Reduction of epinephrine in the lumbar spinal cord following repetitive blast-induced traumatic brain injury in rats

Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury.Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb muscles.Therefore,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in rats.Following three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid chromatography.Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham controls.In other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically significant.These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function.This is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.

Traumatic brain injury induced by exposure to blast overpressure via ear canal

Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations.Unprotected ears are most often damaged following exposure to blasts.Although there is an association between tympanic membrane perforation and TBI in blast exposure victims,little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal.The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in LongEvans rats.Animals were exposed to a single blast(0–30 pounds per square inch(psi))through the ear canal,and brain injury was evaluated by histological and behavioral outcomes at multiple time-points.Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain,including increased expression of c-Fos,induction of a profound chronic neuroinflammatory response,and apoptosis of neurons.The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast,but also affected the forebrain including the hippocampus,amygdala and the habenula,which are all involved in cognitive functions.Indeed,the animals exhibited long-term neurological deficits,including signs of anxiety in open field tests 2 months following blast exposure,and impaired learning and memory in an 8-arm maze 12 months following blast exposure.These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI.This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center(Animal protocol#0932 E,approval date:September 30,2016 and 0932 F,approval date:September 27,2019).

Protective Effects of Shikonin on Brain Injury Induced by Carbon Ion Beam Irradiation in Mice

Radiation encephalopathy is the main complication of cranial radiotherapy. It can cause necrosis of brain tissue and cognitive dysfunction. Our previous work had proved that a natural antioxidant shikonin possessed protective effect on cerebral ischemic injury. Here we investigated the effects of shikonin on carbon ion beam induced radiation brain injury in mice. Pretreatment with shikonin significantly increased the SOD and CAT activities and the ratio of GSH/GSSG in mouse brain tissues compared with irradiated group （P〈0.01）, while obviously reduced the MDA and PCO contents and the RO$ levels derived from of the brain mitochondria.

Effects of Blast Wave-induced Biomechanical Changes on Lung Injury in Rats

Objective To observe the dynamic impacts of shock waves on the severity of lung injury in rats with different injury distances.Methods Simulate open-field shock waves;detect the biomechanical effects of explosion sources at distances of 40,44,and 48 cm from rats;and examine the changes in the gross anatomy of the lungs,lung wet/dry weight ratio,hemoglobin concentration,blood gas analysis,and pathology.Results Biomechanical parameters such as the overpressure peak and impulse were gradually attenuated with an increase in the injury distance.The lung tissue hemorrhage,edema,oxygenation index,and pathology changed more significantly for the 40 cm group than for the 44 and 48 cm groups.The overpressure peak and impulse were significantly higher for the 40 cm group than for the 44 and 48 cm groups(P<0.05 or P<0.01).The animal mortality was significantly higher for the 40 cm group than for the other two groups(41.2%vs.17.8%and 10.0%,P<0.05).The healing time of injured lung tissues for the 40 cm group was longer than those for the 44 and 48 cm groups.Conclusions The effects of simulated open-field shock waves on the severity of lung injuries in rats were correlated with the injury distances,the peak overpressure,and the overpressure impulse.

The Mechanism of Acute Lung Injury Induced by Nickel Carbonyl in Rats

Nickel carbonyl is a highly toxic metal compound produced from the reaction that occurs between nickel and carbon monoxide under pressure. As previously reported, nickel carbonyl can cause acute aspiration pneumonia, and animal experiments showed it was toxic to animal lung, liver, brain, and other vital organs[1]. However, few studies have investigated nickel carbonyl poisoning in humans.

Effects of glucocorticoid dexamethasone on serum nitric oxide synthase activity and nitric oxide levels in a rat model of lung disease-induced brain injury

In this study, we investigated the effects of dexamethasone, pertussis toxin （a Gi protein inhibitor） and actinomycin （a transcription inhibitor） on serum nitric oxide synthase activity and nitric oxide content in a rat model of lung disease-induced brain injury. High-dose dexamethasone （13 mg/kg） and dexamethasone ＋ actinomycin reduced lung water content, increased serum nitric oxide synthase activity and nitric oxide content, diminished inflammatory cell infiltration in pulmonary alveolar interstitium, attenuated meningeal vascular hyperemia, reduced glial cell infiltration, and decreased cerebral edema. These results demonstrate that high-dose glucocorticoid treatment can reduce the severity of lung disease-induced brain injury by increasing nitric oxide synthase activity and nitric oxide levels.

Prevention and treatment of radiation-induced lung injury by hydroxypiperquin phosphate: a clinical and experimental study

Objective: To evaluate the hydroxypiperquin phosphate (HPQP) as a modifier of radiation-induced injury in human and rat lungs. Methods: Sixty-five patients with lung cancer treated with conventional radiotherapy were divided into 2 groups randomly: Thirty cases were treated with HPQP and the others were in a control group. The changes of X - ray manifestation before, after and during taking drug were compared. An animal model of radiation-induced fibrosis of lungs was also established. Hydroxyproling (HP) content in lung tissue and the pathological changes in rat lungs were checked with microscope and electron microscope after 4 months and 6 months respectively. Results: The changes of lung X-ray manifestation in treatment group were much lighter than that in control group. The HP content and the change of pathology in the lungs of those rats with HPQP treatment were obviously less than that in control group. Conclusion: HPQP plays an important role in prevention and treatment of radiation-induced injury in lungs.

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

Traumatic brain injury results in neuronal loss and glial scar formation.Replenishing neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain injury.Neuronal reprogramming is a promising strategy to convert glial scars to neural tissue.However,previous studies have reported inconsistent results.In this study,an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target effects.The results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive astrocytes.Moreover,neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain injury.In summary,this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

Blast injury risks to humans within a military trench

In land warfare,trenches serve as vital defensive fortifications,offering protection to soldiers while engaging in combat.However,despite their protective function,soldiers often sustain injuries within these trenches.The lack of corresponding blast data alongside empirical injury reports presents a significant knowledge gap,particularly concerning the blast pressures propagating within trench spaces following nearby explosions.This absence hinders the correlation between blast parameters,trench geometry,and reported injury cases,limiting our understanding of blast-related risks within trenches.This paper addresses the critical aspect of blast propagation within trench systems,essential for evaluating potential blast injury risks to individuals within these structures.Through advanced computational fluid dynamics(CFD)simulations,the study comprehensively investigates blast injury risks resulting from explosions near military trenches.Employing a sophisticated computational model,the research analyzes the dynamic blast effects within trenches,considering both geometrical parameters and blast characteristics influenced by explosive weight and scaled distance.The numerical simulations yield valuable insights into the impact of these parameters on blast injury risks,particularly focusing on eardrum rupture,lung injury,and traumatic brain injury levels within the trench.The findings elucidate distinct patterns of high-risk zones,highlighting unique characteristics of internal explosions due to confinement and venting dynamics along the trench.This study underscores the significance of detailed numerical modeling in assessing blast injury risks and provides a novel knowledge base for understanding risks associated with explosives detonating near military trenches.The insights gained contribute to enhancing safety measures in both military and civilian contexts exposed to blast events near trench structures.

Early hyperbaric oxygen therapy inhibits aquaporin 4 and adrenocorticotropic hormone expression in the pituitary gland of rabbits with blast-induced craniocerebral injury

In the present study, rabbits were treated with hyperbaric oxygen for 1 hour after detonator-blastinduced craniocerebral injury. Immunohistochemistry showed significantly reduced aquaporin 4 expression and adrenocorticotropic hormone expression in the pituitary gland of rabbits with craniocerebral injury. Aquaporin 4 expression was positively correlated with adrenocorticotropic hormone expression. These findings indicate that early hyperbaric oxygen therapy may suppress adrenocorticotropic hormone secretion by inhibiting aquaporin 4 expression.

Changes of inflammatory factors, reactive oxygen species and cognitive function in mice after brain-blast injury

Objective: To study the changes of cognitive function in mouse after brain-blast injury. Methods: Fourty healthy male C57BL/6 mice were randomly divided into model group and control group. After 24 h of injury, histopathological changesc and reactive oxygen species changes were observed under microscope;while changes of inflammatory cytokines content were determined by Western-blot. Four weeks later, Morris water maze method was used to detect the cognition impairment. Results: HE staining showed blast induced brain injury in C57BL/6 mice. Compared with normal control group, the expression of IL-1β,IL-4, IL-6 were significantly increased in brain tissue of model group whereas IL-10 was significantly decreased (P<0.05);ROS expression in the hippocampus of model group mice was significantly increased compared with that in the control group. Morris water maze showed cognition impairment in mice after brain-blast injury. Conclusions: Brain-blast injury causes cognition impairment in mice, which may be related to the occur of inflammatory change and oxidative stress in the early stage.

Correlation between miR-564, TGF-β1, and radiation-induced lung injury

Objective Our study aimed to analyze the expression of miR-564 and TGF-β1 in cancer tissues and the serum of patients with radiation-induced lung injury,and to investigate the relationship between them and radiation-induced lung injury.Methods In situ hybridization and real-time fluorescence quantitative method were used to detect the expression of miR-564.Additionally,immunohistochemistry and enzyme-linked immunosorbent assay(ELISA)were performed to detect the expression of TGF-β1.Results The overall incidence of acute radiation pneumonia was 55.9%(100/179).The incidence of≥grade 2 radioactive pneumonia was 24.0%(43/179)and that of grade 1 was 31.8%(57/179).The expression of miR-564 in grade≥2 was slightly higher than that in patients without or with grade 1,but there was no statistical difference(P=0.86).The serum level and ratio of miR-564 in patients with grade≥2 were significantly higher than those without or with grade 1(P=0.005,P=0.025,respectively).The expression of TGF-β1 in grade≥2 was significantly higher than that of patients without or with grade 1(P=0.017).The serum levels of TGF-β1 in grade≥2 were significantly higher than those in patients without or with grade 1(P=0.038).Although the ratio of TGF-β1 in radiation pneumonia of grade≥2 was significantly higher than that of without or with grade 1,there was no significant difference(P=0.24).Moreover,patients with higher expression of miR-564 and lower expression of TGF-β1 had better prognosis.Conclusion MiR-564 and TGF-β1 are predictors of radiation-induced lung injury.Monitoring its changing trend can improve the accuracy of predicting radiation-induced lung injury.The levels and ratio of serum miR-564 and TGF-β1 in patients with radiation-induced lung injury are related to the severity of radiationinduced lung injury.

Effects of dynamic ventilatory factors on ventilatorinduced lung injury in acute respiratory distress syndrome dogs

BACKGROUND： Mechanical ventilation is a double-edged sword to acute respiratory distress syndrome （ARDS） including lung injury, and systemic inflammatory response high tidal volumes are thought to increase mortality. The objective of this study is to evaluate the effects of dynamic ventilatory factors on ventilator induced lung injury in a dog model of ARDS induced by hydrochloric acid instillation under volume controlled ventilation and to investigate the relationship between the dynamic factors and ventilator-induced lung injuries （VILI） and to explore its potential mechanisms.METHODS： Thirty-six healthy dogs were randomly divided into a control group and an experimental group. Subjects in the experimental group were then further divided into four groups by different inspiratory stages of flow. Two mL of alveolar fluid was aspirated for detection of IL-8 and TNF-α. Lung tissue specimens were also extracted for total RNA, IL-8 by western blot and observed under an electronic microscope.RESULTS： IL-8 protein expression was significantly higher in group B than in groups A and D. Although the IL-8 protein expression was decreased in group C compared with group B, the difference was not statistically significant. The TNF-a ray degree of group B was significantly higher than that in the other groups （P〈0.01）, especially in group C （P〉0.05）. The alveolar volume of subjects in group B was significantly smaller, and cavity infiltration and cell autolysis were marked with a significant thicker alveolar septa, disorder of interval structures, and blurring of collagenous and elastic fiber structures. A large number of necrotic debris tissue was observed in group B.CONCLUSION： Mechanical ventilation with a large tidal volume, a high inspiratory flow and a high ventilation frequency can cause significant damage to lung tissue structure. It can significantly increase the expression of TNF-α and IL-8 as well as their mRNA expression. Furthermore, the results of our study showed that small tidal ventilation significantly reduces the release of proinflammatory media. This finding suggests that greater deterioration in lung injury during ARDS is associated with high inspiratory flow and high ventilation rate.

Dose-dependent neuroprotective effect of enoxaparin on cold-induced traumatic brain injury

Recent evidence exists that enoxaparin can reduce brain injury because of its anticoagulant activity. To investigate the potential therapeutic effect of enoxaparin on cold-induced traumatic brain injury, at 20 minutes after modeling, male BALB/c mouse models of cold-induced traumatic brain injury were intraperitoneally administered 3 and 10 mg/kg enoxaparin or isotonic saline solution. Twenty-four hours later, enoxaparin at 10 mg/kg greatly reduced infarct volume, decreased cell apoptosis in the cortex and obviously increased serum level of total antioxidant status. By contrast, administration of enoxaparin at 3 mg/kg did not lead to these changes. These findings suggest that enoxaparin exhibits neuroprotective effect on cold-induced traumatic brain injury in a dose-dependent manner.

Characteristics of Neutrophils Infiltration in Ventilation-induced Lung Injury

Neutrophils play a critical role in ventilation-induced lung injury. This study was aimed to investigate the characteristics of neutrophils influx in lungs induced by high tidal volume ventilation. Anaesthetized rats were randomly divided into low tidal volume ventilation group (Vt: 7 mL/kg, LV group) or high tidal volume ventilation group (Vt:42mL/kg, HV group ) (n=40 in each). Rats in each group were ventilated for 0, 60, 90, 120 and 240 min. The wet/dry lung weight ratio (W/D) was measured. The levels of macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α), and the activity of myeloperoxidase (MPO) were detected by enzyme-linked immunosorbent assay (ELISA). The number of neutrophils in bronchoalveolar lavage fluid (BALF) was counted after Wright’s staining, and the percentage of netrophils in lung tissues calculated. Histopatholgical examination was used to observe the changes of lung tissues after different ventilations. The results showed that the W/D weight ratio was increased, and the levels of MIP-2 and TNF-α significantly enhanced in HV group at 90, 120 and 240 min. Neutrophils in BALF and the neutrophil percentage in lung tissues were also elevated at 120 and 240 min, which coincided with the enhanced activity of MPO in HV group. The lung injury was significantly related with the ventilation time and the infiltration of neutrophils in lungs in HV group. In conclusion, in ventilation-induced lung injury, neutrophil infiltration is present in a time-dependent manner and associated with the aggravated lung injury. Pulmonary structural damage may be the main reason for ventilation-induced lung injury.

Radiation-induced brain injury after a conventional dose of intensity-modulated radiotherapy for nasopharyngeal carcinoma:a case report and literature review

A 61-year-old female nasopharyngeal carcinoma patient was admitted to the hospital with sudden cognitive dysfunction one month after Volumetric Intensity Modulated Arc Therapy(VMAT)conventional dose radiotherapy,and the initial diagnosis was radiation-induced brain injury(RBI).After comprehensive treatment with steroid hormones,the patient’s condition rapidly improved.Typically,in nasopharyngeal carcinoma patients treated with VMAT,the incidence of RBI is extremely low when the temporal lobe dose is less than 65 Gy or 1%of the volume is less than 65 Gy.When this limit is exceeded,RBI may occur in varying degrees.However,in this case,even though the temporal lobe dose was under the prescribed limit,the patient still experienced RBI.The rare observations in this case can be used as a reference,and clinicians should seriously consider the possibility of RBI in similar cases.

Neuron-specific enolase expression in a rat model of radiation-induced brain injury following vascular endothelial growth factor-modified neural stem cell transplantation

BACKGROUND： Previous studies have shown that transplantation of vascular endothelial growth factor （VEGF）-modified neural stem cells （NSC） provides better outcomes, compared with neural stem cells, in the treatment of brain damage. OBJECTIVE： To compare the effects of VEGF-modified NSC transplantation and NSC transplantation on radiation-induced brain injury, and to determine neuron-specific enolase （NSE） expression in the brain. DESIGN, TIME, AND SETTING： The randomized, controlled study was performed at the Linbaixin Experimental Center, Second Affiliated Hospital, Sun Yat-sen University, China from November 2007 to October 2008. MATERIALS： VEGF-modified C17.2 NSCs were supplied by Harvard Medical School, USA. Streptavidin-biotin-peroxidase-complex kit （Boster, China） and 5, 6-carboxyfluorescein diacetate succinimidyl ester （Fluka, USA） were used in this study. METHODS： A total of 84 Sprague Dawley rats were randomly assigned to a blank control group （n = 20）, model group （n = 20）, NSC group （n = 20）, and a VEGF-modified NSC group （n = 24）. Rat models of radiation-induced brain injury were established in the model, NSC, and VEGF-modified NSC groups. At 1 week following model induction, 10 pL （5 ×10^4 cells/μL） VEGF-modified NSCs or NSCs were respectively infused into the striatum and cerebral cortex of rats from the VEGF-modified NSC and NSC groups. A total of 10μL saline was injected into rats from the blank control and model groups. MAIN OUTCOME MEASURES： NSE expression in the brain was detected by immunohistochemistry following VEGF-modified NSC transplantation. RESULTS： NSE expression was significantly decreased in the brains of radiation-induced brain injury rats （P 〈 0.05）. The number of NSE-positive neurons significantly increased in the NSC and VEGF-modified NSC groups, compared with the model group （P 〈 0.05）. NSE expression significantly increased in the VEGF-modified NSC group, compared with the NSC group, at 6 weeks following transplantation （P 〈 0.05）. CONCLUSION： VEGF-modified NSC transplantation increased NSE expression in rats with radiation-induced brain injury, and the outcomes were superior to NSC transplantation.

Expiratory flow-limitation in mechanically ventilated patients: A risk for ventilator-induced lung injury?

Expiratory flow limitation(EFL), that is the inability of expiratory flow to increase in spite of an increase of the driving pressure, is a common and unrecognized occurrence during mechanical ventilation in a variety of intensive care unit conditions. Recent evidence suggests that the presence of EFL is associated with an increase in mortality, at least in acute respiratory distress syndrome(ARDS) patients, and in pulmonary complications in patients undergoing surgery. EFL is a major cause of intrinsic positive end-expiratory pressure(PEEPi), which in ARDS patients is heterogeneously distributed, with a consequent increase of ventilation/perfusion mismatch and reduction of arterial oxygenation. Airway collapse is frequently concomitant to the presence of EFL.When airways close and reopen during tidal ventilation, abnormally high stresses are generated that can damage the bronchiolar epithelium and uncouple small airways from the alveolar septa, possibly generating the small airways abnormalities detected at autopsy in ARDS. Finally, the high stresses and airway distortion generated downstream the choke points may contribute to parenchymal injury, but this possibility is still unproven. PEEP application can abolish EFL, decrease PEEPi heterogeneity, and limit recruitment/derecruitment.Whether increasing PEEP up to EFL disappearance is a useful criterion for PEEP titration can only be determined by future studies.

Biomarkers Associated with Radiation-Induced Lung Injury in Cancer Patients

Radiotherapy (RT) is a common and effective non-surgical treatment for thoracic solid tumors, and radiation-induced lung injury (RILI) is the most common side effect of radiotherapy. Even if RT is effective in the treatment of cancer patients, severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) can reduce the quality of life of patients and may even lead to serious consequences of death. Therefore, how to overcome the problem of accurate prediction and early diagnosis of RT for pulmonary toxicity is very important. This review summarizes the related factors of RILI and the related biomarkers for early prediction of RILI.