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Free Radical Biology & Medicine Jan 2019Molecular oxygen, reactive oxygen species and free radicals derived from oxygen play important roles in a broad spectrum of physiological and pathological processes. The...
Molecular oxygen, reactive oxygen species and free radicals derived from oxygen play important roles in a broad spectrum of physiological and pathological processes. The quantitative measurement of molecular oxygen in tissues by electron paramagnetic resonance (EPR) has great potential for understanding and diagnosing a number of diseases, and for developing and guiding therapies. This requires improvements in the free radical probe systems that sense and report molecular oxygen levels in vivo. We report on the encapsulation of existing free radical probes in lipophilic gel implants: an in-situ-oleogel and an emulgel, based only on well-known, safe excipients for the incorporation of lipophilic and hydrophilic radicals, respectively. The EPR signals of encapsulated radicals were not altered compared to dissolved radicals. The high solubility of oxygen in lipophilic solvents enhanced oxygen sensitivity. The gels extended the lifetime of the radicals in tissues from tens of minutes to many days, simplifying studies with extended series of measurements. The encapsulated radicals showed a good in vivo response to changes in oxygen supply and seem to circumvent concerns from toxicity of the radical probes. These gels simplify the development of new oxygen-sensitive free radical probes for EPR oximetry by making their in vivo stability, persistence and toxicity a function of the encapsulating gel and not a set of additional requirements for the free radical probe.
Topics: Animals; Cell Respiration; Cells, Cultured; Electron Spin Resonance Spectroscopy; Female; Free Radicals; Hydrophobic and Hydrophilic Interactions; Mice; Mice, Inbred C3H; Muscles; Organic Chemicals; Oximetry; Oxygen; Reactive Oxygen Species; Trityl Compounds
PubMed: 30416100
DOI: 10.1016/j.freeradbiomed.2018.10.442 -
Artificial Organs Mar 2021Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and... (Review)
Review
Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and morbidity, in large part due to the immaturity of the lungs at this stage of development. The standard of care for these patients includes support with mechanical ventilation, which exacerbates lung pathology. Extracorporeal life support (ECLS), also called artificial placenta technology when applied to extremely preterm (EPT) infants, offers an intriguing solution. ECLS involves providing gas exchange via an extracorporeal device, thereby doing the work of the lungs and allowing them to develop without being subjected to injurious mechanical ventilation. While ECLS has been successfully used in respiratory failure in full-term neonates, children, and adults, it has not been applied effectively to the EPT patient population. In this review, we discuss the unique aspects of EPT infants and the challenges of applying ECLS to these patients. In addition, we review recent progress in artificial placenta technology development. We then offer analysis on design considerations for successful engineering of a membrane oxygenator for an artificial placenta circuit. Finally, we examine next-generation oxygenators that might advance the development of artificial placenta devices.
Topics: Artificial Organs; Equipment Design; Extracorporeal Membrane Oxygenation; Female; Humans; Infant, Extremely Premature; Oxygenators, Membrane; Placenta; Pregnancy
PubMed: 32979857
DOI: 10.1111/aor.13827 -
European Journal of Cardio-thoracic... Jun 2021Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is...
OBJECTIVES
Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics.
METHODS
Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured.
RESULTS
There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P < 0.001) and maximal phosphorylating respiration capacity via convergent input through complexes I and II (OXPHOSCI+CII) (7.40 ± 0.24 vs 4-h CPB: 3.91 ± 0.20, P < 0.0001). At 4-h, experimental animals had significantly higher ROS related to non-phosphorylating respiration through complexes I and II (ETSCI+CII) than shams (1.08 ± 0.13 vs 0.64 ± 0.04, P = 0.026).
CONCLUSIONS
Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.
Topics: Animals; Cardiopulmonary Bypass; Cell Respiration; Energy Metabolism; Mitochondria; Oxygen; Reactive Oxygen Species; Swine
PubMed: 33367535
DOI: 10.1093/ejcts/ezaa439 -
Critical Care (London, England) Apr 2023
Topics: Humans; Extracorporeal Membrane Oxygenation; Oxygenators; Thrombosis; Fibrinolysis; Thrombolytic Therapy
PubMed: 37060093
DOI: 10.1186/s13054-023-04433-6 -
The Journal of Extra-corporeal... Dec 2007Since the introduction of cardiopulmonary bypass, clinicians have tried to define the optimal blood flow for a given patient. The difficulty in determining a correct... (Review)
Review
Since the introduction of cardiopulmonary bypass, clinicians have tried to define the optimal blood flow for a given patient. The difficulty in determining a correct blood flow lies in the fact that cardiac surgery is done in a very inhomogeneous population, from neonates to the octogenarian, and often under non-physiologic conditions (hypothermia, hemodilution, low flow, etc.). Although clinicians acknowledge that maintaining a minimum oxygen delivery is more meaningful than using a fixed flow rate based on the metabolic needs of awake resting volunteers, the latter is most used in clinical practice. This is explained by the fact that no values are available on critical oxygen delivery for adequate tissue oxygenation under a given clinical condition. This was an overview of the relevant literature. In most centers, perfusionists use in-line monitoring, such as venous saturation or venous blood gases, for estimation of adequacy of tissue perfusion. Unfortunately, these oxygen-derived parameters have a poor correlation with anaerobic energy supply. Measurement of intermittent whole blood lactate concentration is used to compensate for this poor relationship, but as it monitors the concentration at given time points, it precludes optimally timely intervention by the perfusionist. The physiologic buffering by bicarbonate of the acid generated by converting pyruvate into lactate will produce carbon dioxide. As a consequence, carbon dioxide-derived parameters do have a good correlation with inadequate tissue perfusion. In-line monitoring of carbon dioxide production gives real-time information on tissue perfusion. Use of a standard reference flow for each patient is a poor option, because it does not reflect the metabolic need of the patient. Oxygen-derived parameters, such as venous saturation or partial venous oxygen tension, are poor predictors of anaerobic metabolism. A combination of intermittent whole blood lactate measurement with carbon dioxide-derived parameters predicts anaerobic energy production and allows proactive intervention by the perfusionist.
Topics: Anaerobiosis; Carbon Dioxide; Cardiac Output; Cardiopulmonary Bypass; Extracorporeal Membrane Oxygenation; Humans; Oxygenators, Membrane; Perfusion; Thoracic Surgery
PubMed: 18293819
DOI: No ID Found -
International Journal of Nanomedicine 2018Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly... (Review)
Review
Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression. Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.
Topics: Animals; Cell Hypoxia; Humans; Immunotherapy; Neoplasms; Oxygen; Radiation-Sensitizing Agents; Tumor Hypoxia
PubMed: 30323592
DOI: 10.2147/IJN.S140462 -
Cell Sep 2016The 2016 Albert Lasker Basic Medical Research Award is being awarded to Gregg Semenza, William Kaelin, and Peter Ratcliffe for discovery of the pathway by which human...
The 2016 Albert Lasker Basic Medical Research Award is being awarded to Gregg Semenza, William Kaelin, and Peter Ratcliffe for discovery of the pathway by which human and animal cells sense and adapt to changes in oxygen availability-an essential requirement for survival. Bill and Peter joined Cell editor João Monteiro in an informal conversation about science, medicine, designing experiments, and training the next generation.
Topics: Animals; Awards and Prizes; Cell Hypoxia; Humans; Oxygen
PubMed: 27634317
DOI: 10.1016/j.cell.2016.08.048 -
Pediatric Critical Care Medicine : a... Jun 2013The extracorporeal membrane oxygenation circuit is made of a number of components that have been customized to provide adequate tissue oxygen delivery in patients with...
The extracorporeal membrane oxygenation circuit is made of a number of components that have been customized to provide adequate tissue oxygen delivery in patients with severe cardiac and/or respiratory failure for a prolonged period of time (days to weeks). A standard extracorporeal membrane oxygenation circuit consists of a mechanical blood pump, gas-exchange device, and a heat exchanger all connected together with circuit tubing. Extracorporeal membrane oxygenation circuits can vary from simple to complex and may include a variety of blood flow and pressure monitors, continuous oxyhemoglobin saturation monitors, circuit access sites, and a bridge connecting the venous access and arterial infusion limbs of the circuit. Significant technical advancements have been made in the equipment available for short- and long-term extracorporeal membrane oxygenation applications. Contemporary extracorporeal membrane oxygenation circuits have greater biocompatibility and allow for more prolonged cardiopulmonary support time while minimizing the procedure-related complications of bleeding, thrombosis, and other physiologic derangements, which were so common with the early application of extracorporeal membrane oxygenation. Modern era extracorporeal membrane oxygenation circuitry and components are simpler, safer, more compact, and can be used across a wide variety of patient sizes from neonates to adults.
Topics: Equipment Design; Extracorporeal Membrane Oxygenation; Humans; Oxygenators, Membrane; Vascular Access Devices
PubMed: 23735989
DOI: 10.1097/PCC.0b013e318292dd10 -
Cancer Biology & Therapy Nov 2009Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the... (Review)
Review
Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2-3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.
Topics: Animals; Cell Hypoxia; Humans; Neoplasms; Oxygen; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction
PubMed: 19823031
DOI: 10.4161/cbt.8.21.9988 -
Redox Biology May 2024Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of...
Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.
Topics: Humans; Calcium; Oxygen Consumption; Cell Respiration; Hypoxia; Muscle, Skeletal; Oxygen
PubMed: 38401291
DOI: 10.1016/j.redox.2024.103037