoxia are consistent with hypoxic ventilatory depression within the brain. In addition, hyperventilation with prolonged CO hypoxia is consistent with a central nervous system mechanism contributing to this phase of hypoxic ventilatory acclimatization in ponies.
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Conde, S. V., E. C. Monteiro, R. Rigual, A. Obeso, and C. Gonzalez. "Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity." Journal of Applied Physiology 112, no. 12 (June 15, 2012): 2002–10. http://dx.doi.org/10.1152/japplphysiol.01617.2011.
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Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O2) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O2) and in response to hypoxias of different intensities (10, 5, and 2% O2) to study the release pathways. We found that ZM241385, an A2 antagonist, decreased the CSN discharges evoked by 0 and 7% O2 by 30.8 and 72.5%, respectively. Suramin, a P2X antagonist, decreased the CSN discharges evoked by 0 and 7% O2 by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O2 levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.
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Yang, B. C., and J. L. Mehta. "Alterations in pulmonary artery tone during repeated episodes of hypoxia." American Journal of Physiology-Lung Cellular and Molecular Physiology 269, no. 3 (September 1, 1995): L293—L298. http://dx.doi.org/10.1152/ajplung.1995.269.3.l293.
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To examine the basis of pulmonary constriction during chronic hypoxia, rat pulmonary artery rings were precontracted and exposed to multiple episodes of hypoxia. The first hypoxic episode resulted in a transient contraction, followed by potent relaxation, and then a slow sustained contraction. Repeated hypoxic exposure resulted in stronger initial contraction and attenuated relaxation. Prolongation of the normoxic interval between hypoxic episodes reversed the attenuation of hypoxic relaxation. Pulmonary artery rings that were deendothelialized or treated with the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester or oxyhemoglobin displayed only hypoxic relaxation without initial or late contractions and no attenuation of relaxation during repeated hypoxia. Pretreatment of rings with indomethacin or adenosine or endothelin receptor antagonists had no effect on the hypoxia-mediated alterations. Thus repetitive exposure to hypoxia results in an increase in initial contraction and a decrease in relaxation of pulmonary artery rings. Frequency of hypoxic episodes and endothelial integrity determine pulmonary tone during repeated hypoxia. However, cyclooxygenase products, adenosine, or endothelin do not play a role in hypoxia-mediated changes in rat pulmonary artery tone.
7
Long, W., D. Lobchuk, and N. R. Anthonisen. "Ventilatory responses to CO2 and hypoxia after sustained hypoxia in awake cats." Journal of Applied Physiology 76, no. 6 (June 1, 1994): 2262–66. http://dx.doi.org/10.1152/jappl.1994.76.6.2262.
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In humans and cats the ventilatory response to 30 min of isocapnic hypoxia is biphasic with an initial increase followed by a decrease, termed “hypoxic depression.” In humans, 30 min of hypoxia reduces the initial response to a subsequent hypoxic exposure. These experiments were to determine whether the same occurred in cats. Cats were studied while awake. End-tidal Po2 and Pco2 were measured by sampling tracheal gas, and ventilation was measured plethysmographically. In seven cats we measured ventilatory responses to two 30-min periods of isocapnic hypoxia (end-tidal Po2 = 60–65 Torr) separated by 5 min of room air breathing. The first hypoxic response was biphasic, with ventilation increasing to 149% of control at 5 min and decreasing to 117% of control at 25 min. During the second exposure, ventilation was 119% of control at 5 min and 113% of control at 25 min; 30 min of hypoxia depressed the subsequent hypoxic response. Hypoxic depression outlasted the hypoxia, suggesting that it was mediated by relatively slow neurochemical events. In five cats ventilatory responses to 5% CO2 were measured before and 5 min after 30 min of isocapnic hypoxia and before and after 30 min of room air breathing. Hypoxia did not affect CO2 responses. Thus the neurochemical events that cause hypoxic depression appear not to involve the neurons generating the response to CO2 and may be specific to those involved in the hypoxic response.
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Dahan, A., D. Ward, M. van den Elsen, J. Temp, and A. Berkenbosch. "Influence of reduced carotid body drive during sustained hypoxia on hypoxic depression of ventilation in humans." Journal of Applied Physiology 81, no. 2 (August 1, 1996): 565–72. http://dx.doi.org/10.1152/jappl.1996.81.2.565.
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To evaluate whether the intact hypoxic drive from the carotid bodies during sustained hypoxia is required for the generation of hypoxic depression of ventilation (VE), 16 volunteers were exposed to two consecutive periods of isocapnic hypoxia (first period 20 min; second period 5 min; end-tidal PO2 45 Torr) separated by 6 min of normoxia. In study A, saline was given. In study B, 3 micrograms.kg-1.min-1 i.v. dopamine (DA), a carotid body inhibitor, was given during the first hypoxic exposure followed by saline during normoxia and the second hypoxic exposure. In study C, 20 min of normoxia with DA preceded 6 min of normoxia and 5 min of hypoxia without DA. The first peak hypoxic VE (PHV) in study A was approximately 100% above normoxic VE. After 20 min of hypoxia, VE declined to 60% above normoxic VE. The second PHV in study A was only 60% of the first PHV. We relate this delayed recovery from hypoxia to "ongoing" effects of hypoxic depression. During DA infusion, the changes in VE due to sustained hypoxia were insignificant (study B). The second PHV in study B was not different from the PHV after air breathing in studies A and C. This indicates that the recovery from sustained hypoxia with a suppressed carotid body drive was complete within 6 min. Our results show that despite central hypoxia the absence of ventilatory changes during 20 min of isocapnic hypoxia due to intravenous DA prevented the generation of central hypoxic depression and the depression of a subsequent hypoxic response.
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Yoon, Donghoon, Prem Ponka, and Josef T. Prchal. "Hypoxia. 5. Hypoxia and hematopoiesis." American Journal of Physiology-Cell Physiology 300, no. 6 (June 2011): C1215—C1222. http://dx.doi.org/10.1152/ajpcell.00044.2011.
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Our understanding of organismal responses to hypoxia has stemmed from studies of erythropoietin regulation by hypoxia that led to the discovery of the master regulator of the hypoxic response, i.e., hypoxia-inducible factor (HIF). This is a transcription factor that is now known to induce the expression of a battery of genes in response to hypoxia. HIF-1 and HIF-2 regulate many genes that are involved in erythropoiesis and iron metabolism, which are essential for tissue oxygen delivery.
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Zonneveld, Marijke, Tom Keulers, and Kasper Rouschop. "Extracellular Vesicles as Transmitters of Hypoxia Tolerance in Solid Cancers." Cancers 11, no. 2 (January 29, 2019): 154. http://dx.doi.org/10.3390/cancers11020154.
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Tumour hypoxia is a common feature of solid tumours that contributes to poor prognosis after treatment. This is mainly due to increased resistance of hypoxic cells to radio- and chemotherapy and the association of hypoxic cells with increased metastasis development. It is therefore not surprising that an increased hypoxic tumour fraction is associated with poor patient survival. The extent of hypoxia within a tumour is influenced by the tolerance of individual tumor cells to hypoxia, a feature that differs considerably between tumors. High numbers of hypoxic cells may, therefore, be a direct consequence of enhanced cellular capability inactivation of hypoxia tolerance mechanisms. These include HIF-1α signaling, the unfolded protein response (UPR) and autophagy to prevent hypoxia-induced cell death. Recent evidence shows hypoxia tolerance can be modulated by distant cells that have experienced episodes of hypoxia and is mediated by the systemic release of factors, such as extracellular vesicles (EV). In this review, the evidence for transfer of a hypoxia tolerance phenotype between tumour cells via EV is discussed. In particular, proteins, mRNA and microRNA enriched in EV, derived from hypoxic cells, that impact HIF-1α-, UPR-, angiogenesis- and autophagy signalling cascades are listed.
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Smith, Zachary M., Erin Krizay, Rui Carlos Sá, Ethan T. Li, Miriam Scadeng, Frank L. Powell, and David J. Dubowitz. "Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia." Journal of Applied Physiology 123, no. 6 (December 1, 2017): 1477–86. http://dx.doi.org/10.1152/japplphysiol.00341.2017.
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Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems.
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Sattiraju, Anirudh, Sangjo Kang, Valerie Marallano, Concetta Brusco, Zhihong Chen, Aarthi Ramakrishnan, Li Shen, Dolores Hambardzumyan, Roland Friedel, and Hongyan Zou. "TAMI-59. RECIPROCAL IMPACT OF CANCER IMMUNITY AND TUMOR HYPOXIA DURING GLIOBLASTOMA PROGRESSION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi210. http://dx.doi.org/10.1093/neuonc/noab196.841.
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Abstract Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but the underlying mechanisms and the environmental factors that initiate tumor hypoxia are poorly understood. We tracked tumor hypoxia in GBM in immunocompetent mice with a hypoxia sensitive fluorescent reporter combined with single cell transcriptomics. We found that hypoxic GBM cells are quiescent, immunosuppressive and display a mesenchymal transition, all of which are linked to malignant potency. We also captured in vivo hypoxia gene signature, which is more represented in recurrent GBM and predicts worse outcome. Interestingly, hypoxic GBM cells is a diverse population, consisted of four subclusters, and enriched for immune pathways. Concordantly, our reporter highlighted a distinct geographic pattern of immune cells in hypoxic regions, with phagocytic tumor-associated macrophages (TAMs) and CD8+ cytotoxic T cells (CTLs) congregated in hypoxic cores confined by hypoxic GBM cells in pseudo-palisading patterns. Mechanistically, this is a dynamic temporospatial process, requiring cytokine CCL8. Remarkably, the sequestered TAMs also experience hypoxia, and they are reprogrammed to express immunotolerant markers by factors released from hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Analyses of human patient GBM samples highlighted a connection of mesenchymal subtype, immune response, and tumor hypoxia, all contributing to poor survival. Altogether, our study revealed a reciprocal influence of anti-tumor immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM.
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Jones, Nicole M., and Marcelle Bergeron. "Hypoxic Preconditioning Induces Changes in HIF-1 Target Genes in Neonatal Rat Brain." Journal of Cerebral Blood Flow & Metabolism 21, no. 9 (September 2001): 1105–14. http://dx.doi.org/10.1097/00004647-200109000-00008.
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Hypoxic preconditioning induces tolerance to hypoxic-ischemic injury in neonatal rat brain and is associated with changes in gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is strongly induced by hypoxia or the hypoxia-mimetic compound cobalt chloride (CoCl2). Hypoxia-inducible factor-1 modulates the expression of several target genes including the glycolytic enzymes, glucose transporter-1 (GLUT-1), and erythropoietin. Recently, HIF-1 expression was shown to increase after hypoxic and CoCl2 preconditioning in newborn rat brain. To study the involvement of HIF-1 target genes in neonatal hypoxia-induced ischemic tolerance, the authors examined the brains of newborn rats after exposure to hypoxia (8% O2 for 3 hours) or injection of CoCl2 (60 mg/kg). Preconditioning with hypoxia or CoCl2 24 hours before hypoxia-ischemia afforded a 96% and 76% brain protection, respectively, compared with littermate control animals. Hypoxic preconditioning increased the expression of GLUT-1 mRNA and protein, and of aldolase, phosphofructokinase, and lactate dehydrogenase proteins but not mRNA. This suggests that the modulation of glucose transport and glycolysis by hypoxia may contribute to the development of hypoxia-induced tolerance. In contrast, preconditioning with CoCl2 did not produce any change in HIF-1 target gene expression suggesting that different molecular mechanisms may be involved in the induction of tolerance by hypoxia and CoCl2 in newborn brain.
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Merellano-Navarro, Eugenio, Marta Camacho-Cardenosa, Gabriel Peinado Costa, Ester Wiggers, Germano Marcolino Putti, Jonatas Evandro Nogueira, Elisangela Aparecida da Silva Lizzi, and Átila Alexandre Trapé. "Effects of Different Protocols of Moderate-Intensity Intermittent Hypoxic Training on Mental Health and Quality of Life in Brazilian Adults Recovered from COVID-19: The AEROBICOVID Double-Blind Randomized Controlled Study." Healthcare 11, no. 23 (November 30, 2023): 3076. http://dx.doi.org/10.3390/healthcare11233076.
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The aim of this study was to investigate the effects of different protocols of moderate-intensity intermittent hypoxic training in patients who had recovered from COVID-19 on quality of life (QoL) and mental health. The sample of this clinical trial-controlled double-blind study consisted of 67 participants aged 30–69 years, who were organized randomly according to Normoxia, Hypoxia, Hypoxia Recovery or Control Group. Eight weeks of cycle ergometer training were performed with a frequency of three training sessions per week in normoxic or hypoxic conditions (with or without hypoxic recovery). Health-related QoL and Mental Health Status were evaluated by 12-Item Short Form Survey and Depression Anxiety and Stress Scale instruments, respectively. All training groups improved the QoL’s physical dimensions (Baseline–Post: Normoxia Group 42.1 (11.0)–48.7 (7.0), Hypoxia Group 46.9 (11.8)–53.5 (6.6) and Hypoxia Recovery Group 45.8 (9.2)–51.1 (5.3)) and mental dimensions (Baseline–Post: Normoxia Group 48.8 (7.9)–54.6 (4.6), Hypoxia Group 45.2 (7.7)–53.2 (3.8) and Hypoxia Recovery Group 46.5 (9.7)–52.0 (9.9)). Regarding mental health outcomes, all training groups decreased depressive symptoms (66.7% Normoxia, 31.2% Hypoxia Recovery and 31% Hypoxia groups), anxiety symptoms (46.5% Normoxia, 45.9% Hypoxia Recovery and 39.5% in the Hypoxia groups) and stress symptoms (40.6% Normoxia, 36.3% Hypoxia Recovery and 22.1% Hypoxia groups). Significant statistical difference was not found between groups. Normoxic and hypoxic training showed a similar effect on QoL and the mental health of Brazilian adults who had recovered from COVID-19.
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Korducki, M. J., H. V. Forster, T. F. Lowry, and M. M. Forster. "Effect of hypoxia on metabolic rate in awake ponies." Journal of Applied Physiology 76, no. 6 (June 1, 1994): 2380–85. http://dx.doi.org/10.1152/jappl.1994.76.6.2380.
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To determine the effect of hypoxia on metabolic rate (VO2) of ponies, on 2 days we studied ponies that were breathing room air for 1 h followed by 5 h of either hypoxic hypoxia (fractional concn of inspired O2 = 0.126) or 5 h of CO hypoxia. Control arterial PO2 was 103 +/- 1.2 Torr, and at 5 min and 5 h of hypoxic hypoxia, arterial PO2 was 53.1 +/- 1.8 and 41.0 +/- 1.8 Torr, respectively. There was a time-dependent hypocapnia and alkalosis during hypoxic hypoxia. During CO hypoxia, carboxyhemoglobin increased to 25% after 30 min and remained constant thereafter. With increased carboxyhemoglobin, arterial PCO2 was 1.3 Torr above (P < 0.05) and 1.5 Torr (P < 0.05) below control levels after 30 min and 3 h, respectively. There were no significant (P > 0.10) changes in VO2 during either hypoxic or CO hypoxia. However, in 50% of the ponies, VO2, pulmonary ventilation, and rectal temperature increased and shivering was evident after 30 min of hypoxia. Peak values of pulmonary ventilation, VO2, and shivering occurred at approximately 2 h with a subsequent return toward control levels. We conclude that, in contrast to smaller mammals, acute hypoxia does not depress VO2 of ponies. The hypermetabolism and hyperthermia during chronic hypoxia in some ponies may reflect a transient failure in thermoregulation.
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Kabakov, Alexander E., and Anna O. Yakimova. "Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing." Cancers 13, no. 5 (March 4, 2021): 1102. http://dx.doi.org/10.3390/cancers13051102.
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Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.
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Hoshikawa, Yasushi, Sadafumi Ono, Satoshi Suzuki, Tatsuo Tanita, Masayuki Chida, Chun Song, Masafumi Noda, Toshiharu Tabata, Norbert F. Voelkel, and Shigefumi Fujimura. "Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia." Journal of Applied Physiology 90, no. 4 (April 1, 2001): 1299–306. http://dx.doi.org/10.1152/jappl.2001.90.4.1299.
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Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.
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Kammerer, Tobias, Valentina Faihs, Nikolai Hulde, Manfred Stangl, Florian Brettner, Markus Rehm, Mareike Horstmann, et al. "Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial." International Journal of Molecular Sciences 21, no. 3 (February 4, 2020): 1034. http://dx.doi.org/10.3390/ijms21031034.
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Induction of hypoxia-inducible-factor-1α (HIF-1α) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that (1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, (2) similar results are seen in vivo under hypobaric hypoxia, and (3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O2) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1β (IL-1β), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic (p = 0.004) or inflammatory (p = 0.006) stimuli induced IL-1β mRNA expression. CCR-2 mRNA expression increased under hypoxia (p = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1β, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all p ≤ 0.05). Of note, proinflammatory IL-1β and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro.
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Ooi, Henry, Elaine Cadogan, Michèle Sweeney, Katherine Howell, R. G. O'Regan, and Paul McLoughlin. "Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 2 (February 1, 2000): H331—H338. http://dx.doi.org/10.1152/ajpheart.2000.278.2.h331.
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Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O2 fraction ([Formula: see text]) = 0.10], chronic hypercapnia (inspiratory CO2 fraction = 0.10), hypoxia-hypercapnia ([Formula: see text]= 0.10, inspiratory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone ( P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk ( P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 ± 1.8 mmHg) was significantly ( P < 0.01, ANOVA) elevated compared with control conditions (12.1 ± 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 ± 0.9 mmHg) or hypercapnia (11.8 ± 1.3 mmHg). HPV ([Formula: see text] = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control ( P < 0.05, ANOVA). Addition of N ω-nitro-l-arginine methyl ester (10−4 M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.
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Chen, Chien-Yi, Wei-Zen Sun, Kai-Hsiang Kang, Hung-Chieh Chou, Po-Nien Tsao, Wu-Shiun Hsieh, and Wen-Mei Fu. "Hypoxic Preconditioning Suppresses Glial Activation and Neuroinflammation in Neonatal Brain Insults." Mediators of Inflammation 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/632592.
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Perinatal insults and subsequent neuroinflammation are the major mechanisms of neonatal brain injury, but there have been only scarce reports on the associations between hypoxic preconditioning and glial activation. Here we use neonatal hypoxia-ischemia brain injury model in 7-day-old rats andin vitrohypoxia model with primary mixed glial culture and the BV-2 microglial cell line to assess the effects of hypoxia and hypoxic preconditioning on glial activation. Hypoxia-ischemia brain insult induced significant brain weight reduction, profound cell loss, and reactive gliosis in the damaged hemisphere. Hypoxic preconditioning significantly attenuated glial activation and resulted in robust neuroprotection. As early as 2 h after the hypoxia-ischemia insult, proinflammatory gene upregulation was suppressed in the hypoxic preconditioning group.In vitroexperiments showed that exposure to 0.5% oxygen for 4 h induced a glial inflammatory response. Exposure to brief hypoxia (0.5 h) 24 h before the hypoxic insult significantly ameliorated this response. In conclusion, hypoxic preconditioning confers strong neuroprotection, possibly through suppression of glial activation and subsequent inflammatory responses after hypoxia-ischemia insults in neonatal rats. This might therefore be a promising therapeutic approach for rescuing neonatal brain injury.
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Neubert, Elias, Beate Rassler, Annekathrin Hoschke, Coralie Raffort, and Aida Salameh. "Effects of Normobaric Hypoxia and Adrenergic Blockade over 72 h on Cardiac Function in Rats." International Journal of Molecular Sciences 24, no. 14 (July 13, 2023): 11417. http://dx.doi.org/10.3390/ijms241411417.
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In rats, acute normobaric hypoxia depressed left ventricular (LV) inotropic function. After 24 h of hypoxic exposure, a slight recovery of LV function occurred. We speculated that prolonged hypoxia (72 h) would induce acclimatization and, hence, recovery of LV function. Moreover, we investigated biomarkers of nitrosative stress and apoptosis as possible causes of hypoxic LV depression. To elucidate the role of hypoxic sympathetic activation, we studied whether adrenergic blockade would further deteriorate the general state of the animals and their cardiac function. Ninety-four rats were exposed over 72 h either to normal room air (N) or to normobaric hypoxia (H). The rodents received infusion (0.1 mL/h) with 0.9% NaCl or with different adrenergic blockers. Despite clear signs of acclimatization to hypoxia, the LV depression continued persistently after 72 h of hypoxia. Immunohistochemical analyses revealed significant increases in markers of nitrosative stress, adenosine triphosphate deficiency and apoptosis in the myocardium, which could provide a possible explanation for the absence of LV function recovery. Adrenergic blockade had a slightly deteriorative effect on the hypoxic LV function compared to the hypoxic group with maintained sympathetic efficacy. These findings show that hypoxic sympathetic activation compensates, at least partially, for the compromised function in hypoxic conditions, therefore emphasizing its importance for hypoxia adaptation.
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Pantazopoulou, Vasiliki, Pauline Jeannot, Rebecca Rosberg, Tracy J. Berg, and Alexander Pietras. "Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties." Cells 10, no. 3 (March 10, 2021): 613. http://dx.doi.org/10.3390/cells10030613.
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Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.
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Yu, Albert C. H., George A. Gregory, and Pak H. Chan. "Hypoxia-Induced Dysfunctions and Injury of Astrocytes in Primary Cell Cultures." Journal of Cerebral Blood Flow & Metabolism 9, no. 1 (February 1989): 20–28. http://dx.doi.org/10.1038/jcbfm.1989.3.
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The effects of severe hypoxia were studied in a primary culture of astrocytes prepared from newborn rat cerebral cortex. Hypoxia was created by placing cultures in an airtight chamber that was flushed with 95% N2/5% CO2 for 15 min before being sealed. The hypoxic environment was maintained constant for up to 24 h. During the first 12 h of hypoxia, astrocytes showed no morphological changes by phase-contrast microscopy. After 18 h of hypoxia, some astrocytes in culture became swollen and started to detach from the culture dish. All cells in the culture were destroyed after 24 h of hypoxia. The lactate dehydrogenase level in the culture medium increased more than tenfold between 12 and 24 h of hypoxia. Glutamate uptake was inhibited 80% by similar hypoxic conditions. The cell volume of astrocytes, as measured by 3-O-methyl-[14C]-D-glucose uptake, was increased. These observations suggested cell membrane dysfunction. The malondialdehyde level of hypoxic cultures increased twofold after 24 h of hypoxia. Verapamil (0.5 m M), furosemide (1 m M), indomethacin (1 m M), MgCl2 (10 m M), and mannitol (10 m M) reduced but never completely abolished the release of lactate dehydrogenase from hypoxic astrocytes. These data suggest multifactorial causes for severe injury in hypoxic astrocytes.
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Ono, Yoko, and Hidemasa Bono. "Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes." Biomedicines 9, no. 5 (May 20, 2021): 582. http://dx.doi.org/10.3390/biomedicines9050582.
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Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.
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Nieuwenhuijs, Diederik, Elise Sarton, Luc Teppema, and Albert Dahan. "Propofol for Monitored Anesthesia Care." Anesthesiology 92, no. 1 (January 1, 2000): 46. http://dx.doi.org/10.1097/00000542-200001000-00013.
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Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. Methods Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. Results Blood propofol concentrations varied among subjects but were stable over time (mean blood concentration 0.6 microg/ml). The sustained hypoxic test showed that propofol decreased acute hypoxic response by approximately 50% and that the magnitude of hypoxic ventilatory decline relative to acute hypoxic response was increased by > 50%. Propofol increased the depression of the acute hypoxic response after 15 min of hypoxia by approximately 25%. In control and propofol studies, no hypoxic ventilatory decline was generated during exposure to hypoxic pulses. The bispectral index-acute hypoxic response data suggest that subjects were either awake (with minimal effect on acute hypoxic response) or sedated (with 50-60% reduction of acute hypoxic response). Conclusions The depression of acute hypoxic response results from an effect of propofol at peripheral or central sites involved in respiratory control or secondary to the induction of sedation or hypnosis by propofol. The relative increase in hypoxic ventilatory decline is possibly related to propofol's action at the gamma-aminobutyric acid A (GABA(A)) receptor complex, causing increased GABAergic inhibition of ventilation during sustained (but not intermittent) hypoxia.
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Frappell, P. B., and J. P. Mortola. "Hamsters vs. rats: metabolic and ventilatory response to development in chronic hypoxia." Journal of Applied Physiology 77, no. 6 (December 1, 1994): 2748–52. http://dx.doi.org/10.1152/jappl.1994.77.6.2748.
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The postnatal developments of the rat and hamster were compared after the animals were raised from birth for 21 days either in normoxia (control animals) or chronic hypoxia (PO2 of 80–90 Torr). Compared with control rats, hypoxic rats had a reduction in body mass. Hypoxic rats had lowered O2 consumption (VO2) and increased (67%) ventilation (VE), whereas hypoxic hamsters maintained the same metabolic rate as control hamsters but increased VE by 100%. As a result, when raised in hypoxia both species increased VE/VO2 to the same extent. When acutely exposed to hypoxia, control animals of both species increased VE (54–58%) and lowered VO2 (26%). Thus, whether the exposure to hypoxia is acute or chronic, both species hyperventilated (i.e., increased VE/VO2) to approximately the same degree. However, in the rat VO2 decreased similarly in both acute and chronic hypoxia, whereas in the hamster VO2 decreased with acute hypoxia but was maintained under chronic hypoxia. Within 1 day of the animals being returned to normoxia, metabolic and ventilatory parameters of hypoxic animals returned to control values. In conclusion, the semifossorial hamster seems better suited to development in chronic hypoxia than the surface-dwelling rat because by avoiding prolonged hypometabolism it can better maintain body growth.
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Stepanek, Jan, Gaurav N. Pradhan, Daniela Cocco, Benn E. Smith, Jennifer Bartlett, Marc Studer, Fabian Kuhn, and Michael J. Cevette. "Acute Hypoxic Hypoxia and Isocapnic Hypoxia Effects on Oculometric Features." Aviation, Space, and Environmental Medicine 85, no. 7 (July 1, 2014): 700–707. http://dx.doi.org/10.3357/asem.3645.2014.
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Dyba, Iryna, Ervin Asanov, Seviliya Asanova, and Juliya Holubova. "Hypoxia resistance among the agedpatients with chronic obstructive lung disease: possibilities of using hypoxic trains." Ageing & Longevity 1, no. 1 (July 7, 2020): 12–18. http://dx.doi.org/10.47855/jal9020-2020-1-3.
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Age-related morphological and functional changes in the body lead to the development of arterial hypoxemia, tissue hypoxia and hypoxic changes, which reduces the body's resistance to hypoxia and contributes to the development of lung diseases, in particular chronic obstructive pulmonary disease (COPD) in the elderly. The aim of the study was to clarify the effect of interval normobaric hypoxic training (INHT) on hypoxia resistance in elderly patients with COPD. The survey showed that with an increase in bronchial obstruction, the shifts of blood saturation during hypoxia increase. The course of INHT leads to increased resistance to hypoxia, and also increases the ventilation response to hypoxia in elderly patients with COPD.
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Halliwill, John R., and Christopher T. Minson. "Cardiovagal regulation during combined hypoxic and orthostatic stress: fainters vs. nonfainters." Journal of Applied Physiology 98, no. 3 (March 2005): 1050–56. http://dx.doi.org/10.1152/japplphysiol.00871.2004.
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We tested the hypothesis that individual differences in the effect of acute hypoxia on the cardiovagal arterial baroreflex would determine individual susceptibility to hypoxic syncope. In 16 healthy, nonsmoking, normotensive subjects (8 women, 8 men, age 20–33 yr), we assessed orthostatic tolerance with a 20-min 60° head-upright tilt during both normoxia and hypoxia (breathing 12% O2). On a separate occasion, we assessed baroreflex control of heart rate (cardiovagal baroreflex gain) using the modified Oxford technique during both normoxia and hypoxia. When subjects were tilted under hypoxic conditions, 5 of the 16 developed presyncopal signs or symptoms, and the 20-min tilt had to be terminated. These “fainters” had comparable cardiovagal baroreflex gain to “nonfainters” under both normoxic and hypoxic conditions (normoxia, fainters: −1.2 ± 0.2, nonfainters: −1.0 ± 0.2 beats·min−1·mmHg−1, P = 0.252; hypoxia, fainters: −1.3 ± 0.2, nonfainters: −1.0 ± 0.1 beats·min−1·mmHg−1, P = 0.208). Furthermore, hypoxia did not alter cardiovagal baroreflex gain in either group (both P > 0.8). It appears from these observations that hypoxic syncope results from the superimposed vasodilator effects of hypoxia on the cardiovascular system and not from a hypoxia-induced maladjustment in baroreflex control of heart rate.
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Yang, B. C., and J. L. Mehta. "Critical role of endothelium in sustained arterial contraction during prolonged hypoxia." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 3 (March 1, 1995): H1015—H1020. http://dx.doi.org/10.1152/ajpheart.1995.268.3.h1015.
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Acute anoxia or severe hypoxia causes an initial transient contraction followed by marked relaxation of vascular tissues. We observed a spontaneous gradual sustained contraction of rat aortic rings following relaxation when hypoxia was prolonged. Deendothelialization as well as treatment of the endothelium-intact rings with nitric oxide synthase inhibitors or oxyhemoglobin abolished the late hypoxic contraction despite prolonged hypoxia. The prolonged hypoxia-induced sustained contraction was not affected by adenosine receptor blockade, cyclooxygenase inhibition, free radical scavengers, or the endothelin receptor antagonists. The ATP-sensitive K+ channel blocker glibenclamide abbreviated the duration of hypoxic relaxation and potentiated the magnitude of late hypoxic contraction. These data suggest that the late-sustained hypoxic contraction of arterial tissues is dependent on the presence of intact functional endothelium. Activation of ATP-sensitive K+ channels may participate in the genesis of hypoxic relaxation. However, cyclooxygenase products, free oxygen radicals, adenosine, and endothelin are not involved in the regulation of hypoxia-mediated events in rat aortic rings.
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Airlie, M. A. A., D. C. Flenley, and P. M. Warren. "Effect of Almitrine on Hypoxic Ventilatory Drive Measured by Transient and Progressive Isocapnic Hypoxia in Normal Men." Clinical Science 77, no. 4 (October 1, 1989): 431–37. http://dx.doi.org/10.1042/cs0770431.
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1. In a double-blind placebo-controlled study, we have investigated the effect of the peripheral chemoreceptor stimulant drug almitrine bismesylate on hypoxic ventilatory drive (expressed as the slope of the minute ventilation/arterial oxygen saturation relationship in litres min−1 %−1) as measured by both progressive isocapnic hypoxia at rest and transient hypoxia (three breaths of 100% N2) during moderate exercise, in seven normal men, to determine if the ventilatory response to the transient hypoxic stimulus is a more specific measure of peripheral chemoreceptor sensitivity to hypoxia. 2. Hypoxic ventilatory drive measured using progressive isocapnic hypoxia ranged from −0.13 to −2.65 litres min−1 % −1 after placebo and from − 0.20 to − 6.48 litres min−1 %−1 after almitrine. The response was greater after almitrine in six of the seven subjects, and the difference was significant for the whole group (P < 0.05). 3. Hypoxic ventilatory drive measured using transient hypoxia ranged from −0.19 to −1.59 litres min−1 %−1 after placebo and from −0.09 to −1.62 litres min−1 %−1 after almitrine. The response was not consistently greater after almitrine, and the difference was not significant for the group. 4. Difficulties in accurately quantifying a brief rise in minute ventilation after transient hypoxia, particularly in subjects with a low hypoxic ventilatory drive, may have masked small changes in the slope of the minute ventilation/arterial oxygen saturation relationship with this method. However, the significant increase in the response to progressive isocapnic hypoxia after almitrine suggests that the failure to demonstrate an effect using transient hypoxic stimuli was not solely due to between-day variation in hypoxic ventilatory drive or the small numbers of subjects studied. 5. We conclude that, although transient hypoxia avoids any central depression of ventilation that might result from the prolonged hypoxia used in the conventional steady state or progressive isocapnic methods (thereby leading to underestimation of the hypoxic ventilatory drive), the ventilatory response to such transient stimuli is also affected by factors other than peripheral chemoreceptor activity.
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Martinez, Chloe-Anne, Bernadette Kerr, Charley Jin, Peter Cistulli, and Kristina Cook. "Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells." International Journal of Molecular Sciences 20, no. 2 (January 21, 2019): 445. http://dx.doi.org/10.3390/ijms20020445.
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Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression. Rapid intermittent hypoxia from OSA has been proposed to increase HIF-1 activity and this may occur in tumors. The effect of exposing a developing tumor to OSA-like intermittent hypoxia is largely unknown. We have built a cell-based model of physiological OSA tissue oxygenation in order to study the effects of intermittent hypoxia in HCT116 colorectal cancer cells. We found that HIF-1α increases following intermittent hypoxia and that the expression of HIF-target genes increases, including those involved in glycolysis, the hypoxic pathway and extracellular matrix remodeling. Expression of these genes acts as a ‘hypoxic’ signature which is associated with a worse prognosis. The total dose of hypoxia determined the magnitude of change in the hypoxic signature rather than the frequency or duration of hypoxia-reoxygenation cycles per se. Finally, transcription of HIF1A mRNA differs in response to chronic and intermittent hypoxia suggesting that HIF-1α may be regulated at the transcriptional level in intermittent hypoxia and not just by the post-translational oxygen-dependent degradation pathway seen in chronic hypoxia.
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Brendel, Heike, Jennifer Mittag, Anja Hofmann, Helene Hempel, Sindy Giebe, Patrick Diaba-Nuhoho, Steffen Wolk, Christian Reeps, Henning Morawietz, and Coy Brunssen. "NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia—Complementing Prostacyclin." Antioxidants 13, no. 10 (September 27, 2024): 1178. http://dx.doi.org/10.3390/antiox13101178.
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Aim: The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H2O2 production. Therefore, we aimed to elucidate NOX4′s significance in endothelial function under hypoxia. Methods: Human vessels, in addition to murine vessels from Nox4-/- mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results: In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase (PTGIS). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4-/- mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusion: Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS.
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Cutler, Michael J., Nicolette Muenter Swift, David M. Keller, Wendy L. Wasmund, and Michael L. Smith. "Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea." Journal of Applied Physiology 96, no. 2 (February 2004): 754–61. http://dx.doi.org/10.1152/japplphysiol.00506.2003.
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Obstructive sleep apnea (OSA) is associated with transient elevation of muscle sympathetic nerve activity (MSNA) during apneic events, which often produces elevated daytime MSNA in OSA patients. Hypoxia is postulated to be the primary stimulus for elevated daytime MSNA in OSA patients. Therefore, we studied the effects of 20 min of intermittent voluntary hypoxic apneas on MSNA during 180 min of recovery. Also, we compared MSNA during recovery after either 20 min of intermittent voluntary hypoxic apneas, hypercapnic hypoxia, or isocapnic hypoxia. Consistent with our hypothesis, both total MSNA and MSNA burst frequency were elevated after 20 min of intermittent hypoxic apnea compared with baseline ( P < 0.05). Both total MSNA and MSNA burst frequency remained elevated throughout the 180-min recovery period and were statistically different from time control subjects throughout this period ( P < 0.05). Finally, MSNA during recovery from intermittent hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia were not different ( P = 0.50). Therefore, these data support the hypothesis that short-term exposure to intermittent hypoxic apnea results in sustained elevation of MSNA and that hypoxia is the primary mediator of this response.
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Wodopia, Ralf, Hyun Soo Ko, Javiera Billian, Rudolf Wiesner, Peter Bärtsch, and Heimo Mairbäurl. "Hypoxia decreases proteins involved in epithelial electrolyte transport in A549 cells and rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 6 (December 1, 2000): L1110—L1119. http://dx.doi.org/10.1152/ajplung.2000.279.6.l1110.
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Fluid reabsorption from alveolar space is driven by active Na reabsorption via epithelial Na channels (ENaCs) and Na-K-ATPase. Both are inhibited by hypoxia. Here we tested whether hypoxia decreases Na transport by decreasing the number of copies of transporters in alveolar epithelial cells and in lungs of hypoxic rats. Membrane fractions were prepared from A549 cells exposed to hypoxia (3% O2) as well as from whole lung tissue and alveolar type II cells from rats exposed to hypoxia. Transport proteins were measured by Western blot analysis. In A549 cells, α1- and β1-Na-K-ATPase, Na/K/2Cl cotransport, and ENaC proteins decreased during hypoxia. In whole lung tissue, α1-Na-K-ATPase and Na/K/2Cl cotransport decreased. α- and β-ENaC mRNAs also decreased in hypoxic lungs. Similar results were seen in alveolar type II cells from hypoxic rats. These results indicate a slow decrease in the amount of Na-transporting proteins in alveolar epithelial cells during exposure to hypoxia that also occurs in vivo in lungs from hypoxic animals. The reduced number of transporters might account for the decreased transport activity and impaired edema clearance in hypoxic lungs.
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White, Hilary A., Yi Jin, Louis G. Chicoine, Bernadette Chen, Yusen Liu, and Leif D. Nelin. "Hypoxic proliferation requires EGFR-mediated ERK activation in human pulmonary microvascular endothelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 5 (May 1, 2017): L649—L656. http://dx.doi.org/10.1152/ajplung.00267.2016.
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We have previously shown that hypoxic proliferation of human pulmonary microvascular endothelial cells (hPMVECs) depends on epidermal growth factor receptor (EGFR) activation. To determine downstream signaling leading to proliferation, we tested the hypothesis that hypoxia-induced proliferation in hPMVECs would require EGFR-mediated activation of extracellular signal-regulated kinase (ERK) leading to arginase II induction. To test this hypothesis, hPMVECs were incubated in either normoxia (21% O2, 5% CO2) or hypoxia (1% O2, 5% CO2) and Western blotting was performed for EGFR, arginase II, phosphorylated-ERK (pERK), and total ERK (ERK). Hypoxia led to greater EGFR, pERK, and arginase II protein levels than did normoxia in hPMVECs. To examine the role of EGFR in these hypoxia-induced changes, hPMVECs were transfected with siRNA against EGFR or a scrambled siRNA and placed in hypoxia. Inhibition of EGFR using siRNA attenuated hypoxia-induced pERK and arginase II expression as well as the hypoxia-induced increase in viable cell numbers. hPMVECs were then treated with vehicle, an EGFR inhibitor (AG1478), or an ERK pathway inhibitor (U0126) and placed in hypoxia. Pharmacologic inhibition of EGFR significantly attenuated the hypoxia-induced increase in pERK level. Both AG1478 and U0126 also significantly attenuated the hypoxia-induced increase in viable hPMVECs numbers. hPMVECs were transfected with an adenoviral vector containing arginase II (AdArg2) and overexpression of arginase II rescued the U0126-mediated decrease in viable cell numbers in hypoxic hPMVECs. Our findings suggest that hypoxic activation of EGFR results in phosphorylation of ERK, which is required for hypoxic induction of arginase II and cellular proliferation.
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Dzhalilova, D. Sh, A. M. Kosyreva, I. S. Tsvetkov, and O. V. Makarova. "Phagocytic activity of peripheral blood monocytes under <i>in vivo</i> and <i>in vitro</i> hypoxia conditions in tolerant and susceptible to oxygen deficiency rats." Medical Immunology (Russia) 25, no. 3 (June 1, 2023): 551–56. http://dx.doi.org/10.15789/1563-0625-pao-2779.
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It is known that there are individual differences in resistance to hypoxia, which can determine the predisposition to the development and severity of various diseases, including infectious, inflammatory and tumor. There are no standardized methods for assessing resistance to hypoxia in experimental animals and humans without hypoxic exposure. The search for molecular-biological markers, identifying people with different resistance to oxygen deficiency under normoxic conditions or under moderate hypoxic exposure is undoubtedly efficient. It is possible that the assessment of the basic resistance to hypoxia can help to predict the development and severity of the course of diseases, the mechanisms of which are associated with oxygen deficiency. One of the methods to assess organism resistance to hypoxia without exposure in a decompression chamber or in highland conditions can be modeling hypoxia in vitro. The aim of the study was to characterize the phagocytic activity of peripheral blood monocytes in tolerant and susceptible to hypoxia Wistar rats under normoxic conditions, as well as after hypoxic exposure in vitro and in vivo. The resistance of rats to hypoxia was determined by the gasping time at an altitude of 11.500 m in a decompression chamber. A month after determining the resistance to hypoxia, one group of rats was placed in a decompression chamber at an altitude of 5,000 m for 1 hour to simulate the hypoxic state in vivo. Blood from the tail vein of the other group of rats was placed in 1% oxygen for 1 hour to simulate the hypoxic state in vitro. The phagocytic activity of peripheral blood monocytes was assessed by flow cytometry. It was demonstrated that phagocytic activity of monocytes did not differ in tolerant and susceptible to hypoxia rats under normoxic conditions. The phagocytic activity of monocytes after in vitro and in vivo hypoxic exposure was higher in tolerant to hypoxia animals in comparison to susceptible ones. An increase in the phagocytic activity of monocytes compared to normoxia conditions was observed only in tolerant rats under in vitro conditions of hypoxic exposure. The obtained results indicate that tolerant and susceptible to hypoxia organisms differ in the phagocytic activity of monocytes under conditions of oxygen deficiency, which can determine the course of inflammatory and tumor diseases. The data obtained will be the basis for further experimental investigations organism hypoxia resistance markers.
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Ogata, M., M. Ohe, D. Katayose, and T. Takishima. "Modulatory role of EDRF in hypoxic contraction of isolated porcine pulmonary arteries." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 3 (March 1, 1992): H691—H697. http://dx.doi.org/10.1152/ajpheart.1992.262.3.h691.
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To examine the hypothesis that suppression of basal release of endothelium-derived relaxing factor (EDRF) by hypoxia might be related to the mechanism of hypoxic pulmonary vasoconstriction, rings of porcine pulmonary artery (PA, 2 mm OD) were suspended in organ chambers and changes in isometric force were measured. Hypoxia significantly reduced endothelium-dependent relaxation induced by acetylcholine and augmented contractile response to phenylephrine. This augmentation by hypoxia was not seen in rings without endothelium. Contractile response to phenylephrine was also enhanced by removal of endothelium. With 15 min of hypoxia, PA contracted and guanosine 3',5'-cyclic monophosphate content decreased. Pretreatment with 10(-6) M methylene blue, 3 x 10(-7) M oxyhemoglobin, and 9.6 x 10(-5) M NG-monomethyl-L-arginine significantly enhanced hypoxic contraction. Furthermore, removal of endothelium also enhanced hypoxic contraction. These results suggest that suppression of basally released EDRF by hypoxia was not the cause of the contractile response to hypoxia and that EDRF modulates the hypoxic contraction of porcine PA in basal conditions at this diameter.
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Huynh, Kenneth N., Sriram Rao, Bradley Roth, Theodore Bryan, Dayantha M. Fernando, Farshid Dayyani, David Imagawa, and Nadine Abi-Jaoudeh. "Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma." Cancers 15, no. 10 (May 12, 2023): 2738. http://dx.doi.org/10.3390/cancers15102738.
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Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.
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Rytkönen, Kalle T., Gillian M. C. Renshaw, Petra P. Vainio, Kevin J. Ashton, Grant Williams-Pritchard, Erica H. Leder, and Mikko Nikinmaa. "Transcriptional responses to hypoxia are enhanced by recurrent hypoxia (hypoxic preconditioning) in the epaulette shark." Physiological Genomics 44, no. 22 (November 15, 2012): 1090–97. http://dx.doi.org/10.1152/physiolgenomics.00081.2012.
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All animals require molecular oxygen for aerobic energy production, and oxygen availability has played a particularly important role in the evolution of aquatic animals. This study investigates how previous exposure to hypoxia (preconditioning) primes protective transcriptional responses in a hypoxia-tolerant vertebrate species, the epaulette shark ( Hemiscyllium ocellatum). The epaulette shark is a basal cartilaginous fish that in its natural environment experiences cyclic hypoxic periods. We evaluated whether the transcription of a set of crucial prosurvival genes is affected differently by a single short-term (2 h) exposure to sublethal hypoxia compared with eight such successive hypoxia exposures (hypoxia preconditioning). We discovered that hypoxia preconditioning amplifies transcriptional responses compared with animals that experienced a single hypoxic bout. In the heart we observed that hypoxic preconditioning, but not a single hypoxic exposure, resulted in higher transcript levels of genes that regulate oxygen and energy homeostasis, including those of hypoxia-inducible factor-1 alpha, adenosine signaling pathway components, and genes affecting circulation [prostaglandin synthetase 2 ( cox-2) and natriuretic peptide C]. This suggests that in a single short-term hypoxic bout, the responses to low oxygen are regulated at the level of pre-existing proteins or translational and posttranslational machinery, whereas transcriptional responses are induced in experiments that parallel the natural environmental cycles of oxygen availability. These findings have general implications for understanding how vertebrates regulate protective gene expression upon physiological stress.
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O’Leary, Andrew J., Sarah E. Drummond, Deirdre Edge, and Ken D. O’Halloran. "Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–19. http://dx.doi.org/10.1155/2018/4805493.
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Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2 = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1α protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy.
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Fletcher, E. C., G. Bao, and C. C. Miller. "Effect of recurrent episodic hypocapnic, eucapnic, and hypercapnic hypoxia on systemic blood pressure." Journal of Applied Physiology 78, no. 4 (April 1, 1995): 1516–21. http://dx.doi.org/10.1152/jappl.1995.78.4.1516.
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We have described a rat model that responds to chronic (8 h/day, 35 days) repetitive nonapneic episodic (cycled every 30 s) hypocapnic hypoxia with sustained increase in systemic blood pressure. Because the usual blood gas change of apnea is mildly increased CO2, we hypothesized that episodic hypoxia ranging from eucapnea to hypercapnia might cause a greater chronic increase in blood pressure than hypocapnic hypoxia in this model. Five groups of male Sprague-Dawley rats were studied: unhandled group received no treatment, sham group received compressed air in their chambers, hypocapnic hypoxic group received episodic hypoxia for 35 days, eucapnic hypoxic group received the same level of hypoxia but with 7–10% inspired fraction of CO2, and hybercarbic hypoxic group received hypoxia with 11–14% inspired fraction of CO2. Mean arterial blood pressure was measured in unrestrained conscious animals at baseline and after 35 days under their respective study conditions. Neither episodic eucapnic nor hypercarbic hypoxia had any additional effect on the changes in chronic diurnal blood pressure compared with hypocapnic hypoxia. These results suggest that the sympathetic nervous system or other neurohumoral systems contributing to chronic diurnal blood pressure elevation may be maximally stimulated by hypoxia or there may be some protective mechanism limiting the blood pressure response to asphyxia in this rat model.
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Cowburn, Andrew S., Alexi Crosby, David Macias, Cristina Branco, Renato D. D. R. Colaço, Mark Southwood, Mark Toshner, et al. "HIF2α–arginase axis is essential for the development of pulmonary hypertension." Proceedings of the National Academy of Sciences 113, no. 31 (July 18, 2016): 8801–6. http://dx.doi.org/10.1073/pnas.1602978113.
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Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.
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Itoh, Mai, Yusuke Takahashi, Yuki Okuhashi, and Shuji Tohda. "Effects of Hypoxia on HIF, Notch, Akt, and NF-κB Signaling in Leukemia Cell Lines." Blood 122, no. 21 (November 15, 2013): 3874. http://dx.doi.org/10.1182/blood.v122.21.3874.3874.
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Abstract Background Leukemia stem cells reside in the bone marrow niche under hypoxic conditions. The activity of various signaling pathways in the hypoxic environment should be known to understand the pathophysiology of leukemia stem cells. Hypoxia is known to stabilize HIF1α, which transactivates various genes allowing the cell to adapt to hypoxic conditions. Two theories have been reported regarding crosstalk between HIF and Notch signaling; one suggests that HIF1α binds to cleaved Notch1, which results in stabilization of Notch signaling, and the second suggests that HIF1α represses a negative feedback loop of the Notch1-Hes1 system by inhibiting Hes1 binding to the HES1 promoter and thus enhancing Notch signaling. In this study, we examined the activity of various signaling pathways in cells cultured under normoxia and hypoxia. We discovered novel processes for HIF, Notch, and their down-stream signaling. Methods Two T-ALL cell lines (KOPT-K1 and DND-41), 3 AML cell lines (NB4, THP-1, and TMD7), and 1 CML cell line (K562) were used in this study. Cells were cultured under normoxia or hypoxia (1% O2). The effect of hypoxia on cell growth was examined using a colorimetric WST-1 assay. The effect of hypoxia on replication of clonogenic cells was studied by colony assay after suspension culture under normoxia or hypoxia. The expression and activation of signaling proteins were examined by immunoblotting using lysates from cells cultured under normoxia or hypoxia for 4, 8, and 24 hours. In some experiments, we used lysates from cells cultured with recombinant Notch ligand Delta1 protein. Results Hypoxic conditions reduced cell growth and amplification of clonogenic cells when compared to the normoxic condition. Hypoxia enhanced HIF1α levels in all 6 cell lines and increased HIF2α levels in 4 cell lines. HIF2α was not expressed in NB4 and THP-1 cells. Hypoxia reduced the levels of Notch1 and cleaved Notch1 in KOPT-K1, DND-41, and NB4 cells. Notch1 expression was not affected by hypoxia in THP-1, TMD7, and K562 cells. In KOPT-K1, DND-41, and NB4 cells, hypoxia reduced Hes1 expression. In KOPT-K1 cells, Hes1 levels decreased after 4–8 hours under hypoxic conditions; however, the levels increased after 24 hours. Hypoxia suppressed Myc expression in 4 cell lines. Hypoxia also promoted Akt phosphorylation in KOPT-K1, NB4, and K562 cells but suppressed Akt phosphorylation in DND-41 cells without affecting total Akt levels. Hypoxia suppressed NF-κB phosphorylation without affecting total NF-κB protein levels in all cell lines. Delta1 enhanced cleaved Notch1 fragment levels in 4 myeloid cell lines under normoxia and hypoxia. The enhanced Hes1 expression was not significantly different between normoxia and hypoxia. Discussion We discovered a novel relationship between hypoxia and Notch signaling. Specifically, hypoxia suppressed Notch1 expression and activation, while hypoxia increased HIF1α and HIF2α levels. We found that Hes1 levels decreased and subsequently increased in KOPT-K1 cells cultured under hypoxia. This could be due to the decrease of cleaved Notch1 as shown here, and subsequent enhancement of Notch signaling owing to increased HIF1α as mentioned in Background section. Hypoxia also suppressed Myc expression and NF-κB phosphorylation, which was likely due to Notch1 suppression. The effect of hypoxia on Akt phosphorylation varied depending on cell lines; however, determining the underlying cause requires further study. In conclusion, we determined that the activities in various signaling pathways under hypoxia differ from those under normoxia. These findings would contribute to the development of various molecular-targeted therapies against leukemic cells, especially leukemia stem cells under hypoxic conditions. Disclosures: No relevant conflicts of interest to declare.
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Massik, J., M. D. Jones, M. Miyabe, Y. L. Tang, M. L. Hudak, R. C. Koehler, and R. J. Traystman. "Hypercapnia and response of cerebral blood flow to hypoxia in newborn lambs." Journal of Applied Physiology 66, no. 3 (March 1, 1989): 1065–70. http://dx.doi.org/10.1152/jappl.1989.66.3.1065.
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Individual effects of hypoxic hypoxia and hypercapnia on the cerebral circulation are well described, but data on their combined effects are conflicting. We measured the effect of hypoxic hypoxia on cerebral blood flow (CBF) and cerebral O2 consumption during normocapnia (arterial PCO2 = 33 +/- 2 Torr) and during hypercapnia (60 +/- 2 Torr) in seven pentobarbital-anesthetized lambs. Analysis of variance showed that neither the magnitude of the hypoxic CBF response nor cerebral O2 consumption was significantly related to the level of arterial PCO2. To determine whether hypoxic cerebral vasodilation during hypercapnia was restricted by reflex sympathetic stimulation we studied an additional six hypercapnic anesthetized lambs before and after bilateral removal of the superior cervical ganglion. Sympathectomy had no effect on base-line CBF during hypercapnia or on the CBF response to hypoxic hypoxia. We conclude that the effects of hypoxic hypoxia on CBF and cerebral O2 consumption are not significantly altered by moderate hypercapnia in the anesthetized lamb. Furthermore, we found no evidence that hypercapnia results in a reflex increase in sympathetic tone that interferes with the ability of cerebral vessels to dilate during hypoxic hypoxia.
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Bureau, M. A., A. Cote, P. W. Blanchard, S. Hobbs, P. Foulon, and D. Dalle. "Exponential and diphasic ventilatory response to hypoxia in conscious lambs." Journal of Applied Physiology 61, no. 3 (September 1, 1986): 836–42. http://dx.doi.org/10.1152/jappl.1986.61.3.836.
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This study was undertaken to test the hypothesis that in the neonate the hypoxic chemoreflex drive adapts to steady-state hypoxia but not to progressive hypoxia. First we have compared the ventilatory (VE) response of 2-day-old conscious lambs to steady-state hypoxia with their response to progressive hypoxia. Second, we have quantified the chemoreceptor excitatory function operating at the end of each period of hypoxia by studying the immediate VE response to the withdrawal of the hypoxic stimulus. Lambs responded to steady-state hypoxia [fractional concentration of inspired O2 (FIO2) = 0.08] by a diphasic VE response but responded to progressive hypoxia (FIO2 0.21–0.08) by an exponential VE increase. Hyperventilation in steady-state hypoxia was transient; VE increased immediately from 532 to a mean peak response of 712 ml X kg-1 X min-1 and decreased to 595 ml X kg-1. min-1 within 10 min. With progressive hypoxia, VE increased within 13 min from 514 to 705 ml X kg-1 X min-1. At the end of steady-state and progressive hypoxia the abrupt withdrawal of the hypoxic drive caused an instantaneous VE decrease to 390 and 399 ml X kg-1 X min-1, respectively; the VE decrease was respectively 306 and 205 ml X kg-1 X min-1 (P less than 0.05). This demonstrates that during steady-state hypoxia the lambs had suffered a loss of one third of the chemoreceptor excitatory function.(ABSTRACT TRUNCATED AT 250 WORDS)
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Wilkinson, Katherine A., Kimberly Huey, Bruce Dinger, Liang He, Salvatore Fidone, and Frank L. Powell. "Chronic hypoxia increases the gain of the hypoxic ventilatory response by a mechanism in the central nervous system." Journal of Applied Physiology 109, no. 2 (August 2010): 424–30. http://dx.doi.org/10.1152/japplphysiol.01311.2009.
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We studied the effects of the ventilatory stimulant doxapram to test the hypothesis that chronic hypoxia increases the translation of carotid body afferent input into ventilatory motor efferent output by the central nervous system. Chronic hypoxia (inspired Po2 = 70 Torr, 2 days) significantly increased the ventilatory response to an intravenous infusion of a high dose of doxapram in conscious, unrestrained rats breathing normoxic or hypoxic gas. The in vitro carotid body response to hypoxia increased with chronic hypoxia, but the response was not increased with a high dose of doxapram. Similarly, the phrenic nerve response to doxapram in anesthetized rats with carotid bodies denervated did not change with 7 days of chronic hypoxia. The results support the hypothesis that chronic hypoxia causes plasticity in the central component of the carotid chemoreceptor ventilatory reflex, which increases the hypoxic ventilatory response. We conclude that doxapram provides a promising tool to study the time course of changes in the central gain of the hypoxic ventilatory response during chronic hypoxia in awake animals and humans.
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Chin, K., M. Ohi, M. Hirai, T. Kuriyama, Y. Sagawa, and K. Kuno. "Breathing during sleep with mild hypoxia." Journal of Applied Physiology 67, no. 3 (September 1, 1989): 1198–207. http://dx.doi.org/10.1152/jappl.1989.67.3.1198.
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To investigate ventilatory response to mild hypoxia during non-rapid-eye-movement sleep, we administered approximately 16% O2 (which corresponds to concentrations found in commercial high altitude air craft) to 12 normal subjects by using a Venturi mask, which did not alter the breathing pattern during this study. Under mild hypoxia, inspiratory minute ventilation during sleep showed an initial rapid increase (P less than 0.001) but then declined significantly (P less than 0.001) and stabilized. Stable levels differed among individuals and, compared with those measured before hypoxia, were significantly lower in some subjects, higher in one, and essentially unchanged in the others. The initial rapid increase in minute ventilation after mild hypoxia during sleep correlated with the respective values of hypoxic ventilatory response during the awake state (P less than 0.01), but the final lowered levels did not. We conclude that the ventilatory response after mild hypoxia during sleep is biphasic and hypoxic depression exerts considerable influence on ventilation under mild hypoxia during sleep. So we should take hypoxic depression into consideration to evaluate the response to hypoxia during sleep.
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Tátrai, Enikő, Ivan Ranđelović, Sára Eszter Surguta, and József Tóvári. "Role of Hypoxia and Rac1 Inhibition in the Metastatic Cascade." Cancers 16, no. 10 (May 14, 2024): 1872. http://dx.doi.org/10.3390/cancers16101872.
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The hypoxic condition has a pivotal role in solid tumors and was shown to correlate with the poor outcome of anticancer treatments. Hypoxia contributes to tumor progression and leads to therapy resistance. Two forms of a hypoxic environment might have relevance in tumor mass formation: chronic and cyclic hypoxia. The main regulators of hypoxia are hypoxia-inducible factors, which regulate the cell survival, proliferation, motility, metabolism, pH, extracellular matrix function, inflammatory cells recruitment and angiogenesis. The metastatic process consists of different steps in which hypoxia-inducible factors can play an important role. Rac1, belonging to small G-proteins, is involved in the metastasis process as one of the key molecules of migration, especially in a hypoxic environment. The effect of hypoxia on the tumor phenotype and the signaling pathways which may interfere with tumor progression are already quite well known. Although the role of Rac1, one of the small G-proteins, in hypoxia remains unclear, predominantly, in vitro studies performed so far confirm that Rac1 inhibition may represent a viable direction for tumor therapy
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Hannifin, Sean, Ashley M. Mello, Tenzin Ngodup, Katelyn L. Donahue, Marina Pasca di Magliano, and Kyoung Eun Lee. "Abstract A038: The hypoxic regulation of macrophage function in pancreatic cancer." Cancer Research 84, no. 17_Supplement_2 (September 15, 2024): A038. http://dx.doi.org/10.1158/1538-7445.pancreatic24-a038.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is marked by an extensive fibroinflammatory stroma and a low-oxygen (hypoxic) microenvironment, which contribute to disease progression and therapeutic resistance. Within the PDAC stroma, macrophages and cancer-associated fibroblasts (CAFs) are the predominant cell types. Macrophages are a major immunosuppressive population in PDAC. These cells are highly plastic and, as a result, their environment plays an important role in regulating their function. Macrophages adapt to hypoxia primarily by stabilizing hypoxia-inducible factors (HIFs), which are oxygen-labile transcription factors. Although PDAC is profoundly hypoxic and both the tumor cells and stromal cells experience hypoxia, the effects of hypoxia and HIFs on macrophages and their interactions with other stromal cells in PDAC are not yet fully understood. We found that hypoxia promotes the acquisition of inflammatory cancer-associated fibroblasts (inflammatory CAFs), a fibroblast subtype that produces high levels of cytokines and chemokines. Utilizing a hypoxia marker in mouse models of PDAC, we have observed that inflammatory CAFs and macrophages are predominantly situated in hypoxic tumor regions compared with normoxic regions, while T cells are largely absent from these oxygen-poor regions. These preliminary data raise the possibility that inflammatory fibroblasts induced by hypoxia promote macrophage infiltration into hypoxic tumor regions and facilitate an immunosuppressive macrophage phenotype. We have also found that when macrophages are exposed to conditioned media derived from fibroblast cultures under either hypoxic or normoxic conditions, factors secreted from the hypoxia-exposed fibroblasts promote an immunosuppressive macrophage phenotype. We are currently identifying the factors released from hypoxic fibroblasts that drive the immunosuppressive macrophage phenotype. Future work will focus on evaluating the effects of macrophage-intrinsic responses to hypoxia through HIFs on pancreatic tumorigenesis in vivo. Citation Format: Sean Hannifin, Ashley M Mello, Tenzin Ngodup, Katelyn L Donahue, Marina Pasca di Magliano, Kyoung Eun Lee. The hypoxic regulation of macrophage function in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A038.