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Cells Dec 2021Mitochondrial dehydrogenases are differentially stimulated by Ca. Ca has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the...
Mitochondrial dehydrogenases are differentially stimulated by Ca. Ca has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca effects are biphasic: small increases in Ca concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca-dependent O utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific.
Topics: Animals; Calcium; Cell Respiration; Energy Metabolism; Kidney; Mitochondria, Heart; Models, Biological; Oxidative Phosphorylation; Oxygen Consumption; Rats, Sprague-Dawley; Substrate Specificity; Time Factors; Rats
PubMed: 35011693
DOI: 10.3390/cells11010131 -
Journal of Artificial Organs : the... Mar 2024Hollow fiber membrane is incorporated into an extracorporeal membrane oxygenator (ECMO), and the function of the membrane determines the ECMO's functions, such as gas... (Review)
Review
Hollow fiber membrane is incorporated into an extracorporeal membrane oxygenator (ECMO), and the function of the membrane determines the ECMO's functions, such as gas transfer rate, biocompatibility, and durability. In Japan, the membrane oxygenator to assist circulation and ventilation is approved for ECMO support. However, in all cases, the maximum use period has been only 6 h, and so-called 'off-label use' is common for ECMO support of severely ill COVID-19 patients. Under these circumstances, the HLS SET Advanced (Getinge Group Japan K.K.) was approved in 2020 for the first time in Japan as a membrane oxygenator with a two-week period of use. Following this membrane oxygenator, it is necessary to establish a domestic ECMO system that is approved for long-term use and suitable for supporting patients. Looking back on the evolution of ECMO so far, Japanese researchers and manufacturers have also contributed to the developments of ECMO globally. Currently, excellent membrane oxygenators and systems have been marketed by Japanese manufacturers and some of them are globally acclaimed, but in fact, most of the ECMO membranes are not made in Japan. Fortunately, Japan has led the world in the fields of membrane separation technology and hollow fiber membrane production. In the wake of this pandemic, from the perspective of medical and economic security, the practical use of purely domestic hollow fiber membranes and membrane oxygenators for long-term ECMO is imperative in anticipation of the next pandemic.
Topics: Humans; Oxygenators, Membrane; Extracorporeal Membrane Oxygenation; Equipment Design; Japan
PubMed: 36914927
DOI: 10.1007/s10047-023-01389-w -
The Journal of Extra-corporeal... Mar 2021New cardiopulmonary bypass device techniques emerge and are reported in the scientific literature. The extent to which they are actually adopted into clinical practice...
New cardiopulmonary bypass device techniques emerge and are reported in the scientific literature. The extent to which they are actually adopted into clinical practice is not well known. Since 1989, we have periodically surveyed pediatric cardiac centers to ascertain practice patterns. In December 2016, a 186-question perfusion survey was distributed to pediatric cardiac surgery centers all over the world using a Web-based survey tool. Responses were received from 93 North American (NA) centers (the United States and Canada) and 67 non-NA (NNA) centers, representing 19,645 cumulative annual procedures in NA and 27,776 in NNA centers on patients <18 years. Wide variation in practice was evident across geographic regions. However, the most common pediatric circuit consisted of a hard-shell (open) venous reservoir, an arterial roller pump, and a hollow-fiber membrane oxygenator with a separate or integrated arterial filter. Compared with our previous surveys, there was increased utilization of all types of safety devices. The use of an electronic perfusion record was reported by 50% of NA centers and 31% of NNA centers. There was wide regional variation in cardioplegia delivery systems and cardioplegia solutions. Seventy-nine percent of the centers reported the use of some form of modified ultrafiltration. The survey demonstrated that there remains variation in perfusion practice for pediatric patients. Future surveys will be useful to evaluate the adoption of emerging perfusion practice guidelines.
Topics: Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child; Heart Arrest, Induced; Humans; Oxygenators; Perfusion
PubMed: 33814602
DOI: 10.1182/ject-2000033 -
Scientific Reports Jun 2021Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy is a rescue strategy for severe cardiopulmonary failure. The estimation of cardiac output during...
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy is a rescue strategy for severe cardiopulmonary failure. The estimation of cardiac output during VA-ECMO is challenging. A lung circuit ([Formula: see text]) and an ECMO circuit ([Formula: see text]) with oxygenators for CO removal ([Formula: see text]CO) and O uptake ([Formula: see text]O) simulated the setting of VA-ECMO with varying ventilation/perfusion ([Formula: see text]/[Formula: see text]) ratios and shunt. A metabolic chamber with a CO/N blend simulated [Formula: see text]CO and [Formula: see text]O. [Formula: see text] was estimated with a modified Fick principle: [Formula: see text] = [Formula: see text] × ([Formula: see text] CO or [Formula: see text]O)/([Formula: see text]CO or [Formula: see text]O). A normalization procedure corrected [Formula: see text]CO values for a [Formula: see text]/[Formula: see text] of 1. Method agreement was evaluated by Bland-Altman analysis. Calculated [Formula: see text] using gaseous [Formula: see text]CO and [Formula: see text]O correlated well with measured [Formula: see text] with a bias of 103 ml/min [- 268 to 185] ml/min; Limits of Agreement: - 306 ml/min [- 241 to - 877 ml/min] to 512 ml/min [447 to 610 ml/min], r 0.85 [0.79-0.88]). Blood measurements of [Formula: see text]CO showed an increased bias (- 260 ml/min [- 1503 to 982] ml/min), clinically not applicable. Shunt and [Formula: see text]/[Formula: see text] mismatch decreased the agreement of methods significantly. This in-vitro simulation shows that [Formula: see text]CO and [Formula: see text]O in steady-state conditions allow for clinically applicable calculations of [Formula: see text] during VA-ECMO therapy.
Topics: Carbon Dioxide; Child; Extracorporeal Membrane Oxygenation; Humans; Models, Cardiovascular; Oxygen; Oxygen Consumption
PubMed: 34075067
DOI: 10.1038/s41598-021-90747-w -
Mitochondrion Jul 2020Plant mitochondrial oxidative phosphorylation is characterised by alternative electron transport pathways with different energetic efficiencies, allowing turnover of... (Review)
Review
Plant mitochondrial oxidative phosphorylation is characterised by alternative electron transport pathways with different energetic efficiencies, allowing turnover of cellular redox compounds like NAD(P)H. These electron transport chain pathways are profoundly affected by soil nitrogen availability, most commonly as oxidized nitrate (NO) and/or reduced ammonium (NH). The bioenergetic strategies involved in assimilating different N sources can alter redox homeostasis and antioxidant systems in different cellular compartments, including the mitochondria and the cell wall. Conversely, changes in mitochondrial redox systems can affect plant responses to N. This review explores the integration between N assimilation, mitochondrial redox metabolism, and apoplast metabolism.
Topics: Ammonium Compounds; Cell Respiration; Energy Metabolism; Gene Expression Regulation, Plant; Homeostasis; NAD; Nitrates; Oxidation-Reduction; Oxidative Phosphorylation; Plant Proteins; Plants
PubMed: 32485334
DOI: 10.1016/j.mito.2020.05.010 -
Clinical Pharmacokinetics Dec 2020Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary life support frequently utilized in catastrophic lung and or cardiac failure. Patients on ECMO... (Observational Study)
Observational Study
BACKGROUND
Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary life support frequently utilized in catastrophic lung and or cardiac failure. Patients on ECMO often receive vancomycin therapy for treatment or prophylaxis against Gram-positive organisms. It is unclear if ECMO affects vancomycin pharmacokinetics, thus we modeled the pharmacokinetic behavior of vancomycin according to ECMO-specific variables.
METHODS
Adult patients receiving vancomycin and Veno-Arterial-ECMO between 12/1/2016 and 10/1/2017 were prospectively enrolled. Extracorporeal membrane oxygenation settings and four sets of pre- and post-oxygenator vancomycin concentrations were collected for each patient. Compartmental models were built and assessed ECMO flow rates on vancomycin clearance and potential circuit sequestration. Bayesian posterior concentrations of the pre- and post-oxygenator concentrations were obtained for each patient, and summary pharmacokinetic parameters were calculated. Simulations were performed from the final model for efficacy and toxicity predictions.
RESULTS
Eight patients contributed 64 serum concentrations. Patients were a median (interquartile range) age of 58.5 years (50.8-62.3) with a calculated creatinine clearance of 39 mL/min (29.5-62.5) and ECMO flow rates of 3980 mL/min (interquartile range = 3493.75-4132.5). A three-compartment model best fit the data (Bayesian: plasma pre-oxygenation R = 0.99, post-oxygenation R = 0.99). Vancomycin clearance was not impacted by ECMO flow rate (p = 0.7). Simulations demonstrated that vancomycin 1 g twice daily was rarely sufficient for minimum inhibitory concentrations > 0.5 mg/L. Doses ≥ 1.5 g twice daily often exceeded toxicity thresholds for exposure.
CONCLUSIONS
Extracorporeal membrane oxygenation flow rates did not influence vancomycin clearance between flow rates of 3500 and 5000 mL/min and vancomycin was not sequestered in ECMO. Common vancomycin regimens resulted in suboptimal efficacy and/or excessive toxicity. Individual therapeutic drug monitoring is recommended for patients on ECMO.
Topics: Anti-Bacterial Agents; Bayes Theorem; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Middle Aged; Oxygenators; Vancomycin
PubMed: 32468446
DOI: 10.1007/s40262-020-00902-1 -
The FEBS Journal Sep 2020Hypoxia-inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected... (Review)
Review
Hypoxia-inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected tissues. Subsequent myeloid cell HIF stabilisation plays key roles in the innate immune response, alongside emerging oxygen-independent roles. Manipulation of regulatory proteins of the HIF transcription factor family can profoundly influence inflammatory profiles, innate immune cell function and pathogen clearance and, as such, has been proposed as a therapeutic strategy against inflammatory diseases. The direction and mode of HIF manipulation as a therapy are dictated by the inflammatory properties of the disease in question, with innate immune cell HIF reduction being, in general, advantageous during chronic inflammatory conditions, while upregulation of HIF is beneficial during infections. The therapeutic potential of targeting myeloid HIFs, both genetically and pharmacologically, has been recently illuminated in vitro and in vivo, with an emerging range of inhibitory and activating strategies becoming available. This review focuses on cutting edge findings that uncover the roles of myeloid cell HIF signalling on immunoregulation in the contexts of inflammation and infection and explores future directions of potential therapeutic strategies.
Topics: Animals; Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunity, Innate; Inflammation; Models, Biological; Oxygen; Signal Transduction
PubMed: 32633061
DOI: 10.1111/febs.15476 -
Artificial Organs Jul 2020The roles of the large membrane surface of the oxygenator and the high mechanical shear stress (HMSS) of the pump in the extracorporeal membrane oxygenation (ECMO)...
The roles of the large membrane surface of the oxygenator and the high mechanical shear stress (HMSS) of the pump in the extracorporeal membrane oxygenation (ECMO) circuit were examined under a pediatric support setting. A clinical centrifugal pump and a pediatric oxygenator were used to construct the ECMO circuit. An identical circuit without the oxygenator was constructed for comparison. Fresh human blood was circulated in the two circuits for 4 hours under the identical pump speed and flow. Blood samples were collected hourly for blood damage assessment, including platelet activation, generation of platelet-derived microparticles (PDMP), losses of key platelet hemostasis receptors (glycoprotein (GP) Ibα (GPIbα) and GPVI), and high molecular weight multimers (HMWM) of von Willebrand factor (VWF) and plasma free hemoglobin (PFH). Platelet adhesion on fibrinogen, VWF, and collagen was further examined. The levels of platelet activation and generation of PDMP and PFH exhibited an increasing trend with circulation time while the expression levels of GPIbα and GPVI receptors on the platelet surface decreased. Correspondingly, the platelets in the blood samples exhibited increased adhesion capacity to fibrinogen and decreased adhesion capacities on VWF and collagen with circulation time. Loss of HMWM of VWF occurred in both circuits. No statistically significant differences were found in all the measured parameters for blood damage and platelet adhesion function between the two circuits. The results indicate that HMSS from the pump played a dominant role in blood damage associated with ECMO and the impact of the large surface of the oxygenator on blood damage was insignificant.
Topics: Blood Platelets; Cell-Derived Microparticles; Child; Extracorporeal Membrane Oxygenation; Healthy Volunteers; Hemorrhage; Humans; Oxygenators, Membrane; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Stress, Mechanical; Thrombosis
PubMed: 31970795
DOI: 10.1111/aor.13646 -
Circulation. Heart Failure Apr 2023Exposure to hyperoxia, a high arterial partial pressure of oxygen (PaO2), may be associated with worse outcomes in patients receiving extracorporeal membrane oxygenator...
BACKGROUND
Exposure to hyperoxia, a high arterial partial pressure of oxygen (PaO2), may be associated with worse outcomes in patients receiving extracorporeal membrane oxygenator (ECMO) support. We examined hyperoxia in the Extracorporeal Life Support Organization Registry among patients receiving venoarterial ECMO for cardiogenic shock.
METHODS
We included Extracorporeal Life Support Organization Registry patients from 2010 to 2020 who received venoarterial ECMO for cardiogenic shock, excluding extracorporeal CPR. Patients were grouped based on PaO2 after 24 hours of ECMO: normoxia (PaO2 60-150 mmHg), mild hyperoxia (PaO2 151-300 mmHg), and severe hyperoxia (PaO2 >300 mmHg). In-hospital mortality was evaluated using multivariable logistic regression.
RESULTS
Among 9959 patients, 3005 (30.2%) patients had mild hyperoxia and 1972 (19.8%) had severe hyperoxia. In-hospital mortality increased across groups: normoxia, 47.8%; mild hyperoxia, 55.6% (adjusted odds ratio, 1.37 [95% CI, 1.23-1.53]; <0.001); severe hyperoxia, 65.4% (adjusted odds ratio, 2.20 [95% CI, 1.92-2.52]; <0.001). A higher PaO2 was incrementally associated with increased in-hospital mortality (adjusted odds ratio, 1.14 per 50 mmHg higher [95% CI, 1.12-1.16]; <0.001). Patients with a higher PaO2 had increased in-hospital mortality in each subgroup and when stratified by ventilator settings, airway pressures, acid-base status, and other clinical variables. In the random forest model, PaO2 was the second strongest predictor of in-hospital mortality, after older age.
CONCLUSIONS
Exposure to hyperoxia during venoarterial ECMO support for cardiogenic shock is strongly associated with increased in-hospital mortality, independent from hemodynamic and ventilatory status. Until clinical trial data are available, we suggest targeting a normal PaO2 and avoiding hyperoxia in CS patients receiving venoarterial ECMO.
Topics: Humans; Shock, Cardiogenic; Hyperoxia; Oxygenators, Membrane; Heart Failure; Oxygen; Hospital Mortality; Hypertension; Retrospective Studies
PubMed: 36871240
DOI: 10.1161/CIRCHEARTFAILURE.122.010328 -
Beyond the Extra Respiration of Phagocytosis: NADPH Oxidase 2 in Adaptive Immunity and Inflammation.Frontiers in Immunology 2021Reactive oxygen species (ROS) derived from the phagocyte NADPH oxidase (NOX2) are essential for host defence and immunoregulation. Their levels must be tightly... (Review)
Review
Reactive oxygen species (ROS) derived from the phagocyte NADPH oxidase (NOX2) are essential for host defence and immunoregulation. Their levels must be tightly controlled. ROS are required to prevent infection and are used in signalling to regulate several processes that are essential for normal immunity. A lack of ROS then leads to immunodeficiency and autoinflammation. However, excess ROS are also deleterious, damaging tissues by causing oxidative stress. In this review, we focus on two particular aspects of ROS biology: (i) the emerging understanding that NOX2-derived ROS play a pivotal role in the development and maintenance of adaptive immunity and (ii) the effects of excess ROS in systemic disease and how limiting ROS might represent a therapeutic avenue in limiting excess inflammation.
Topics: Adaptive Immunity; Animals; Autoimmunity; Cell Respiration; Humans; Inflammation; NADPH Oxidase 2; Oxidative Stress; Phagocytosis; Reactive Oxygen Species
PubMed: 34539670
DOI: 10.3389/fimmu.2021.733918