The Effect of Mechanical Ventilation on TASK-1 Expression in the Brain in a Rat Model

is closely related to respiratory central control and neuronal injury. We investigated the effect of MV on TASK-1's functions and explored the mechanism using a rat model.  Male Sprague-Dawley rats were randomized to three groups: (1) high tidal volume (HVt): MV for four hours with Vt at 10 mL/kg; (2) low Vt (LVt): MV for four hours with Vt at 5 mL/kg; (3) basal (BAS): anesthetized and unventilated animals. We measured lung histology and plasma and brain levels of proteins (IL-6, TNF-α, and S-100B) and determined TASK-1 levels in rat brainstems as a marker of respiratory centre activity.  The LISs (lung injury scores) were significantly higher in the HVt group. Brain inflammatory cytokines levels were different to those in serum. TASK-1 levels were significantly lower in the MV groups (P = 0.002) and the HVt group tended to have a lower level of TASK-1 than the LVt group.  MV causes not only lung injury, but also brain injury. MV affects the regulation of the respiratory centre, perhaps causing damage to it. Inflammation is probably not the main mechanism of ventilator-related brain injury.

Related papers:

title: Ventilator-induced lung injury: historical perspectives and clinical implications
abstract: Mechanical ventilation can produce lung physiological and morphological alterations termed ventilator-induced lung injury (VILI). Early experimental studies demonstrated that the main determinant of VILI is lung end-inspiratory volume. The clinical relevance of these experimental findings received resounding confirmation with the results of the acute respiratory distress syndrome (ARDS) Network study, which showed a 22% reduction in mortality in patients with the acute respiratory distress syndrome through a simple reduction in tidal volume. In contrast, the clinical relevance of low lung volume injury remains debated and the application of high positive end-expiratory pressure levels can contribute to lung overdistension and thus be deleterious. The significance of inflammatory alterations observed during VILI is debated and has not translated into clinical application. This review examines seminal experimental studies that led to our current understanding of VILI and contributed to the current recommendations in the respiratory support of ARDS patients.

title: Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice
abstract: IntroductionMechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis.MethodsHealthy C57Bl/6 mice (n = 66) or BALB/c mice (n = 66) were ventilated (tidal volume = 7.5 ml/kg or 15 ml/kg; positive end-expiratory pressure = 2 cmH2O; fraction of inspired oxygen = 0.5) for five hours. Normal saline or sodium bicarbonate were used to correct for hypovolaemia. Lung histopathology, lung wet-to-dry ratio, bronchoalveolar lavage fluid protein content, neutrophil influx and levels of proinflammatory cytokines and coagulation factors were measured.ResultsAnimals remained haemodynamically stable throughout the whole experiment. Lung histopathological changes were minor, although significantly more histopathological changes were found after five hours of MV with a larger tidal volume. Lung histopathological changes were no different between the strains. In both strains and with both ventilator settings, MV caused higher wet-to-dry ratios, higher bronchoalveolar lavage fluid protein levels and more influx of neutrophils, and higher levels of proinflammatory cytokines and coagulation factors. Also, with MV higher systemic levels of cytokines were measured. All parameters were higher with larger tidal volumes. Correcting for metabolic acidosis did not alter endpoints.ConclusionsMV induces VILI, in the absence of a priming pulmonary insult and even with use of relevant (least injurious) ventilator settings. This model offers opportunities to study the pathophysiological mechanisms behind VILI and the contribution of MV to lung injury in the absence of pre-existing lung injury.

title: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.
abstract: ContextStudies have shown that an inflammatory response may be elicited by
mechanical ventilation used for recruitment or derecruitment of collapsed
lung units or to overdistend alveolar regions, and that a lung-protective
strategy may reduce this response.ObjectiveTo test the hypothesis that mechanical ventilation induces a pulmonary
and systemic cytokine response that can be minimized by limiting recruitment
or derecruitment and overdistention.Design and SettingRandomized controlled trial in the intensive care units of 2 European
hospitals from November 1995 to February 1998, with a 28-day follow-up.PatientsForty-four patients (mean [SD] age, 50 [18] years) with acute respiratory
distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.InterventionsAfter admission, volume-pressure curves were measured and bronchoalveolar
lavage and blood samples were obtained. Patients were randomized to either
the control group (n=19): tidal volume to obtain normal values of arterial
carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure
(PEEP) producing the greatest improvement in arterial oxygen saturation without
worsening hemodynamics; or the lung-protective strategy group (n=18): tidal
volume and PEEP based on the volume-pressure curve. Measurements were repeated
24 to 30 and 36 to 40 hours after randomization.Main Outcome MeasuresPulmonary and systemic concentrations of inflammatory mediators approximately
36 hours after randomization.ResultsPhysiological characteristics and cytokine concentrations were similar
in both groups at randomization. There were significant differences (mean
[SD]) between the control and lung-protective strategy groups in tidal volume
(11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5]
vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P<.001). Patients in the control group
had an increase in bronchoalveolar lavage concentrations of interleukin (IL)
1β, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage
and plasma concentrations of tumor necrosis factor (TNF) α, IL-6, and
TNF-α receptors over 36 hours (P<.05 for
all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar
lavage concentrations of polymorphonuclear cells, TNF-α, IL-1β,
soluble TNF-α receptor 55, and IL-8, and in plasma and bronchoalveolar
lavage concentrations of IL-6, soluble TNF-α receptor 75, and IL-1 receptor
antagonist (P<.05). The concentration of the inflammatory
mediators 36 hours after randomization was significantly lower in the lung-protective
strategy group than in the control group (P<.05).ConclusionsMechanical ventilation can induce a cytokine response that may be attenuated
by a strategy to minimize overdistention and recruitment/derecruitment of
the lung. Whether these physiological improvements are associated with improvements
in clinical end points should be determined in future studies.

title: Organ crosstalk during acute lung injury, acute respiratory distress syndrome, and mechanical ventilation
abstract: Purpose of reviewMultiple organ failure is the main cause of morbidity and mortality in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients. Moreover, survivors of both ALI and ARDS often show significant neurocognitive decline at discharge. These data suggest a deleterious organ crosstalk between lungs and distal organs. This article reviews the recent literature concerning the role of this organ crosstalk during ALI, ARDS, and mechanical ventilation, especially focusing on brain–lung communication. Recent findingsNumerous pulmonary and extrapulmonary disorders could predispose critically ill patients to ALI and ARDS. Mechanical ventilation, although a lifesaving intervention, could contribute by modulating the mechanisms involved in the pathophysiology of lung damage and their impact on remote organs. Emerging clinical and experimental evidence supports the hypothesis of a multidirectional organ crosstalk between lungs and distal organs. SummaryOrgan crosstalk is an emerging area of research in lung disease in critically ill patients. The findings of these studies are clinically relevant and show the importance of an integrative approach in the management of critical patients. However, further studies are necessary to understand the complex interactions concurring in these pathologies.

title: Neurological outcome after experimental lung injury
abstract: We examined the influences of acute lung injury and hypoxia on neurological outcome. Functional performance was assessed using a neurocognitive test and a neurologic deficit score (NDS) five days before. On experimental day, mechanically ventilated pigs were randomized to hypoxia only (HO group, n=5) or to acute lung injury (ALI group, n=5). Hemodynamics, respiratory mechanics, systemic cytokines and further physiologic variables were obtained at baseline, at the time of ALI, 2, 4 and 8h thereafter. Subsequently, injured lungs were recruited and animals weaned from the ventilator. Neurocognitive testing was re-examined for five days. Then, brains were harvested for neurohistopathology. After the experiment, neurocognitive performance was significantly worsened and the NDS increased in the ALI group. Histopathology revealed no significant differences. Oxygenation was comparable between groups although significantly higher inspiratory pressures occured after ALI. Cytokines showed a trend towards higher levels after ALI. Neurocognitive compromise after ALI seems due to a more pronounced inflammatory response and complex mechanical ventilation.

title: Initiation of Resuscitation with High Tidal Volumes Causes Cerebral Hemodynamic Disturbance, Brain Inflammation and Injury in Preterm Lambs
abstract: Preterm infants can be inadvertently exposed to high tidal volumes (VT) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high VT resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury.  Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High VT targeting 10–12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot VT), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial VT (7 mL/kg; n = 6). Both groups were subsequently ventilated with a VT 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison.  High VT lambs had worse oxygenation and required greater ventilatory support than Prot VT lambs. High VT resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High VT resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High VT lambs, but not in UVC or Prot VT lambs.  High VT resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot VT strategy. The initiation of resuscitation targeting Prot VT may reduce the severity of brain injury in preterm neonates.

title: Early Detection of Ventilation-Induced Brain Injury Using Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: An In Vivo Study in Preterm Lambs
abstract: High tidal volume (VT) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs.  Newborn lambs (0.85 gestation) were stabilized with a “protective ventilation” strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH2O) or an initial 15 minutes of “injurious ventilation” (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations.  No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups.  Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation-induced brain injury.

title: Potassium leak channels and the KCNK family of two-p-domain subunits
abstract: With a bang, a new family of potassium channels has exploded into view. Although KCNK channels were discovered only five years ago, they already outnumber other channel types. KCNK channels are easy to identify because of their unique structure — they possess two pore-forming domains in each subunit. The new channels function in a most remarkable fashion: they are highly regulated, potassium-selective leak channels. Although leak currents are fundamental to the function of nerves and muscles, the molecular basis for this type of conductance had been a mystery. Here we review the discovery of KCNK channels, what has been learned about them and what lies ahead. Even though two-P-domain channels are widespread and essential, they were hidden from sight in plain view — our most basic questions remain to be answered.

title: TASK-1, a Two–Pore Domain K+ Channel, Is Modulated by Multiple Neurotransmitters in Motoneurons
abstract: Inhibition of "leak" potassium (K+) channels is a widespread CNS mechanism by which transmitters induce slow excitation. We show that TASK-1, a two pore domain K+ channel, provides a prominent leak K+ current and target for neurotransmitter modulation in hypoglossal motoneurons (HMs). TASK-1 mRNA is present at high levels in motoneurons, including HMs, which express a K+ current with pH- and voltage-dependent properties virtually identical to those of the cloned channel. This pH-sensitive K+ channel was fully inhibited by serotonin, norepinephrine, substance P, thyrotropin-releasing hormone, and 3,5-dihydroxyphenylglycine, a group I metabotropic glutamate receptor agonist. The neurotransmitter effect was entirely reconstituted in HEK 293 cells coexpressing TASK-1 and the TRH-R1 receptor. Given its expression patterns and the widespread prevalence of this neuromodulatory mechanism, TASK-1 also likely supports this action in other CNS neurons.

title: Serotonergic Raphe Neurons Express TASK Channel Transcripts and a TASK-Like pH- and Halothane-Sensitive K+ Conductance
abstract: The recently described two-pore-domain K+channels, TASK-1 and TASK-3, generate currents with a unique set of properties; specifically, the channels produce instantaneous open-rectifier (i.e., “leak”) K+ currents that are modulated by extracellular pH and by clinically useful anesthetics. In this study, we used histochemical and in vitroelectrophysiological approaches to determine that TASK channels are expressed in serotonergic raphe neurons and to show that they confer a pH and anesthetic sensitivity to these neurons. By combining in situ hybridization for TASK-1 or TASK-3 with immunohistochemical localization of tryptophan hydroxylase, we found that a majority of serotonergic neurons in both dorsal and caudal raphe cell groups contain TASK channel transcripts (∼70–90%). Whole-cell voltage-clamp recordings were obtained from raphe cells that responded to 5-HT in a manner characteristic of serotonergic neurons (i.e., with activation of an inwardly rectifying K+ current). In those cells, we isolated an endogenous K+conductance that had properties expected of TASK channel currents; raphe neurons expressed a joint pH- and halothane-sensitive open-rectifier K+ current. The pH sensitivity of this current (pK ∼7.0) was intermediate between that of TASK-1 and TASK-3, consistent with functional expression of both channel types. Together, these data indicate that TASK-1 and TASK-3 are expressed and functional in serotonergic raphe neurons. The pH-dependent inhibition of TASK channels in raphe neurons may contribute to ventilatory and arousal reflexes associated with extracellular acidosis; on the other hand, activation of raphe neuronal TASK channels by volatile anesthetics could play a role in their immobilizing and sedative–hypnotic effects.

title: The TASK background K2P channels: chemo- and nutrient sensors
abstract: Specialized chemo- and nutrient-sensing cells share a common electrophysiological mechanism by transducing low O(2), high CO(2) and low glucose stimuli into a compensatory cellular response: the closing of background K(+) channels encoded by the K(2P) subunits. Inhibition of the TASK K(2P) channels by extracellular acidosis leads to an increased excitability of brainstem respiratory neurons. Moreover, hypoxic down-modulation of TASK channels is implicated in the activation of glomus cells in the carotid body. Stimulation of both types of cell leads to an enhanced ventilation and to cardiocirculatory adjustments. Differential modulation of TASK channels by acidosis and high glucose alters excitability of the hypothalamic orexin neurons, which influence arousal, food seeking and breathing. These recent results shed light on the role of TASK channels in sensing physiological stimuli.

title: TASK Channels Contribute to the K+-Dominated Leak Current Regulating Respiratory Rhythm Generation In Vitro
abstract: Leak channels regulate neuronal activity and excitability. Determining which leak channels exist in neurons and how they control electrophysiological behavior is fundamental. Here we investigated TASK channels, members of the two-pore domain K+ channel family, as a component of the K+-dominated leak conductance that controls and modulates rhythm generation at cellular and network levels in the mammalian pre-Bötzinger complex (pre-BötC), an excitatory network of neurons in the medulla critically involved in respiratory rhythmogenesis. By voltage-clamp analyses of pre-BötC neuronal current–voltage (I-V) relations in neonatal rat medullary slices in vitro, we demonstrated that pre-BötC inspiratory neurons have a weakly outward-rectifying total leak conductance with reversal potential that was depolarized by ∼4 mV from the K+ equilibrium potential, indicating that background K+ channels are dominant contributors to leak. This K+ channel component had I-V relations described by constant field theory, and the conductance was reduced by acid and was augmented by the volatile anesthetic halothane, which are all hallmarks of TASK. We established by single-cell RT-PCR that pre-BötC inspiratory neurons express TASK-1 and in some cases also TASK-3 mRNA. Furthermore, acid depolarized and augmented bursting frequency of pre-BötC inspiratory neurons with intrinsic bursting properties. Microinfusion of acidified solutions into the rhythmically active pre-BötC network increased network bursting frequency, halothane decreased bursting frequency, and acid reversed the depressant effects of halothane, consistent with modulation of network activity by TASK channels. We conclude that TASK-like channels play a major functional role in chemosensory modulation of respiratory rhythm generation in the pre-Bötzinger complex in vitro.

title: TASK-1 is a highly modulated pH-sensitive 'leak' K(+) channel expressed in brainstem respiratory neurons.
abstract: Central respiratory chemoreceptors adjust respiratory drive in a homeostatic response to alterations in brain pH and/or P(CO(2)). Multiple brainstem sites are proposed as neural substrates for central chemoreception, but molecular substrates that underlie chemosensitivity in respiratory neurons have not been identified. In rat brainstem neurons expressing transcripts for TASK-1, a two-pore domain K(+) channel, we characterized K(+) currents with kinetic and voltage-dependent properties identical to cloned rat TASK-1 currents. Native currents were sensitive to acid and alkaline shifts in the same physiological pH range as TASK-1 (pK approximately 7.4), and native and cloned pH-sensitive currents were modulated similarly by neurotransmitters and inhalational anesthetics. This pH-sensitive TASK-1 channel is an attractive candidate to mediate chemoreception because it is functionally expressed in respiratory-related neurons, including airway motoneurons and putative chemoreceptor neurons of locus coeruleus (LC). Inhibition of TASK-1 channels by extracellular acidosis can depolarize and increase excitability in those cells, thereby contributing to chemoreceptor function in LC neurons and directly enhancing respiratory motoneuronal output.

title: Altered neuronal expression of TASK1 and TASK3 potassium channels in rodent and human autoimmune CNS inflammation
abstract: Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are characterized by T cell-mediated autoimmune inflammation of the central nervous system (CNS) leading to oligodendrocyte loss and demyelination accompanied by neuronal cell death. Neuronal TWIK-related acid-sensitive potassium (TASK) channels allow the regulated efflux of potassium ions. These channels might either protect neurons in the inflamed CNS by modulating electrical excitability or even contribute to inflammatory neurodegeneration mediating intracellular potassium depletion. Using a combination of in-situ-hybridisation and immunofluorescence staining, we found increased neuronal expression of TASK1 and TASK3 channels in the optic nerve and decreased expression in the spinal cord and thalamus of rats undergoing MOG-induced EAE. Inflammatory plaques of human MS patients displayed profoundly lowered expression of both TASK isoforms. Thus, regulated expression of TASK channels might contribute to a molecular switch between death and survival of neurons in autoimmune CNS inflammation.

title: Protective mechanical ventilation in the non-injured lung: review and meta-analysis
abstract: Acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in critically ill patients. Injured lungs can be protected by optimum mechanical ventilator settings, using low tidal volume (VT) values and higher positive-end expiratory pressure (PEEP); the benefits of this protective strategy on outcomes have been confirmed in several prospective randomized controlled trials (RCTs). The question is whether healthy lungs need specific protective ventilatory settings when they are at risk of injury. We performed a systematic review of the scientific literature and a meta-analysis regarding the rationale of applying protective ventilatory strategies in patients at risk of ARDS in the perioperative period and in the intensive care unit (ICU).

title: High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study
abstract: BackgroundTo examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.MethodsRats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.ResultsOxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.ConclusionsDuring MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.

title: Ventilator-induced endothelial activation and inflammation in the lung and distal organs
abstract: IntroductionResults from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung.MethodsHealthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretch in vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH2O peak inspiratory pressure (PIP) and 0 cmH20 positive end expiratory pressure (PEEP). Non-ventilated, sham-operated animals served as a reference group (non-ventilated controls, NVC).ResultsAlveolar stretch imposed by MV did not only induce de novo synthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs.ConclusionsOur data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs.

title: Low Tidal Volume Ventilation in a Porcine Model of Acute Lung Injury Improves Cerebral Tissue Oxygenation
abstract: In study, we investigated the effects of different tidal volumes on cerebral tissue oxygenation and cerebral metabolism in a porcine model of acute lung injury (ALI). We hypothesized that mechanical ventilation with low tidal (LT) volumes improves cerebral tissue oxygenation and metabolism after experimentally induced ALI. After inducing experimental ALI by surfactant depletion, we studied two conditions in 10 female pigs: 1) LT volume ventilation with 6 mL/kg body weight, and 2) high tidal (HT) volume ventilation with 12 mL/kg body weight. Variables of gas exchange, hemodynamic, continuous cerebral tissue oxygen tension (ptiO2), cerebral microdialysis, and systemic cytokines were analyzed. After induction of ALI, data were collected at 2, 4, and 8 h. The primary end point was the change in ptiO2. For group comparisons, a t-test was used. A value of <0.05 was considered to indicate statistical significance. At baseline and after induction of ALI, no differences between groups were found in ptiO2; however, ptiO2 was significantly lower in the HT group after 4 and 8 h. Pao2 and Paco2 showed no significant differences between the groups at all timepoints. Regarding cerebral microdialysis, a significantly higher level of extracellular lactate could be demonstrated after 2, 4, and 8 h in the HT group. The release of cytokines resulted in higher values for interleukin-6 and interleukin-8 in the HT group. Protective ventilation with LT yielded a significant improvement in cerebral tissue oxygenation and metabolism compared to HT ventilation in a porcine model of ALI. There was dissociation between arterial and cerebral tissue oxygenation. Cerebral oxygenation and metabolism might have possibly been impaired by a more distinctive inflammatory response in the HT group.

title: Mediation of neuronal apoptosis by enhancement of outward potassium current.
abstract: Apoptosis of mouse neocortical neurons induced by serum deprivation or by staurosporine was associated with an early enhancement of delayed rectifier (IK) current and loss of total intracellular K+. This IK augmentation was not seen in neurons undergoing excitotoxic necrosis or in older neurons resistant to staurosporine-induced apoptosis. Attenuating outward K+ current with tetraethylammonium or elevated extracellular K+, but not blockers of Ca2+, Cl-, or other K+ channels, reduced apoptosis, even if associated increases in intracellular Ca2+ concentration were prevented. Furthermore, exposure to the K+ ionophore valinomycin or the K+-channel opener cromakalim induced apoptosis. Enhanced K+ efflux may mediate certain forms of neuronal apoptosis.

title: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome.
abstract: Recent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy.



To examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction.



In vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11).



In vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand.



The injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P =.03) and 8 hours (P =.002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P =.002).



Mechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.

title: Bench-to-bedside review: Brain-lung interaction in the critically ill – a pending issue revisited
abstract: Brain and/or lung injury is the most frequent cause of admission to critical care units and patients in this setting frequently develop multiple organ dysfunction with high rates of morbidity and mortality. Mechanical ventilation is commonly used in the management of these critically ill patients and the consequent inflammatory response, together with other physiological factors, is also thought to be involved in distal organ dysfunction. This peripheral imbalance is based on a multiple-pathway cross-talk between the lungs and other organs, including the brain. Interestingly, acute respiratory distress syndrome survivors frequently present some cognitive deterioration at discharge. Such neurological dysfunction might be a secondary marker of injury and the neuroanatomical substrate for downstream impairment of other organs. Brain-lung interactions have received little attention in the literature, but recent evidence suggests that both the lungs and brain are promoters of inflammation through common mediators. This review addresses the current status of evidence regarding brain-lung interactions, their pathways and current interventions in critically ill patients receiving mechanical ventilation.

title: Neurobiochemical markers of brain damage in cerebrospinal fluid of acute ischemic stroke patients.
abstract: Ischemic injury to the central nervous system causes cellular activation and disintegration, leading to release of cell-type-specific proteins into the cerebrospinal fluid (CSF). We investigated CSF concentrations of myelin basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B, and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial stroke severity, stroke location, and long-term stroke outcome.



CSF concentrations of MBP, GFAP, S100B, and NSE were assessed in 89 stroke patients on admission (mean 8.7 h after stroke onset) and in 35 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIH Stroke Scale [NIHSS] score on admission, infarct volume), (b) stroke location, and (c) stroke outcome (modified Rankin Scale [mRS] score at month 3).



MBP concentration was significantly higher in subcortical than in cortical infarcts (median MBP, 1.18 vs 0.66 microg/L, P < 0.001). GFAP and S100B concentrations correlated with the NIHSS score on admission (GFAP, R = 0.35, P = 0.001; S100B, R = 0.29, P = 0.006), infarct volume (GFAP, R = 0.34, P = 0.001; S100B, R = 0.28, P = 0.008), and mRS score at month 3 (R = 0.42, P < 0.001 and R = 0.28, P = 0.007). Concentrations of NSE did not correlate with stroke characteristics.



MBP, GFAP, S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B correlate with stroke severity and outcome.

title: Serum levels of S100B and NSE proteins in Alzheimer's disease patients
abstract: BackgroundAlzheimer's disease is the most common dementia in the elderly, and the potential of peripheral biochemical markers as complementary tools in the neuropsychiatric evaluation of these patients has claimed further attention.MethodsWe evaluated serum levels of S100B and neuron-specific enolase (NSE) in 54 mild, moderate and severe Alzheimer's disease (AD) patients and in 66 community-dwelling elderly. AD patients met the probable NINCDS-ADRDA criteria. Severity of dementia was ascertained by the Clinical Dementia Rating (CDR) scale, cognitive function by the Mini Mental State Examination (MMSE), and neuroimage findings with magnetic resonance imaging. Serum was obtained from all individuals and frozen at -70°C until analysis.ResultsBy comparing both groups, serum S100B levels were lower in AD group, while serum NSE levels were the same both groups. In AD patients, S100B levels were positively correlated with CDR scores (rho = 0.269; p = 0.049) and negatively correlated with MMSE scores (rho = -0.33; P = 0.048). NSE levels decreased in AD patients with higher levels of brain atrophy.ConclusionsThe findings suggest that serum levels of S100B may be a marker for brain functional condition and serum NSE levels may be a marker for morphological status in AD.

title: Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones
abstract: To assess levels of glial fibrillar acidic protein (GFAP), myelin basic protein (MBP), neurone-specific enolase (NSE) and S100B in patients with first-onset schizophrenia.  We investigated CSF and serum samples from 12 patients with first-onset schizophrenia and from 17 control subjects by ELISA (GFAP, MBP) or immunoluminometric sandwich assays (NSE, S100B).  Patients with schizophrenia had significantly higher levels of S100B in CSF (p = 0.004; 2.73 (SD 0.80) v 1.92 (0.58) μg/l) and serum (p = 0.032; 0.09 (0.03) v 0.08 (0.02) μg/l) in comparison with those in the matched control group. No diagnosis-dependent differences of protein concentration were seen for GFAP, MBP and NSE.  Our finding of increased levels of S100B in patients with schizophrenia without an indication for significant glial (GFAP, MBP) or neuronal (NSE) damage may be interpreted as indirect evidence for increased active secretion of S100B during acute psychosis.

title: Cardiorespiratory neurons of the rat ventrolateral medulla contain TASK-1 and TASK-3 channel mRNA
abstract: The potassium channels TASK-1 and TASK-3 are neuronal 'leak' channels that are inhibited by extracellular acidification and numerous neurotransmitters. Here we tested whether in the rat TASK-1 and TASK-3 mRNAs are present in ventrolateral medulla neurons that regulate respiration or circulation (C1 adrenergic neurons). The mRNAs were identified by in situ hybridization. Respiratory neurons were identified by anatomical markers (neurokinin-1 receptors, NK1R, or somatostatin) or directly by juxtacellular labeling of bulbospinal neurons. C1 neurons were identified by the presence of tyrosine-hydroxylase. TASK-1 and TASK-3 transcripts were present in all hypoglossal and facial motor neurons, in most C1 cells (85-95%), in most small and large NK1R-ir neurons (>90%) of the ventral respiratory group (VRG) and in all the inspiratory-augmenting bulbospinal neurons of the rostral ventral respiratory group. In conclusion, TASK channels are expressed by respiratory cells with putative rhythmogenic function and by premotor and motor neurons. TASK channels presumably mediate excitatory effects of numerous transmitters on these neurons and may contribute to their pH-sensitivity.

title: S-100 Protein and Neurohistopathologic Changes in a Porcine Model of Acute Lung Injury
abstract: Survivors of acute respiratory distress syndrome exhibit neuropsychological sequelae that might be attributable to hippocampal damage. The authors sought to determine the effects of hypoxemia in a pig model of acute lung injury on the hippocampal region and the release of S-100 protein in comparison to a control group in which hypoxemia was induced by reducing the inspired oxygen fraction.  Hypoxemia was induced in 14 female pigs by repeated lung lavages (lung injury group; n = 7) or by reducing the inspired oxygen fraction (hypoxia-only group; n = 7). Hemodynamic variables, gas exchange, and serum concentrations of S-100 protein were measured at baseline, after induction of acute lung injury, and subsequently for 12 h. Animals were euthanized, and the brains were removed for histopathologic examination.  Comparable blood gases were seen in both groups. Serum S-100 protein concentrations were comparable for both groups at baseline. At all other time points, S-100 concentrations were significantly higher in the lung injury group. Neuropathologic examination showed basophilic and shrunken neurons of the pyramidal cell layer in the hippocampal CA1 subregion of all pigs in the lung injury group. Few abnormalities were seen in the hypoxia-only group.  The same degree of hypoxemia induced in a lavage model of acute lung injury results in greater brain damage assessed by S-100 protein and histopathologic findings when compared to a group in which hypoxemia at the same degree was induced by reducing the inspired oxygen fraction. This suggests that acute lung injury leads to neuropathologic changes independent of hypoxemia.

title: Early CSF and Serum S100B Concentrations for Outcome Prediction in Traumatic Brain Injury and Subarachnoid Hemorrhage
abstract: S100B has been proposed as a putative biochemical marker in determining the extent of brain injury and corresponding prognosis in neurotrauma. The aim of this study was to evaluate the prognostic value of S100B early concentrations in serum and cerebrospinal fluid (CSF) in traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), to determine prognostically relevant threshold values and to evaluate fluctuation following EVD placement.



In 102 patients (45 SAH and 57 TBI) under intensive care unit (ICU) treated between January 2011 and December 2012 with external ventricular drain (EVD) S100B measurements were performed simultaneously in serum and CSF during the first 5 days and before and after EVD exchange. Glasgow coma scale (GCS) was assessed on admission and Glasgow outcome scale (GOS) 6 months later.



Peak S100B levels in CSF and serum were measured on the first day after admission and concentrations decreased during the ensuing days post injury gradually. CSF and serum S100B concentrations in TBI patients were significantly higher than in SAH (p<0.005). Both in TBI and SAH patients S100B concentrations in CSF and serum were significantly higher in patients with an unfavorable outcome (GOS 1-3) in comparison to patients with a good outcome (GOS 4-5). Correlation of S100B concentrations in serum and GOS score at 6 months was significant both in TBI and SAH (p<0.05). Serum S100B concentrations >0.7μg/l correlated with 100% mortality. Correlation between S100B in CSF and GOS was significant in SAH (p<0.05), whereas it was not significant in TBI. After EVD exchange (n=53) we found a significant increase of S100B concentration in CSF (p<0.005).



Initial S100B levels have a limited prognostic value in neurotrauma with CSF concentrations being highly sensitive to smallest influences like EVD placement. However, high initial S100B levels of >0.7μg/dl in serum are associated with 100% mortality, which might help to guide therapy strategies in severe neurotrauma.

title: Glial and axonal body fluid biomarkers are related to infarct volume, severity, and outcome.
abstract: Body fluid biomarkers of central nervous system damage may help improve the prognostic and diagnostic accuracy in ischemic stroke. We studied 53 patients. Stroke severity and outcome was rated using the National Institutes of Health Stroke Scale and modified Rankin scale. Ferritin, S100B, and NfH were measured in cerebrospinal fluid (CSF) and serum. Infarct volume was calculated from T2W images. CSF S100B (median 1.00 ng/mL) and CSF ferritin (10.0 ng/mL) levels were elevated in patients with stroke compared with control subjects (0.62 ng/mL, P < .0001; 2.34 ng/mL, P < .0001). Serum S100B (0.09 ng/mL) was higher in patients with stroke compared with control subjects (0.01 ng/mL). CSF S100B levels were higher in patients with a cardioembolic stroke (2.88 ng/mL) than in those with small-vessel disease (0.89 ng/mL, P < .05). CSF S100B levels correlated with the National Institutes of Health Stroke Scale score on admission (R = 0.56, P < .01) and the stroke volume (R = 0.44, P = .01). CSF S100B and NfH-SMI35 levels correlated with outcome on the modified Rankin scale. CSF S100B levels were related to stroke severity and infarct volume and highest in cardioembolic stroke.

title: A Primary Role for K+ and Na+ Efflux in the Activation of Apoptosis*
abstract: Cell shrinkage is a major characteristic of apoptosis, but the mechanism and role of this process in cell death are poorly understood. The primary factor that controls volume regulation in all cells is ions, and thus we have examined the movement of ions at the single cell level in lymphocytes during apoptosis. Activation of the death program with several stimuli that act through independent pathways to stimulate apoptosis results in a synchronous shift of cells from a normal cell size to a shrunken cell size. Only the shrunken cells exhibit DNA fragmentation and an approximate 4-fold elevation of caspase-3-like activity. Analysis of K+ and Na+ ion content of individual cells by flow cytometry revealed that the intracellular ionic strength of apoptotic cells decreased substantially from their non-shrunken counterparts. Additionally, we show apoptosis is enhanced under conditions where the intracellular K+ concentration is diminished and that apoptosis is inhibited when K+ efflux is prevented. These data show that the efflux of ions, primarily potassium, plays a necessary and perhaps a pivotal role in the cell death program.

title: K+-dependent Cerebellar Granule Neuron Apoptosis
abstract: Rat mature cerebellar granule, unlike hippocampal neurons, die by apoptosis when cultured in a medium containing a physiological concentration of K+ but survive under high external K+ concentrations. Cell death in physiological K+ parallels the developmental expression of the TASK-1 and TASK-3 subunits that encode the pH-sensitive standing outward K+ current IKso. Genetic transfer of the TASK subunits in hippocampal neurons, lacking IKso, induces cell death, while their genetic inactivation protects cerebellar granule neurons. Neuronal death of cultured rat granule neurons is also prevented by conditions that specifically reduce K+ efflux through the TASK-3 channels such as extracellular acidosis and ruthenium red. TASK leak K+ channels thus play an important role in K+-dependent apoptosis of cerebellar granule neurons in culture.

title: TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system.
abstract: We provide evidence that TWIK-related acid-sensitive potassium channel 1 (TASK1), a member of the family of two-pore domain potassium channels relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation. After induction of experimental autoimmune encephalomyelitis, an experimental model mimicking multiple sclerosis, TASK1(-/-) mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls. T cells from TASK1(-/-) mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal. In addition to these effects on systemic T cell responses, TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves. Anandamide, an endogenous cannabinoid and inhibitor of TASK channels, reduced outward currents and inhibited effector functions of T cells (IFN-gamma production and proliferation); an effect completely abrogated in TASK1(-/-) mice. Accordingly, preventive blockade of TASK1 significantly ameliorated experimental autoimmune encephalomyelitis after immunization. Therapeutic application of anandamide significantly reduced disease severity and was capable of lowering progressive loss of brain parenchymal volume as assessed by magnetic resonance imaging. These data support the identification and characterization of TASK1 as potential molecular target for the therapy of inflammatory and degenerative central nervous system disorders.

title: Protective effects of TASK-3 (KCNK9) and related 2P K channels during cellular stress
abstract: Tandem pore domain (or 2P) K channels form a recently isolated family of channels that are responsible for background K currents in excitable tissues. Previous studies have indicated that 2P K channel activity produces membrane hyperpolarization, which may offer protection from cellular insults. To study the effect of these channels in neuroprotection, we overexpressed pH-sensitive 2P K channels by transfecting the partially transformed C8 cell line with these channels. Tandem pore weak inward rectifier K channel (TWIK)-related acid-sensitive K channel 3 (TASK-3, KCNK9) as well as other pH sensitive 2P K channels (TASK-1 and TASK-2) enhanced cell viability by inhibiting the activation of intracellular apoptosis pathways. To explore the cellular basis for this protection in a more complex cellular environment, we infected cultured hippocampal slices with Sindbis virus constructs containing the coding sequences of these channels. Expression of TASK-3 throughout the hippocampal structure afforded neurons within the dentate and CA1 regions significant protection from an oxygen-glucose deprivation (OGD) injury. Neuroprotection within TASK-3 expressing slices was also enhanced by incubation with isoflurane. These results confirm a protective physiologic capability of TASK-3 and related 2P K channels, and suggest agents that enhance their activity, such as volatile anesthetics may intensify these protective effects.

title: Inhibition of Resting Potassium Conductances by Long-Term Activation of the NO/cGMP/Protein Kinase G Pathway: A New Mechanism Regulating Neuronal Excitability
abstract: Glutamate-induced excitotoxicity, the most common pathological mechanism leading to neuronal death, may occur even with normal levels of glutamate if it coincides with a persistent enhancement of neuronal excitability. Neurons expressing nitric oxide (NO) synthase (NOS-I), which is upregulated in many human chronic neurodegenerative diseases, are highly susceptible to neurodegeneration. We hypothesized that chronic production of NO in damaged neurons may increase their intrinsic excitability via modulation of resting or “leak” K+ currents. Peripheral XIIth nerve injury in adult rats induced de novo NOS-I expression and an increased incidence of low-threshold motor units, the latter being prevented by chronic inhibition of the neuronal NO/cGMP pathway. Accordingly, sustained synthesis of NO maintained an enhanced basal activity in injured motoneurons that was slowly reverted (over the course of 2–3 h) by NOS-I inhibitors. In slice preparations, persistent, but not acute, activation of the NO/cGMP pathway evoked a robust augment in motoneuron excitability independent of synaptic activity. Furthermore, chronic activation of the NO/cGMP pathway fully suppressed TWIK-related acid-sensitive K+ (TASK) currents through a protein kinase G (PKG)-dependent mechanism. Finally, we found evidence for the involvement of this long-term mechanism in regulating membrane excitability of motoneurons, because their pH-sensitive currents were drastically reduced by nerve injury. This NO/cGMP/PKG-mediated modulation of TASK conductances might represent a new pathological mechanism that leads to hyperexcitability and sensitizes neurons to excitotoxic damage. It could explain why de novo expression of NOS-I and/or its overexpression makes them susceptible to neurodegeneration under pathological conditions.

title: S100β as an early biomarker of excitotoxic damage in spinal cord organotypic cultures
abstract: S100β is a cytoplasmic calcium‐binding protein mainly expressed by glia and considered to be a useful biomarker for brain or spinal cord injury. Indeed, clinical studies suggest that the S100β concentration in serum or cerebrospinal fluid may predict lesion outcome and prognosis. The relation of S100β levels to damage severity and its timecourse remains, however, unclear. This study used a validated in vitro model of spinal cord injury induced by kainate‐mediated excitotoxicity to investigate these issues. After 22 days in vitro, rat organotypic spinal cord slices were subjected to one transient application (1 h) of 1 or 100 μM kainate followed by washout. While the lower kainate concentration did not evoke neuronal loss or S100β increase, the larger concentration elicited 40% neuronal death, no change in glial number and a delayed, significant rise in extracellular S100β that peaked at 24 h. This increase was associated with a stronger expression of the S100β protein as indicated by western blotting and immunohistochemistry. Application of the microtubule disrupting agent colchicine did not change the rise in S100β induced by kainate, an effect blocked by the glutamate receptor antagonists CNQX and APV. Our data suggest that excitotoxicity was followed by release of S100β perhaps from a readily releasable pool through a mechanism independent of microtubule assembly. The raised extracellular level of S100β appeared to reflect glial reactivity to the kainate‐evoked lesion in accordance with the view that this protein may be involved in tissue protection and repair after acute injury.

title: Time‐dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury
abstract: Time‐dependent changes of protein biomarkers in the cerebrospinal fluid (CSF) can be used to identify the pathological processes in traumatic brain injury (TBI) as well as to follow the progression of the disease. We obtained CSF from a large animal model (swine) of blast‐induced traumatic brain injury prior to and at 6, 24, 72 h, and 2 wk after a single exposure to blast overpressure, and determined changes in the CSF levels of neurofilament‐heavy chain, neuron‐specific enolase, brain‐specific creatine kinase, glial fibrillary acidic protein, calcium‐binding protein β (S100β), Claudin‐5, vascular endothelial growth factor, and von Willebrand factor using reverse phase protein microarray. We detected biphasic temporal patterns in the CSF concentrations of all tested protein markers except S100β. The CSF levels of all markers were significantly increased 6 h after the injury compared to preinjury levels. Values were then decreased at 24 h, prior to a second increase in all markers but S100β at 72 h. At 2 wk postinjury, the CSF concentrations of all biomarkers were decreased once again; brain‐specific creatine kinase, Claudin‐5, von Willebrand factor, and S100β levels were no longer significantly higher than their preinjury values while neurofilament‐heavy chain, neuron‐specific enolase, vascular endothelial growth factor, and glial fibrillary acidic protein levels remained significantly elevated compared to baseline. Our findings implicate neuronal and glial cell damage, compromised vascular permeability, and inflammation in blast‐induced traumatic brain injury, as well as demonstrate the value of determining the temporal pattern of biomarker changes that may be of diagnostic value.