Does growth restriction increase the vulnerability to acute ventilation-induced brain injury in newborn lambs? Implications for future health and disease

2017 ◽  
Vol 8 (5) ◽  
pp. 556-565 ◽  
Author(s):  
B. J. Allison ◽  
S. B. Hooper ◽  
E. Coia ◽  
G. Jenkin ◽  
A. Malhotra ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Brain Injury ◽  
Cell Damage ◽  
Inflammatory Marker ◽  
Neurovascular Unit ◽  
Early Brain Injury ◽  
Growth Restriction ◽  
Future Health ◽  
Fetal Sheep ◽  
The Brain

Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGRVENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGRVENT and AGVENT lambs. Abnormalities in the neurovascular unit and increased blood–brain barrier permeability were observed in FGRVENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero.

The brain development of infants with intrauterine growth restriction: role of glucocorticoids

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Ying-xue Ding ◽  
Hong Cui
Keyword(s):  
Endothelial Cells ◽  
Brain Injury ◽  
Intrauterine Growth Restriction ◽  
Growth And Development ◽  
Growth Restriction ◽  
Microvascular Endothelial Cells ◽  
Intrauterine Growth ◽  
Growth Restrictions ◽  
The Brain

Abstract Brain injury is a serious complication of intrauterine growth restriction (IUGR), but the exact mechanism remains unclear. While glucocorticoids (GCs) play an important role in intrauterine growth and development, GCs also have a damaging effect on microvascular endothelial cells. Moreover, intrauterine adverse environments lead to fetal growth restriction and the hypothalamus-pituitary-adrenal (HPA) axis resetting. In addition, chronic stress can cause a decrease in the number and volume of astrocytes in the hippocampus and glial cells play an important role in neuronal differentiation. Therefore, it is speculated that the effect of GCs on cerebral neurovascular units under chronic intrauterine stimulation is an important mechanism leading to brain injury in infants with growth restrictions.

scholarly journals Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

2019 ◽  
Vol 20 (24) ◽  
pp. 6125 ◽  
Author(s):  
Ning Liu ◽  
Yinghua Jiang ◽  
Joon Yong Chung ◽  
Yadan Li ◽  
Zhanyang Yu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Neurovascular Unit ◽  
Annexin A2 ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Endogenous Factors ◽  
The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

scholarly journals Temporal Profile of Transporter mRNA Expression in the Brain after Traumatic Brain Injury in Developing Rats

2019 ◽  
Author(s):  
Solomon M. Adams ◽  
Fanuel T. Hagos ◽  
Jeffrey P. Cheng ◽  
Robert S. B. Clark ◽  
Patrick M. Kochanek ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mrna Expression ◽  
Neurovascular Unit ◽  
Post Injury ◽  
Adult Rats ◽  
Order Of Magnitude ◽  
Liver And Kidney ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTTraumatic brain injury (TBI) is a leading cause of death in children and young adults; however, new pharmacologic approaches have failed to improve outcomes in clinical trials. Transporter proteins are central to the maintenance of homeostasis within the neurovascular unit, and regulate drug penetration into the brain. Our objective was to measure transporter temporal changes in expression in the hippocampus and cortex after experimental TBI in developing rats. We also evaluated the expression of transporters in brain, liver, and kidney across the age spectrum in both pediatric and adult rats. Eighty post-natal day (PND)-17 rats and four adult rats were randomized to receive controlled cortical impact (CCI), sham surgery, or no surgery. mRNA transcript counts for 27 ATP-binding cassette and solute carrier transporters were measured in the hippocampus, cortex, choroid plexus, liver, and kidney at 3h, 12h, 24h, 72h, 7d, and 14d post injury. After TBI, the expression of many transporters (Abcc2, Slc15a2, Slco1a2) decreased significantly in the first 24 hours, with a return to baseline over 7-14 days. Some transporters (Abcc4, Abab1a/b, Slc22a4) showed a delayed increase in expression. Baseline expression of transporters was of a similar order of magnitude in brain tissues relative to liver and kidney. Findings suggest that transporter-regulated processes may be impaired in the brain early after TBI and are potentially involved in the recovery of the neurovascular unit. Our data also suggest that transport-dependent processes in the brain are of similar importance as those seen in organs involved in drug metabolism and excretion.Significance StatementBaseline transporter mRNA expression in the central nervous system is of similar magnitude as liver and kidney, and experimental traumatic brain injury is associated with acute decrease in expression of several transporters, while others show delayed increase or decrease in expression. Pharmacotherapy following traumatic brain injury should consider potential pharmacokinetic changes associated with transporter expression.

scholarly journals Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

2014 ◽  
Vol 34 (10) ◽  
pp. 1637-1645 ◽  
Author(s):  
Amandine Jullienne ◽  
Jill M Roberts ◽  
Viorela Pop ◽  
M Paul Murphy ◽  
Elizabeth Head ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Amyloid Beta ◽  
Vascular Dysfunction ◽  
Neurovascular Unit ◽  
Early Brain Injury ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Blood Microvessels

In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Aβ) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Aβ clearance. Rodent-Aβ staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood–brain barrier alongside vascular dysfunction and altered Aβ trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Buqi Na ◽  
Hong Zhang ◽  
Guangfa Wang ◽  
Li Dai ◽  
Guoguang Xia
Keyword(s):  
Mechanical Ventilation ◽  
Brain Injury ◽  
Lung Injury ◽  
Rat Model ◽  
Central Control ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Lung Histology ◽  
Respiratory Centre ◽  
The Brain

Background and Objective. TWIK-related acid-sensitive potassium channel 1 (TASK-1) 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.Methods. 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.Results. 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.Conclusion. 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.

scholarly journals Clinical Trials in Cardiac Arrest and Subarachnoid Hemorrhage: Lessons from the Past and Ideas for the Future

2013 ◽  
Vol 2013 ◽  
pp. 1-42
Author(s):  
Jennifer A. Frontera
Keyword(s):  
Clinical Trials ◽  
Cardiac Arrest ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Randomized Clinical Trials ◽  
Early Brain Injury ◽  
Aneurysm Rupture ◽  
Neurological Outcomes ◽  
Injury Research ◽  
The Brain

Introduction. Elevated intracranial pressure that occurs at the time of cerebral aneurysm rupture can lead to inadequate cerebral blood flow, which may mimic the brain injury cascade that occurs after cardiac arrest. Insights from clinical trials in cardiac arrest may provide direction for future early brain injury research after subarachnoid hemorrhage (SAH).Methods. A search of PubMed from 1980 to 2012 and clinicaltrials.gov was conducted to identify published and ongoing randomized clinical trials in aneurysmal SAH and cardiac arrest patients. Only English, adult, human studies with primary or secondary mortality or neurological outcomes were included.Results. A total of 142 trials (82 SAH, 60 cardiac arrest) met the review criteria (103 published, 39 ongoing). The majority of both published and ongoing SAH trials focus on delayed secondary insults after SAH (70%), while 100% of cardiac arrest trials tested interventions within the first few hours of ictus. No SAH trials addressing treatment of early brain injury were identified. Twenty-nine percent of SAH and 13% of cardiac arrest trials showed outcome benefit, though there is no overlap mechanistically.Conclusions. Clinical trials in SAH assessing acute brain injury are warranted and successful interventions identified by the cardiac arrest literature may be reasonable targets of the study.

Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep

2009 ◽  
Vol 296 (3) ◽  
pp. R640-R650 ◽  
Author(s):  
Susan Y. S. Feng ◽  
David J. Phillips ◽  
Elaine M. Stockx ◽  
Victor Y. H. Yu ◽  
Adrian M. Walker
Keyword(s):  
Brain Injury ◽  
Cerebral Circulation ◽  
Cerebral Hypoperfusion ◽  
Fetal Sheep ◽  
Cerebral Vasoconstriction ◽  
Cerebral Vasodilatation ◽  
Two Phases ◽  
The Impact ◽  
Acute And Chronic Effects ◽  
The Brain

We studied the impact of endotoxemia on cerebral blood flow (CBF), cerebral vascular resistance (CVR), and cerebral oxygen transport (O2 transport) in fetal sheep. We hypothesized that endotoxemia impairs CBF regulation and O2 transport, exposing the brain to hypoxic-ischemic injury. Responses to lipopolysaccharide (LPS; 1 μg/kg iv on 3 consecutive days, n = 9) or normal saline ( n = 5) were studied. Of LPS-treated fetuses, five survived and four died; in surviving fetuses, transient cerebral vasoconstriction at 0.5 h (ΔCVR approximately +50%) was followed by vasodilatation maximal at 5–6 h (ΔCVR approximately −50%) when CBF had increased (approximately +60%) despite reduced ABP (approximately −20%). Decreased CVR and increased CBF persisted 24 h post-LPS and the two subsequent LPS infusions. Cerebral O2 transport was sustained, although arterial O2 saturation was reduced ( P < 0.05). Histological evidence of neuronal injury was found in all surviving LPS-treated fetuses; one experienced grade IV intracranial hemorrhage. Bradykinin-induced cerebral vasodilatation (ΔCVR approximately −20%, P < 0.05) was abolished after LPS. Fetuses that died post-LPS ( n = 4) differed from survivors in three respects: CVR did not fall, CBF did not rise, and O2 transport fell progressively. In conclusion, endotoxin disrupts the cerebral circulation in two phases: 1) acute vasoconstriction (1 h) and 2) prolonged vasodilatation despite impaired endothelial dilatation (24 h). In surviving fetuses, LPS causes brain injury despite cerebral O2 transport being maintained by elevated cerebral perfusion; thus sustained O2 transport does not prevent brain injury in endotoxemia. In contrast, cerebral hypoperfusion and reduced O2 transport occur in fetuses destined to die, emphasizing the importance of sustaining O2 transport for survival.

scholarly journals Ventilasi Mekanik yang Memanjang pada Pasien Cedera Otak Traumatik Berat dengan Subdural Hematoma

2020 ◽  
Vol 9 (2) ◽  
pp. 92-101
Author(s):  
Dini Handayani Putri ◽  
Iwan Abdul Rachman ◽  
Sri Rahardjo
Keyword(s):  
Mechanical Ventilation ◽  
Brain Injury ◽  
Ct Scan ◽  
Subdural Hematoma ◽  
Glasgow Outcome Scale ◽  
The Body ◽  
Antibiotic Administration ◽  
Ventilator Associated Pneumonia ◽  
Severe Tbi ◽  
The Brain

Cedera otak traumatik (COT) adalah suatu proses patologis pada otak yang berasal dari luar tubuh, yang dapat menyebabkan kerusakan permanen atau sementara dari fungsi otak. Salah satu perdarahan otak yang sering menyertai terjadinya COT berat adalah subdural hematoma (SDH). Pasien laki-laki 41 tahun, datang ke rumah sakit dengan penurunan kesadaran GCS E2M2V2 akibat kecelakaan. Pasien dilakukan tatalaksana dan diintubasi di IGD, hasil CT-Scan memperlihatkan SDH, dan edema serebri. Pasien dilakukan evakuasi hematom dengan anestesi umum, diinduksi dengan fentanil 100 μgr, propofol 20 mg dan atracurium 20 mg intravena. Pemeliharaan dengan sevofluran, propofol kontinyu, fentanil dan atracurium intermiten. Pascaoperasi pasien mengalami ventilator associated pneumonia (VAP), diberikan antibiotik sprektum luas untuk pemulihan paru, pada hari ke 10 pasien dilakukan trakeostomi. Pasien dapat disapih dari ventilator hari ke 21 dengan GCS E4M4Vtrach tanpa kontak, dengan skor GOS (Glasgow Outcome Scale) 3, direncanakan untuk homecare. COT berat membutuhkan tatalaksana pascaoperasi yang lebih kompleks, antisipasi penggunaan ventilasi mekanik yang memanjang, risiko VAP serta pertimbangan pemasangan trakeostomi secara cepat hingga pemberian antibiotik yang adekuat untuk mendapatkan hasil luaran terbaik. Prolonged Mechanical Ventilation in Severe Traumatic Brain Injury Patients with Subdural HematomasAbstractTraumatic brain injury (TBI) is a pathological process in the brain that originates from outside the body, which can lead to permanent or temporary damage to brain function. One of the brain hemorrhages that often accompanies severe TBI is subdural hematoma (SDH). Male patient 41 years old, was admitted to our hospital with decreased of consciusness with GCS E2M2V2 due to a motorcycle accident. The patient was intubated in the emergency room and then performed head CT scan examination which showed SDH and cerebral edema as the result. Patients then underwent hematoma evacuation under general anesthesia, induced with fentanyl 100 g, propofol 20 mg and atracurium 20 mg intravenously. Maintenance of anesthesia with sevoflurane, continuous propofol, fentanyl and intermittent atracurium. Postoperatively the patient experienced ventilator associated pneumonia (VAP) and given broad-spectrum antibiotics for lung recovery, then on the 10th day tracheostomy was performed. Patients can be weaned from the ventilator on day 21st with GCS E4M4Vtrach without contact, with a GOS (Glasgow Outcome Scale) score of 3, and was planned for homecare. Severe TBI requires more complex postoperative management, anticipation of prolonged use of mechanical ventilation, risk of VAP and consideration of rapid tracheostomy installation to adequate antibiotic administration to obtain the best outcome.

scholarly journals CURRENT CONCEPTS OF PERINATAL ISCHEMIC INJURY IN THE BRAIN NEUROVASCULAR UNIT: MOLECULAR TARGETS FOR NEUROPROTECTION

2013 ◽  
Vol 68 (12) ◽  
pp. 26-35 ◽  
Author(s):  
A. V. Morgun ◽  
N. V. Kuvacheva ◽  
T. E. Taranushenko ◽  
E. D. Khilazhieva ◽  
N. A. Malinovskaya ◽  
...  
Keyword(s):  
Brain Injury ◽  
Neurovascular Unit ◽  
Cell Communication ◽  
Molecular Targets ◽  
Ischemic Injury ◽  
Ischemic Brain Injury ◽  
Perinatal Brain Injury ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
The Brain

Perinatal hypoxic-ischemic brain injury is a relevant medical and social problem. Among many pathological processes in the neonatal period perinatal hypoxic-ischemic injury is a major cause of further hemorrhage, necrotic and atrophic changes in the brain.  This review presents recent data on the basic mechanisms of the hypoxic-ischemic brain injury along the concept of neurovascular unit (neurons, astrocytes, endothelial cells, pericytes) with the focus on alterations in cell-to-cell communication. Pathological changes caused by ischemia-hypoxia are considered within two phases of injury (ischemic phase and reperfusion phase). The review highlights changes in each individual component of the neurovascular unit and their interactions. Molecular targets for pharmacological improvement of intercellular communication within neurovascular unit as a therapeutic strategy in perinatal brain injury are discussed. 

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