Milder Hypoxia Research Articles

Recurringly Hypoxic: Bottom Water Oxygen Depletion Is Linked to Temperature and Precipitation in a Great Lakes Estuary

Hypolimnetic hypoxia is expanding globally due to anthropogenic eutrophication and climate warming. Muskegon Lake, a Great Lakes estuary, experiences annually recurring hypoxia, impairing ecological, social, and economic benefits. Using high-frequency, time-series Muskegon Lake Observatory (MLO) data, we quantified the dynamics of hypoxia and developed a hypoxia severity index to estimate the spatiotemporal extent of hypoxia during 2011–2021. We also analyzed United States Geological Survey’s temperature and discharge data on the Muskegon River to explain the annual variability in the hypoxia severity index. Severe hypoxia occurred in warmer years with greater stratification, fewer wind mixing events, warmer winter river temperatures, and less winter and spring precipitation, as in 2012 and 2021. Conversely, milder hypoxia was prevalent in colder years with a later stratification onset, more mixing events, colder river temperatures, and more winter and spring precipitation, as in 2015 and 2019. Thus, knowledge of environmental conditions prior to the onset of stratification may be useful for predicting the potential severity of hypoxia for any year. While consistent multi-year trends in hypoxia were not discernible, our findings suggest that temperature and precipitation are major drivers of hypoxia and that as surface waters warm, it will lead to the further deoxygenation of Earth’s inland waters.

Is serotonin uptake by peripheral tissues sensitive to hypoxia exposure?

In the Gulf toadfish (Opsanus beta), the serotonin (5-HT) transporter (SERT) is highly expressed in the heart, and the heart and gill both demonstrate the capacity for SERT-mediated uptake of 5-HT from the circulation. Because 5-HT is a potent vasoconstrictor in fish, we hypothesized that hypoxia exposure may increase 5-HT uptake by these tissues-and increase excretion of 5-HT-to prevent branchial vasoconstriction that would hamper gas exchange. Spot sampling of blood, bile, and urine revealed that fish exposed to chronic hypoxia (1.83 ± 0.12mg·L-1 O2 for 24-26h) had 41% lower plasma 5-HT in the ventral aorta (immediately following the heart) than in the hepatic vein (immediately before the heart), suggesting enhanced cardiac 5-HT uptake during hypoxia. 5-HT concentrations in the bile were greater than those in the urine, but there were no effects of acute (1.31 ± 0.06mg·L-1 O2 for 25min) or chronic hypoxia on 5-HT levels in these fluids. In 5-HT radiotracer experiments, the presence of tracer in the bile decreased upon hypoxia exposure, but, surprisingly, neither acute nor chronic hypoxia-induced changes in [3H]5-HT uptake in the heart, gill, or other tissues. Given the likely impact of the hypoxia exposure on metabolic rate, future studies should examine the effects of a milder hypoxia exposure on 5-HT uptake into these tissues and the role of 5-HT degradation.

Hypoxic hypometabolism in chicken embryos: conformism and downregulation

Postnatally, during hypoxia the decrease in oxygen consumption (V̇O2) can exceed what expected from the limitation in O2 availability, meaning that V̇O2 -downregulation exceeds O2-conformism. We questioned whether a similar phenomenon could occur prenatally, in chicken embryos at mid- (E11, out of 20.5 days) or near end- (E18) incubation. V̇O2 was measured with an open-flow system in the sequence of normoxia-normothermia (21% O2, 37 °C, 30 min), hypoxia in normothermia (Hx-NT, either 18, 15, 12 or 9% O2, 37 °C, 1 hour), hypoxia in hyperthermia (Hx-HT, up to 43 °C, 1 hour) and return to normoxia-normothermia (30 min). During Hx-NT V̇O2 invariably decreased in a [O2]-dependent fashion. The hypoxic drop in V̇O2 did not require a post-hypoxic payment of the O2-debt, implying that the decrease in V̇O2 reflected hypometabolism. V̇O2 did not differ significantly between Hx-HT and Hx-NT for [O2] = 15% or less, as expected by O2-conformism. Differently, with milder hypoxia (18% O2), V̇O2 during Hx-HT significantly exceeded that in Hx-NT, meaning that the value of V̇O2 in Hx-NT was not limited by O2 supply. We conclude that a phenomenon of hypoxic V̇O2 downregulation like that observed in postnatal mammals can occur also prenatally, in the chicken embryos. The mechanisms at the basis of the downregulation remain unresolved and could combine physiological and cellular processes.

Abstract 502: Sp1 and HIFs mediate synergistic activation of ICAM1 gene under serum starved hypoxia and promotes growth of ovarian cancer

Abstract Cancer tissues are generally exposed to severe hypoxia conditions due to sparse and aberrant vasculature. Hypoxia-inducible factors HIF-1α and HIF-2α (HIF1 and HIF2, respectively) are major transcription factors required for adaptive responses to hypoxia. HIFs complexed with arylhydrocarbon receptor nuclear translocator bind target genes and act as enhancer of transcriptional regulation. This conventional mechanism regulates genes such as VEGF, GLUT1, and HO to improve mild to severe hypoxia conditions. It is likely that various oxygen concentrations and their duration exist within tumor tissue. It appears that adaptive response by HIFs is a major way to overcome stresses under milder hypoxia. However, majority of tumor tissues of many cancer types are known to undergo more severe hypoxic conditions. Thus, additional molecular mechanisms supporting HIFs signaling may be required to enhance survival activity of cancer cells. We have previously demonstrated that FVII gene, which is essential for initiation of extrinsic blood coagulation can be induced in ovarian clear cell carcinoma (CCC) cells in response to hypoxia. Activation of this gene potentially results in thrombotic events frequently observed in cancer patients. We have demonstrated that a physical interaction between Sp1 and HIF2 is a major cause of the activation of this gene under hypoxia. Furthermore, FVII activation is synergistically enhanced when cells are cultured under ischemic condition, in which hypoxia and serum-free conditions coexist. We envisioned that genes regulated by this mechanism are responsible for adaptive response to hypoxia with severity and/or duration characteristic to CCC tissues. Furthermore, ovarian cancer is a most malignant among gynecological diseases. CCC is highly tolerant to chemotherapy and the prognosis is poor. Thus, we first explored genes those are regulated by both Sp1 and HIFs in CCC cells by cDNA microarray analysis. We found that Sp1 and hypoxia inducible factors activate multiple genes under the ischemic condition in CCC cells. Among genes which meet this criteria, ICAM1 is one of a most dramatically induced gene. This transcriptional induction involves activation of NFκB associated with mTOR and autonomously produced TNFα. We further performed xenograft tumor experiments to test whether ICAM1 can be induced and contributes to CCC progression in vivo. It was found that ICAM1 is dramatically induced within xenograft tumor tissues. Tumor growth was evidently suppressed when ICAM1 inducton was abrogated by shRNA transfection. Thus, interplay among transcription factors associated with serum deficiency results in cancer progression. This study highlights importance of adaptive response to serum-starved condition as to how cancer cells overcome severe hypoxic stress. Citation Format: Shiro Koizume, Shin Ito, Yoshiyasu Nakamura, Mitsuyo Yoshihara, Yasuo Takano, Yohei Miyagi. Sp1 and HIFs mediate synergistic activation of ICAM1 gene under serum starved hypoxia and promotes growth of ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 502. doi:10.1158/1538-7445.AM2014-502

Quality of life in adolescents followed after neonatal hypoxic-ishaemic encephalopathy

Background: Hypoxic-ischaemic encephalopathy (HIE) during the perinatal period is a commonly recognized cause of severe, long-term neurological sequelae in children. Milder hypoxia- ischaemia can lead to minor disabilities, which can manifest only later with age-specific cognitive abilities and demands. Methods: We have used prospective, observational study of an inception cohort of 16 adolescents, who had neonatal HIE, compared to a gender- and age-matched control of 16 healthy medical students. Our cohort was selected from the Slovenian population of neonates, referred to the Pediatric Intensive Care Unit at the University Medical Centre Ljubljana, due to mild and moderate HIE, Sarnat stage 1 and 2. HIE was confirmed by generally accepted criteria. We estimated the self-assessed health-related quality of life by using SF-36v2 questionnaire, Rosenberg self-esteem inventory and Unwholesome behaviour questionnaire. Results: Our study included 16 adolescents with HIE, 7 girls (43.8 %) and 9 boys (56.3 %), who were born at a mean gestational age of 35.75 weeks (SD = 3.80) and mean birthweight of 2644g (SD = 815), which represents 50th percentile. Mean age was 21.69 years (SD = 0.87). Adolescents with a history of HIE reported a higher number of additional morbidity yet with a good quality of life. Health-related quality of life was rated high: for adolescents with HIE M = 81.9 (SD = 11.2) and for healthy adolescents M = 75.3 (SD = 11.,5); p = 0.112. The adolescents with HIE odsodid not differ from the healthy adolescents in self-esteem (p = 0.68) and unwholesome behaviours, except for over-eating (p = 0.01). Conclusions: Based on our data of higher morbidity, we propose that children with mild to moderate HIE, even when discharged as healthy, should be subject to a follow-up. They develop compensatory strategies, which enable them to have a good quality of life. We can hope that their compensatory strategies, rather than becoming insufficient when they reach adulthood, will enable them to have a high quality of life.

Oxygenation State and Twilight Vision at 2438 m

Under twilight viewing conditions, hypoxia, equivalent to breathing air at 3048 m (10,000 ft), compromises low contrast acuity, dynamic contrast sensitivity, and chromatic sensitivity. Selected past experiments have been repeated under milder hypoxia, equivalent to altitude exposure below 2438 m (8000 ft), to further define the influence of oxygenation state on mesopic vision. To assess photopic and mesopic visual function, 12 subjects each undertook three experiments using the Contrast Acuity Assessment test, the Frequency Doubling Perimeter, and the Color Assessment and Diagnosis (CAD) test. Experiments were conducted near sea level breathing 15.2% oxygen (balance nitrogen) and 100% oxygen, representing mild hypobaric hypoxia at 2438 m (8000 ft) and the benefit of supplementary oxygen, respectively. Oxygenation state was a statistically significant determinant of visual performance on all three visual parameters at mesopic, but not photopic, luminance. Mesopic sensitivity was greater with supplementary oxygen, but the magnitude of each hypoxic decrement was slight. Hypoxia elevated mesopic contrast acuity thresholds by approximately 4%; decreased mesopic dynamic contrast sensitivity by approximately 2 dB; and extended mean color ellipse axis length by approximately one CAD unit at mesopic luminance (that is, hypoxia decreased chromatic sensitivity). The results indicate that twilight vision may be susceptible to conditions of altered oxygenation at upper-to-mid mesopic luminance with relevance to contemporary night flying, including using night vision devices. Supplementary oxygen should be considered when optimal visual performance is mission-critical during flight above 2438 m (8000 ft) in dim light.

The relationship between sudden severe hypoxia and ischemia-associated spreading depolarization in adult rat brainstem in vivo

Severe ischemia can induce spreading depolarization (SD) in the cerebral cortex, which is thought to contribute significantly to cerebral dysfunction. Whether the mature brainstem shows SD upon reduced oxygen supply has not been investigated although SDs may significantly influence brainstem functions. In anesthetized adult rats, we induced severe short-lasting hypoxia (SSH) by stopping artificial respiration for about 1 min or by ventilation with pure nitrogen for 1, 2 or 3 min, and milder hypoxia by ventilation with 6% O 2 in N 2 for 10 min. We measured DC potentials in the brainstem and cerebral cortex, systemic arterial blood pressure, heart rate and local blood flow at the brainstem or cerebral cortex surface. SSH lasting up to 1 min did not induce DC shifts in native brainstem but reduced heart rate, systemic blood pressure and blood flow in cortex and brainstem. Longer lasting SSH protocols both reduced systemic blood pressure and induced SD in the brainstem, but the magnitude of the cardiovascular response was not influenced by the simultaneous occurrence of SD. When neuronal excitability in the brainstem was artificially enhanced, SSH of 1 min evoked SD but again the magnitude of cardiovascular changes during SSH was not increased. SSH lasting 3 min evoked non-reversible sustained depolarization. SSH did not render the brainstem more excitable for classical SD evoked by local KCl application. Thus, sudden severe hypoxia/ischemia evokes SDs in the brainstem, but the occurrence of the so-elicited SD does not influence the immediate cardiovascular response to SSH.

Hypoxia, hyperoxia, ischemia, and brain necrosis.

Human brains show widespread necrosis when death occurs after coma due to cardiac arrest, but not after hypoxic coma. It is unclear whether hypoxia alone can cause brain damage without ischemia. The relationship of blood oxygenation and vascular occlusion to brain necrosis is also incompletely defined. We used physiologically monitored Wistar rats to explore the relationship among arterial blood oxygen levels, ischemia, and brain necrosis. Hypoxia alone (PaO2 = 25 mm Hg), even at a blood pressure (BP) of 30 mm Hg for 15 minutes, yielded no necrotic neurons. Ischemia alone (unilateral carotid ligation) caused necrosis in 4 of 12 rats, despite a PaO2 > 100 mm Hg. To reveal interactive effects of hypoxia and ischemia, groups were studied with finely graded levels of hypoxia at a fixed BP, and with controlled variation in BP at fixed PaO2. In separate series, focal ischemic stroke was mimicked with transient middle cerebral artery (MCA) occlusion, and the effect of low, normal, and high PaO2 was studied. Quantitated neuropathology worsened with every 10 mm Hg decrement in BP, but the effect of altering PaO2 by 10 mm Hg was not as great, nor as consistent. Autoradiographic study of cerebral blood flow with 14C-iodoantipyrine revealed no hypoxic vasodilatation during ischemia. In the MCA occlusion model, milder hypoxia than in the first series (PaO2 = 46.5 +/- 1.4 mm Hg) exacerbated necrosis to 24.3 +/- 4.7% of the hemisphere from 16.6 +/- 7.0% with normoxia (PaO2 = 120.5 +/- 4.1 mm Hg), whereas hyperoxia (PaO2 = 213.9 +/- 5.8 mm Hg) mitigated hemispheric damage to 7.50 +/- 1.86%. Cortical damage was strikingly sensitive to arterial PaO2, being 12.8 +/- 3.1% of the hemisphere with hypoxia, 7.97 +/-4.63% with normoxia, and only 0.3 +/- 0.2% of the hemisphere with hyperoxia (p < 0.01), and necrosis being eliminated completely in 8 of 10 animals. Hypoxia without ischemia does not cause brain necrosis but hypoxia exacerbates ischemic necrosis. Hyperoxia potently mitigates brain damage in this MCA occlusion model, especially in neocortex.

Developmental changes in ATP utilization during graded hypoxia and reoxygenation in the heart in vivo.

Myocardial ATP utilization and resynthesis during hypoxia and reoxygenation were studied in vivo as a function of maturation. Graded hypoxia was performed in newborn (NB; 4-10 days old, n = 6) and mature sheep (MAT; 30-60 days old, n = 6). Time-resolved 31P-nuclear magnetic resonance was used to monitor myocardial phosphates throughout hypoxia and to monitor reoxygenation concomitant with rate of myocardial O2 consumption (MVO2) measurement. Oxygen delivery and MVO2 were constant in both groups throughout hypoxia, with substantial and similar increases in both parameters during reoxygenation. Hypoxic myocardial lactate release was similar in NB and MAT. Phosphocreatine (PCr), but not ATP, decreased in NB only during milder hypoxia. Rapid PCr and slower ATP depletion occurred with severe hypoxia, consistent with ATP utilization/synthesis imbalance. Depletion rates were higher in MAT. Creatine rephosphorylation rates, measures of mitochondrial function reported as percentage of predicted values, were similar. 34 +/- 12 in NB and 26 +/- 9% in mature lambs. In conclusion, 1) phosphorylation potential decreases in NB but not MAT in response to a decreasing oxygen gradient; 2) ATP utilization during hypoxia increases more in mature lambs; 3) anaerobic ATP production is not greater in NB; and 4) despite the greater energy imbalance imposed on MAT during hypoxia, mitochondrial function is similar to NB during reoxygenation.

Influence of dopamine and norepinephrine on the central ventilatory response to hypoxia in conscious cats

The effects of intravenous administration of agonists and antagonists of dopamine (DA) and norepinephrine (NE) on the central ventilatory response to hypoxia were studied in unanesthetized cats. The experiments were performed in intact animals exposed to CO-hypoxia and in carotid-body denervated animals breathing a hypoxic mixture. The DA agonist, apomorphine (APO) significantly decreased minute ventilation in response to central hypoxia, whereas the opposite effect occurred with the DA antagonist, haloperidol (HAL). Indeed, the characteristic tachypnea elicited by CO or hypoxia was inhibited by APO as the respiratory frequency markedly decreased while tidal volume concomitantly increased. Conversely, HAL administration enhanced the tachypnea during milder hypoxia or reversed the inhibitory action of APO. In contrast, the NE agonist, clonidine (CLO) and antagonists propranolol (PRO) and phenoxybenzamine (PHE) did not cause significant changes in minute ventilation and breathing pattern although CLO tended to attenuate the hypoxic tachypnea. This study confirms, therefore, that catecholamines are involved in the central ventilatory responses to hypoxia and suggests that the brain dopaminergic system plays a major role in the CO of hypoxic tachypnea.

Effect of Hypoxia on Traumatic Brain Injury in Rats: Part 2

The effect of different degrees of hypoxia on phosphate metabolism in the brains of impact-injured rats was studied using in vivo phosphorus-31 magnetic resonance (P-31 MR) spectroscopy. Sequential changes in P-31 MR spectra within 60 minutes of insult were compared among rats with hypoxia alone, impact injury alone, or a combined impact-hypoxic insult. Hypoxia alone (PaO2 of 40 mm Hg for 30 minutes) caused no remarkable changes in phosphorus spectra except a decrease in intracellular pH. In impact-injured rats, the concentration of inorganic phosphate (Pi) increased, but signals for phosphocreatine (PCr) and beta-adenosine triphosphate (beta-ATP) did not change, and the ratio of PCr/Pi changed only slightly to 7% below control value. When rats with a fluid percussion impact injury of 5 atm were subjected to hypoxic conditions of a PaO2 of 40 mm Hg for 15 minutes, the PCr/Pi ratio decreased by 14%, a value significantly below that of the impact alone group (P less than 0.05). After longer periods of hypoxia (PaO2 of 40 mm Hg for 30 minutes) in impact-injured rats, there were marked increases of Pi and significant decreases in signals for PCr and beta-ATP, which caused a marked decrease in the PCr/Pi ratio to 39% below control values (P less than 0.001). Milder hypoxia (PaO2 of 50 mm Hg for 30 minutes) plus impact injury caused smaller changes in high energy metabolite concentrations, and the PCr/Pi ratio decreased to 15% below control values.(ABSTRACT TRUNCATED AT 250 WORDS)