Tissue Oxygen Tension Research Articles

Advanced monitoring in traumatic brain injury: microdialysis.

Here, we review the present state-of-the-art of microdialysis for monitoring patients with severe traumatic brain injury, highlighting the newest developments. Microdialysis has evolved in neurocritical care to become an established bedside monitoring modality that can reveal unique information on brain chemistry. A major advance is recent consensus guidelines for microdialysis use and interpretation. Other advances include insight obtained from microdialysis into the complex, interlinked traumatic brain injury disorders of electrophysiological changes, white matter injury, inflammation and metabolism. Microdialysis has matured into being a standard clinical monitoring modality that takes its place alongside intracranial pressure and brain tissue oxygen tension measurement in specialist neurocritical care centres, as well as being a research tool able to shed light on brain metabolism, inflammation, therapeutic approaches, blood-brain barrier transit and drug effects on downstream targets. Recent consensus on microdialysis monitoring is paving the way for improved neurocritical care protocols. Furthermore, there is scope for future improvements both in terms of the catheters and microdialysate analyser technology, which may further enhance its applicability.

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease

IntroductionWe examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. MethodsThirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). ResultsAt baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DiscussionOur results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Notch1 Signaling Contributes to Hypoxia-induced High Expression of Integrin \u03b21 in Keratinocyte Migration

Oxygen tension is an important micro-environmental factor that affects epidermal development and function. After injury, high oxygen consumption and vascular injury result in partial hypoxia. However, whether hypoxia benefits or hurts wound healing remains controversial. In this study, a tissue oxygen tension monitor was used to detect the spatial and temporal distribution of oxygen in burn wounds. In vitro, we demonstrate that hypoxia promoted the expression of integrin β1 and the migration of keratinocytes. Furthermore, hypoxia-induced migration was slowed by Notch1 ligands and a siRNA against ITGB1 (integrin β1). Our findings suggest that integrin β1 may be an oxygen-sensitive molecule that promotes keratinocyte migration during wound healing and that Notch1 signaling is involved in this process.

Recurrence of glioblastoma is associated with elevated microvascular transit time heterogeneity and increased hypoxia

Dynamic susceptibility contrast (DSC) perfusion MRI provide information about differences in macro- and microvasculature when executed with gradient-echo (GE; sensitive to macrovasculature) and spin-echo (SE; sensitive to microvasculature) contrast. This study investigated whether there are differences between macro- and microvascular transit time heterogeneity (MVTH and µVTH) and tissue oxygen tension (PO2mit) in newly-diagnosed and recurrent glioblastoma. Fifty-seven patients with glioblastoma (25 newly-diagnosed/32 recurrent) were examined with GE- and SE-DSC perfusion sequences, and a quantitative blood-oxygen-level-dependent (qBOLD) approach. Maps of MVTH, µVTH and coefficient of variation (MCOV and µCOV) were calculated from GE- and SE-DSC data, respectively, using an extended flow-diffusion equation. PO2mit maps were calculated from qBOLD data. Newly-diagnosed and recurrent glioblastoma showed significantly lower (P ≤ 0.001) µCOV values compared to both normal brain and macrovasculature (MCOV) of the lesions. Recurrent glioblastoma had significantly higher µVTH (P = 0.014) and µCOV (P = 0.039) as well as significantly lower PO2mit values (P = 0.008) compared to newly-diagnosed glioblastoma. The macrovasculature, however, showed no significant differences. Our findings provide evidence of microvascular adaption in the disorganized tumor vasculature for retaining the metabolic demands in stress response of therapeutically-uncontrolled glioblastomas. Thus, µVTH and PO2mit mapping gives insight into the tumor microenvironment (vascular and hypoxic niches) responsible for therapy resistance.

Impaired Cerebral Oxygenation, But Preserved Cerebrovascular Reactivity, In An Animal Model of Hepatic Encephalopathy

Introduction: We have recently obtained evidence of energy deficiency, in the form of impaired lactate release, in the brains of cirrhotic animals with hepatic encephalopathy (HE). Previous reports of cerebral hypoperfusion in patients with HE indicated that cerebral oxygen supply could also be compromised [[1]Philips B.J. Armstrong I.R. Pollock A. Lee A. Cerebral blood flow and metabolism in patients with chronic liver disease undergoing orthotopic liver transplantation.Hepatology. 1998; 27: 369-376Crossref PubMed Scopus (43) Google Scholar]. Decreased lactate and reduced oxygen supply may lead to the CNS energy deficiency and have important neurological consequences, particularly in patients with advanced cirrhosis. Objectives: In this study we assessed cerebral tissue oxygen tension and CO2 cerebrovascular reactivity in an animal model of HE. Methods: HE was induced by bile duct ligation (BDL) and after 4 weeks rats were anesthetized with α-chloralose (100 mg kg−1), instrumented for arterial blood pressure recording and artificially ventilated. Blood gas tensions and pH were monitored and maintained within the physiological ranges in both BDL (n = 10) and sham operated (n = 6) rats. Cerebral tissue PO2 was monitored by fluorescence method (Oxylite™, Oxford Optronics). After a small craniotomy, optical sensors were placed in the somatosensory cortex and sealed. PO2 at baseline and in response to systemic hypercapnia (10% CO2; 5 min) was recorded. Results: At the similar levels of blood PO2 (120 ± 4 vs. 113 ± 4 mmHg) and PCO2 (34 ± 1 vs. 35 ± 2 mmHg), BDL rats had a significantly lower brain PO2 (15.3 ± 2 mmHg; n = 10) compared to the shams (26 ± 2 mmHg; n = 6; P = 0.001). Systemic hypercapnia resulted in similar increases in cerebral PO2 in BDL and sham animals (ΔPO2 21 ± 2 vs. 24 ± 2 mmHg; P = 0.6). However, the peak increases in parenchymal PO2 was significantly smaller in BDL rats when compared to sham-operated animals; 36 ± 4 ± 2 vs. 50 ± 3 mmHg (P = 0.03). Additionally, under anesthesia, the mean systemic arterial blood pressure was found to be significantly lower in BDL animals (60 ± 3 vs. 84 ± 8 mmHg; P = 0.04). Conclusion: In the BDL model of HE, cerebral tissue oxygen tension is compromised but cerebrovascular reactivity to CO2 appears to be preserved. The cause of the low basal PO2 remains unknown however; low systemic arterial blood pressure could be a contributing factor considering the maximum increase in PO2 induced by hypercapnia was lower in BDL animals indicating decreased brain perfusion. The authors have none to declare.

Intraoperative Magnetic Resonance Imaging of Cerebral Oxygen Metabolism During Resection of Brain Lesions.

Tissue oxygen tension is an important parameter for brain tissue viability and its noninvasive intraoperative monitoring in the whole brain is of highly clinical relevance. The purpose of this study was the introduction of a multiparametric quantitative blood oxygenation dependent magnetic resonance imaging (MRI) approach for intraoperative examination of oxygen metabolism during the resection of brain lesions. Sixteen patients suffering from brain lesions were examined intraoperatively twice (before craniotomy and after gross-total resection) via the quantitative blood oxygenation dependent technique and a 1.5-Tesla MRI scanner, which is installed in an operating room. The MRI protocol included T2*- and T2 mapping and dynamic susceptibility weighted perfusion. Data analysis was performed with a custom-made, in-house MatLab software for calculation of maps of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) as well as of cerebral blood volume and cerebral blood flow. Perilesional edema showed a significant increase in both perfusion (cerebral blood volume+21%, cerebral blood flow+13%) and oxygen metabolism (OEF+32%, CMRO2+16%) after resection of the lesions. In perilesional nonedematous tissue only, however, oxygen metabolism (OEF+19%, CMRO2+11%) was significantly increased, but not perfusion. No changes were found in normal brain. Fortunately, no neurovascular adverse events were observed. This approach for intraoperative examination of oxygen metabolism in the whole brain is a new application of intraoperative MRI additionally to resection control (residual tumor detection) and updating of neuronavigation (brain shift detection). It may help to detect neurovascular adverse events early during surgery.

Brain Tissue PO2 Measurement During Normoxia and Hypoxia Using Two-Photon Phosphorescence Lifetime Microscopy.

Key to the understanding of the principles of physiological and structural acclimatization to changes in the balance between energy supply (represented by substrate and oxygen delivery, and mitochondrial oxidative phosphorylation) and energy demand (initiated by neuronal activity) is to determine the controlling variables, how they are sensed and the mechanisms initiated to maintain the balance. The mammalian brain depends completely on continuous delivery of oxygen to maintain its function. We hypothesized that tissue oxygen is the primary sensed variable. In this study two-photon phosphorescence lifetime microscopy (2PLM) was used to determine and define the tissue oxygen tension field within the cerebral cortex of mice to a cortical depth of between 200-250μm under normoxia and acute hypoxia (FiO2=0.10). High-resolution images can provide quantitative distributions of oxygen and intercapillary oxygen gradients. The data are best appreciated by quantifying the distribution histogram that can then be used for analysis. For example, in the brain cortex of a mouse, at a depth of 200μm, tissue oxygen tension was mapped and the distribution histogram was compared under normoxic and mild hypoxic conditions. This powerful method can provide for the first time a description of the delivery and availability of brain oxygen in vivo.

Brain Multimodality Monitoring: A New Tool in Neurocritical Care of Comatose Patients.

Neurocritical care patients are at risk of developing secondary brain injury from inflammation, ischemia, and edema that follows the primary insult. Recognizing clinical deterioration due to secondary injury is frequently challenging in comatose patients. Multimodality monitoring (MMM) encompasses various tools to monitor cerebral metabolism, perfusion, and oxygenation aimed at detecting these changes to help modify therapies before irreversible injury sets in. These tools include intracranial pressure (ICP) monitors, transcranial Doppler (TCD), Hemedex™ (thermal diffusion probe used to measure regional cerebral blood flow), microdialysis catheter (used to measure cerebral metabolism), Licox™ (probe used to measure regional brain tissue oxygen tension), and continuous electroencephalography. Although further research is needed to demonstrate their impact on improving clinical outcomes, their contribution to illuminate the black box of the brain in comatose patients is indisputable. In this review, we further elaborate on commonly used MMM parameters, tools used to measure them, and the indications for monitoring per current consensus guidelines.

Multimodality Monitoring: Illuminating the Comatose Human Brain.

The field of neurocritical care has evolved tremendously in recent years, a development explained vastly by the advent of neurophysiological monitoring. From basic intracranial pressure measurements to brain tissue oxygenation, microdialysis, cerebral blood flow (CBF), and surface and intracortical electroencephalography (EEG), our ability to detect and control physiologic endpoints of brain function in comatose patients has grown substantially. The integration of these data gave birth to the concept of multimodality monitoring (MMM). Real-time data acquisition and analysis systems are crucial for fully understanding the relationship between physiologic drivers such as blood pressure, temperature and end-tidal CO2, and end-point measures of brain metabolism such as brain tissue oxygen tension, CBF, lactate/pyruvate ratio, and EEG. Multimodality monitoring provides an early warning system for detecting physiological derangements that can be corrected before secondary brain injury occurs. Multimodality monitoring also allows for the creation of an optimized physiological environment for the injured brain, with the goal of preventing secondary injury events. The authors review the basic ideas and technical aspects of MMM, and therefore provide a unique window of illumination into the comatose human brain.

Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aβ in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD–specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.

Abstract 11150: Hyperbaric Oxygenation Enhances Transplanted Cell Graft Survival and Functional Recovery in Critical Limb Ischemia

Introduction: One of the major limitations in the application of stem-cell therapy to repair ischemic tissue is the low survival of transplanted cells, possibly due to poor oxygenation. Also the effect of hyperbaric oxygen therapy (HBOT) on bone marrow-derived mesenchymal stem cells (MSCs) is poorly understood. Hypothesis: We hypothesized that HBOT could be used as an adjuvant treatment to augment stem-cell therapy. Therefore, this study aimed to evaluate the effect of HBOT on the engraftment of bone marrow-derived MSCs transplanted in critical limb ischemia (CLI). Methods: Sixty-nine consecutive CLI patients refractory to peripheral revascularization therapy were enrolled. MSC transplantation was performed in all patients. HBOT (given 100% oxygen under 2.8 atmosphere absolute, for 60 min) was administered to 36 patients with and 33 patients without, by 2 weeks after those therapies. These patients were followed up by an outpatient clinic after limb survival. The primary endpoint was tissue oxygen tension of blood flow recovery, and secondary endpoint was adverse event rate (death and major limb amputation), analyzed by intention-to-treat. Results: Mean follow up was 11.4 ± 0.6 years. Limb survival rate was 84.1% and survival was 76.8%. The effect of HBOT was independent of background conditions, such as diabetes and hemodialysis (NS, respectively, Breslow-Day analysis). After 4 weeks, recovery of skin oxygen tension was significantly increased in MSC+HBO group compared to that in MSC group (22.7±16.3 to 34.5±21.4 vs 24.4±15.4 to 28.3±19.6, p = 0.045, odds ratio; 0.194). Surprisingly, in diabetic patients, MSC+HBOT group had significantly lower adverse event rate compared to MSC group (2 vs. 10 cases, p = 0.043, log-rank test, figure). Conclusions: HBOT appears to be a potential and clinically viable non-invasive adjuvant treatment for CLI stem-cell therapy.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells.

Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277-87. ©2016 AACR.

Tissue Oxygen Tension Monitoring of Organ Perfusion

Tissue oxygen tension is the partial pressure of oxygen within the interstitial space of an organ bed. As it represents the balance between local oxygen delivery and consumption at any given time, it offers a ready monitoring capability to assess the adequacy of tissue perfusion relative to local demands. This review covers the various methodologies used to measure tissue oxygen tension, describes the underlying physiological and pathophysiological principles, and summarizes human and laboratory data published to date.

Modeling Glucose Metabolism in the Kidney.

The mammalian kidney consumes a large amount of energy to support the reabsorptive work it needs to excrete metabolic wastes and to maintain homeostasis. Part of that energy is supplied via the metabolism of glucose. To gain insights into the transport and metabolic processes in the kidney, we have developed a detailed model of the renal medulla of the rat kidney. The model represents water and solute flows, transmural fluxes, and biochemical reactions in the luminal fluid of the nephrons and vessels. In particular, the model simulates the metabolism of oxygen and glucose. Using that model, we have identified parameters concerning glucose transport and basal metabolism that yield predicted blood glucose concentrations that are consistent with experimental measurements. The model predicts substantial axial gradients in blood glucose levels along various medullary structures. Furthermore, the model predicts that in the inner medulla, owing to the relatively limited blood flow and low tissue oxygen tension, anaerobic metabolism of glucose dominates.

Monitoring of brain oxygenation during hypothermic CPR – A prospective porcine study

Background and aimLimited data are available concerning the impact of CPR interventions on cerebral oxygenation during hypothermic cardiac arrest. We therefore studied cerebral perfusion pressure (CPP), brain tissue oxygen tension (PbtO2), cerebral venous oxygen saturation (ScvO2) and regional cerebral oxygen saturation (rSO2) in an animal model of hypothermic CPR. We also assessed the correlation between rSO2 and CPP, PbtO2 and ScvO2 to clarify whether near-infrared spectroscopy (NIRS) may be used to non-invasively monitor changes in cerebral oxygenation during hypothermic CPR. MethodsNine pigs were surface-cooled to a core temperature of 28°C and underwent a period of asphyxia before cardiac arrest was induced. After 2min of untreated cardiac arrest they were resuscitated for 45min. CPP, PbtO2, ScvO2 and rSO2 were monitored after periods of stable external chest compression, a short interruption of CPR and after epinephrine administration. ResultsDuring external chest-compressions before adrenalin administration CPP, PbtO2, ScvO2 and rSO2 increased in parallel and changes in rSO2 closely correlated with changes in CPP (r=.844; p<.001) and ScvO2 (r=.868; p<.001). After adrenaline administration CPP and PbtO2 increased, ScvO2 decreased and rSO2 values did not change and there was no significant correlation between rSO2 and CPP, PbtO2, or ScvO2. ConclusionIn this animal model of hypothermic cardiac arrest adrenaline was associated with an increase in global cerebral oxygen extraction despite an increase in CPP. Discrepancies in the time course of PbtO2 and ScvO2 suggest differences in regional oxygen metabolism after adrenalin. rSO2 values correlated closely with CPP and ScvO2 only during periods of external chest compression without adrenaline administration.

Myogenic and metabolic feedback in cerebral autoregulation: Putative involvement of arachidonic acid-dependent pathways

The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension. The metabolic feedback pathway is much faster than 20-HETE-dependent myogenic feedback, and the former thus initiates the cerebral autoregulatory response, while myogenic feedback comprises a relatively slower mechanism that functions to set the basal cerebrovascular tone. Therefore, assessments of dynamic cerebral autoregulation, which may provide information on the response time of the cerebrovasculature, may specifically be used to yield information on metabolic feedback mechanisms, while data based on assessments of static cerebral autoregulation represent the integrated functionality of myogenic and metabolic feedback.

Measurements of Blood Flow, Tissue Oxygen Tension, and Oxygen Consumption in Rat Skeletal Muscle during Recovery from Bouts of Brief, Transient Ischemia

In resting muscle, blood flow is regulated to meet the demand for O2 by the respiring tissue. A locally induced ischemia/reperfusion protocol was utilized to investigate the effects of transient ischemia (5, 15, 30, and 60 s duration) in rat skeletal muscle. The results will be utilized in a model that relates blood flow, interstitial oxygenation, and oxygen consumption. We anticipate that this study will aid in furthering our understanding of the local regulation of blood flow and tissue oxygenation. 29 spinotrapezius muscles from male Sprague‐Dawley rats were surgically exteriorized for intravital microscopy. Interstitial PO2 (PISFO2) and arteriolar PO2 (PaO2) measurements were made using phosphorescence quenching microscopy (PQM). Red cell velocity was measured using Optical Doppler velocimetry and used to calculate blood flow (Q). Oxygen consumption (VO2) was measured with a quasi‐continuous, flash‐synchronized, rapidly pressurizing airbag system to both initiate ischemia and sample the rate of change in oxygen tension (dPO2/dt). The average baseline value of arteriolar blood flow was measured as 5.8±0.8 μl/min; as expected, reactive hyperemia was observed during the recovery from ischemia. Flow recovery (dQ/dt) was fastest [3.88±0.64 (μl·min−1)/s] after 60 seconds of ischemia. Average baseline PISFO2 was 62±4 mmHg; PISFO2 decreased to 75%, 34%, 10% and 2% of baseline following 5, 15, 30 and 60 s of ischemia, respectively. Up to 30 s of ischemia, the rate of recovery of PISFO2 steadily increased as the ischemic duration increased; however, it dropped off following 60 seconds of ischemia. The rate of recovery of PISFO2 was fastest (4.2±0.7 mmHg/s) following 30 seconds of ischemia. Average baseline VO2 was 120±19 nl O2/cm3·s and it increased above baseline during the early part of the recovery period. As is consistent with our current understanding, the time course of recovery of PISFO2 represents a balance between oxygen delivery, proportional to the local arteriolar tissue perfusion, and local oxygen consumption. When the ischemic duration increased, the interstitial oxygen tension decreased. An assumption was made in the modeling process that the arteriolar oxygen tension did not change during the course of each trial. Further investigation of both intravascular and perivascular PaO2 using the PQM system and the same ischemia/reperfusion protocol will highlight any differences in the supply of oxygen to the interstitium versus what was already present at baseline.Support or Funding InformationSupported by AHA Award #14GRNT20380551

Intra‐renal and Urinary Oxygenation during Resuscitation with Norepinephrine and Angiotensin II in Ovine Acute Kidney Injury

Background and AimsAcute kidney Injury (AKI) is a common phenotype of sepsis leading to high mortality rates. Norepinephrine (NE) is the first choice vasopressor used clinically to restore blood pressure and renal function, whilst there is emerging interest in angiotensin II (Ang II) as an effective adjunctive therapy in patients with septic shock. Increasing evidence suggests that hypoxia in the renal medulla may play a critical role in the pathogenesis of AKI. We therefore measured renal cortical and medullary tissue oxygen tension (PO2) in conscious sheep during development of septic AKI and following resuscitation with NE and Ang II. In addition, since the renal medullary vasa recta run close and parallel to the collecting ducts, we examined whether urinary PO2 and medullary tissue PO2 changed in a similar manner during development of septic AKI and treatment with NE and Ang II.MethodsSheep were surgically instrumented with a renal artery flow probe and fibre‐optic probes in the cortex and medulla to measure tissue perfusion and oxygenation. An oxygen probe was inserted into the tip of the bladder catheter for measurement of urinary oxygenation. Conscious sheep received a continuous infusion of live Escherichia coli (2.8 × 109 bolus + 1.26 × 109 colony forming units i.v) for 32 h. NE (0.4–0.8 μg/kg/h, n=8) or Ang II (0.5–33μg/kg/min, n=8) or saline‐vehicle (n=8) were infused from 24–30 h of sepsis.ResultsPrior to treatment, septic AKI was characterized by hypotension (~14 mmHg), renal hyperperfusion (~70%) and reduced glomerular filtration rate (~65%). Medullary perfusion (1289±95 to 628±113 blood perfusion units (BPU)), medullary oxygenation (32±3 to 16±4 mmHg) and urinary oxygenation (36±2 to 24±2 mmHg) were all significantly reduced. Restoring blood pressure with NE further reduced medullary perfusion (331±64 BPU), medullary PO2 (8±2 mmHg) and urinary PO2 (18±4 mmHg). In contrast, Ang II reversed the sepsis‐induced hypotension without further exacerbating medullary perfusion (553±58 BPU), medullary PO2 (26±2 mmHg) or urinary PO2 (24±1 mmHg). Cortical perfusion and oxygenation were preserved during development of septic AKI and resuscitation with NE and Ang II.ConclusionsRenal medullary hypoxia due to intra‐renal blood flow redistribution may contribute to the development of septic AKI. Resuscitation with NE reversed sepsis‐induced hypotension, but exacerbated the medullary hypoxia, which may have long‐term effects to worsen kidney injury. Interestingly, Ang II restored blood pressure without worsening medullary hypoxia, suggesting that Ang II has less adverse effects than NE on kidney oxygenation during treatment of septic AKI. The parallel changes in medullary tissue and urinary PO2 during development of sepsis and vasopressor treatment suggest that urinary PO2 may be a useful real‐time biomarker to monitor patients at risk of developing AKI.Support or Funding InformatioThis work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC, 454615, 1009280, 1050672), and by funding from the Victorian Government Operational Infrastructure Support Grant.

Hypoxia-inducible factor-1α inhibits interleukin-6 and -8 production in gingival epithelial cells during hypoxia.

Hypoxia has been widely studied in inflammatory diseases as it can modulate the inflammatory response, mainly via the hypoxia-inducible factor (HIF). However, little is known about the effects of hypoxia and the role of HIF in the inflammatory responses to periodontitis. In this study, we focused on the gingival epithelium that is exposed to relatively low levels of oxygen. We investigated whether hypoxic conditions have an impact on inflammatory responses in human gingival epithelial cells (HGECs). Pimonidazole HCl, which accumulates in hypoxic cells, was administered intraperitoneally to C57BL/6 mice with or without Porphyromonas gingivalis infection. Immunohistochemistry was then performed to detect the hypoxic cells in periodontal tissue. Immortalized HGECs were cultured under hypoxic conditions with or without interleukin (IL)-1β, and the expression levels of IL-6 and IL-8 were measured by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. HIF-1α expression was detected by western blotting. The DNA-binding activity of HIF-1α was determined by a DNA-binding enzyme-linked immunosorbent assay. The involvement of HIF-1α in the hypoxic response was examined by transfection with HIF-1α siRNA. Immunohistochemistry revealed pimonidazole HCl accumulation in the gingival epithelium of both normal and P. gingivalis-infected mice, with a slightly stronger signal in the P. gingivalis-infected mice than in the normal mice. The IL-1β-induced IL-6 and IL-8 production by HGECs was suppressed under hypoxic conditions. HIF-1α accumulated during hypoxia, and this accumulation was further enhanced by IL-1β treatment. The hypoxia-dependent suppression of IL-6 and IL-8 expression was reversed by treating the cells with HIF-1α siRNA. Our results suggest that the gingival epithelium is exposed to low oxygen tension in periodontal tissue and that this hypoxic condition modulates the local inflammatory response of gingival epithelial cells in an HIF-1α-dependent manner.