Hyperoxia results in increased aerobic metabolism following acute brain injury.
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ABSTRACT:
SUBMITTER: Ghosh A
PROVIDER: S-EPMC5536254 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p?<?0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p?<?0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required.
| S-EPMC5622132 | biostudies-other
Project description:Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are major contributors to morbidity and mortality. Following the initial insult, patients may deteriorate due to secondary brain damage. The underlying molecular and cellular cascades incorporate components of the innate immune system. There are different approaches to assess and monitor cerebral inflammation in the neuro intensive care unit. The aim of this narrative review is to describe techniques to monitor inflammatory activity in patients with TBI and SAH in the acute setting. The analysis of pro- and anti-inflammatory cytokines in compartments of the central nervous system (CNS), including the cerebrospinal fluid and the extracellular fluid, represent the most common approaches to monitor surrogate markers of cerebral inflammatory activity. Each of these compartments has a distinct biology that reflects local processes and the cross-talk between systemic and CNS inflammation. Cytokines have been correlated to outcomes as well as ongoing, secondary injury progression. Alongside the dynamic, focal assay of humoral mediators, imaging, through positron emission tomography, can provide a global in vivo measurement of inflammatory cell activity, which reveals long-lasting processes following the initial injury. Compared to the innate immune system activated acutely after brain injury, the adaptive immune system is likely to play a greater role in the chronic phase as evidenced by T-cell-mediated autoreactivity toward brain-specific proteins. The most difficult aspect of assessing neuroinflammation is to determine whether the processes monitored are harmful or beneficial to the brain as accumulating data indicate a dual role for these inflammatory cascades following injury. In summary, the inflammatory component of the complex injury cascade following brain injury may be monitored using different modalities. Using a multimodal monitoring approach can potentially aid in the development of therapeutics targeting different aspects of the inflammatory cascade and improve the outcome following TBI and SAH.
| S-EPMC5517395 | biostudies-other
Project description:OBJECTIVE:To examine cognitive function in individuals with traumatic brain injury (TBI) prior to and after participation in an aerobic exercise training program. DESIGN:Pre-post intervention study. SETTING:Medical research center. PARTICIPANTS:Volunteer sample of individuals (N=7) (age, 33.3±7.9y) with chronic nonpenetrating TBI (injury severity: 3=mild, 4=moderate; time since most current injury: 4.0±5.5y) who were ambulatory. INTERVENTION:Twelve weeks of supervised vigorous aerobic exercise training performed 3 times a week for 30 minutes on a treadmill. MAIN OUTCOME MEASURES:Cognitive function was assessed using the Trail Making Test Part A (TMT-A), Trail Making Test Part B (TMT-B), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sleep quality and depression were measured with the Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory, version 2 (BDI-II). Indices of cardiorespiratory fitness were used to examine the relation between improvements in cognitive function and cardiorespiratory fitness. RESULTS:After training, improvements in cognitive function were observed with greater scores on the TMT-A (10.3±6.8; P=.007), TMT-B (9.6±7.0; P=.011), and RBANS total scale (13.3±9.3; P=.009). No changes were observed in measures of the PSQI and BDI-II. The magnitude of cognitive improvements was also strongly related to the gains in cardiorespiratory fitness. CONCLUSIONS:These findings suggest that vigorous aerobic exercise training may improve specific aspects of cognitive function in individuals with TBI and cardiorespiratory fitness gains may be a determinant of these improvements.
| S-EPMC4380661 | biostudies-literature
Project description:Alterations in the expression of the vascular endothelial growth factors (VEGF) A and B occur during blood⁻brain barrier (BBB) breakdown and angiogenesis following a brain injury. In this study, the temporal and spatial expression of VEGF-D and VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3, respectively) was determined at the mRNA and protein level in the rat cortical cold-injury model over a period of 0.5 to 6 days post-injury. In order to relate endothelial VEGF-D protein expression with BBB breakdown, dual labeling immunofluorescence was performed using antibodies to VEGF-D and to fibronectin, a marker of BBB breakdown. In control rats, VEGF-D signal was only observed in scattered perivascular macrophages in the cerebral cortex. The upregulation of VEGF-D mRNA expression was observed in the injury site between days 0.5 to 4, coinciding with the periods of BBB breakdown and angiogenesis. At the protein level, intracerebral vessels with BBB breakdown to fibronectin in the lesion on days 0.5 to 4 failed to show endothelial VEGF-D. Between days 0.5 to 6, increased VEGF-D immunoreactivity was noted in the endothelium of pial vessels overlying the lesion site, in neutrophils, macrophages, and free endothelial cells within the lesion. The upregulation of VEGFR-2 and -3 mRNA and protein expression was observed early post-injury on day 0.5. Although there was concurrent expression of VEGF-A, VEGF-B, and VEGF-D post-injury, differences in their spatial expression during BBB breakdown and angiogenesis suggest that they had specific and separate roles in these processes.
| S-EPMC6479775 | biostudies-literature
Project description:Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.
| S-EPMC5297819 | biostudies-literature
Project description:Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and β-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.
| S-EPMC6928557 | biostudies-literature
Project description:RationaleHuman data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown.ObjectivesTo determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury.MethodsWild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O(2)) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo.Measurements and main resultsLung leptin levels were increased both in wild-type and leptin receptor-defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice.ConclusionsThese results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.
| S-EPMC1899284 | biostudies-literature
Project description:Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase kinase (MAP3K) family, is activated by various stimuli, which include oxidative stress, endoplasmic reticulum (ER) stress, calcium influx, DNA damage-inducing agents and receptor-mediated signaling through tumor necrosis factor receptor (TNFR). Inspiration of a high concentration of oxygen is a palliative therapy which counteracts hypoxemia caused by acute lung injury (ALI)-induced pulmonary edema. However, animal experiments so far have shown that hyperoxia itself could exacerbate ALI through reactive oxygen species (ROS). Our previous data indicates that ASK1 plays a pivotal role in hyperoxia-induced acute lung injury (HALI). However, it is unclear whether or not deletion of ASK1 in vivo protects against HALI. In this study, we investigated whether ASK1 deletion would lead to attenuation of HALI. Our results show that ASK1 deletion in vivo significantly suppresses hyperoxia-induced elevation of inflammatory cytokines (i.e. IL-1? and TNF-?), cell apoptosis in the lung, and recruitment of immune cells. In summary, the results from the study suggest that deletion of ASK1 in mice significantly inhibits hyperoxic lung injury.
| S-EPMC4726536 | biostudies-literature
Project description:Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a leading cause of mortality in older adults with an increasing prevalence. Oxygen therapy, is a common treatment for ALI, involving exposure to a high concentration of oxygen. Unfortunately, hyperoxia induces the formation of reactive oxygen species which can cause an increase in 4-HNE (4-hydroxy 2 nonenal), a toxic byproduct of lipid peroxidation. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an endogenous shield against oxidative stress-mediated damage by clearing 4-HNE. Alda-1 [(N-(1, 3 benzodioxol-5-ylmethyl)-2, 6- dichloro-benzamide)], a small molecular activator of ALDH2, protects against reactive oxygen species-mediated oxidative stress by promoting ALDH2 activity. As a result, Alda-1 shields against ischemic reperfusion injury, heart failure, stroke, and myocardial infarction. However, the mechanisms of Alda-1 in hyperoxia-induced ALI remains unclear. C57BL/6 mice implanted with Alzet pumps received Alda-1 in a sustained fashion while being exposed to hyperoxia for 48 h. The mice displayed suppressed immune cell infiltration, decreased protein leakage and alveolar permeability compared to controls. Mechanistic analysis shows that mice pretreated with Alda-1 also experience decreased oxidative stress and enhanced levels of p-Akt and mTOR pathway associated proteins. These results show that continuous delivery of Alda-1 protects against hyperoxia-induced lung injury in mice.
| S-EPMC7883597 | biostudies-literature
Project description:Decreases in energy metabolism following traumatic brain injury (TBI) are attributed to impairment of glycolytic flux and oxidative phosphorylation. Glucose utilization post-TBI is decreased while administration of alternative substrates has been shown to be neuroprotective. Changes in energy metabolism following TBI happens in two phases; a period of hyper-metabolism followed by prolonged hypo-metabolism. It is not understood how different cerebral metabolic states may impact substrate metabolism and ultimately mitochondrial function. Adult male or female Sprague Dawley rats were given sham surgery or controlled cortical impact (CCI) and were assigned one of two administration schemes. Glucose, lactate or beta-hydroxybutyrate (BHB) were infused i.v. either starting immediately after injury or beginning 6 h post-injury for 3 h to reflect the hyper- and hypo-metabolic stages. Animals were euthanized 24 h post-injury. The peri-contusional cortex was collected and assayed for mitochondrial respiration peroxide production, and citrate synthase activity. Tissue acetyl-CoA, ATP, glycogen and HMGB1 were also quantified. Sex differences were observed in injury pattern. Administration based on cerebral metabolic state identified that only early lactate and late BHB improved mitochondrial function and peroxide production and TCA cycle intermediates in males. In contrast, both early and late BHB had deleterious effects on all aspects of metabolic measurements in females. These data stress there is no one optimal alternative substrate, but rather the fuel type used should be guided by both cerebral metabolic state and sex.
| S-EPMC8168752 | biostudies-literature