Molecular hydrogen alleviates lung injury after traumatic brain injury: Pyroptosis and apoptosis

Abstract BACKGROUND: Severe traumatic brain injury (TBI) in children is associated with substantial long-term morbidity and mortality. Currently, there are no successful neuroprotective/neuroreparative treatments for TBI. Numerous preclinical studies suggest that bone marrow-derived mononuclear cells (BMMNCs), their derivative cells (marrow stromal cells), or similar cells (umbilical cord blood cells) offer neuroprotection. OBJECTIVE: To determine whether autologous BMMNCs are a safe treatment for severe TBI in children. METHODS: Ten children aged 5 to 14 years with a postresuscitation Glasgow Coma Scale of 5 to 8 were treated with 6 × 106 autologous BMMNCs/kg body weight delivered intravenously within 48 hours after TBI. To determine the safety of the procedure, systemic and cerebral hemodynamics were monitored during bone marrow harvest; infusion-related toxicity was determined by pediatric logistic organ dysfunction (PELOD) scores, hepatic enzymes, Murray lung injury scores, and renal function. Conventional magnetic resonance imaging (cMRI) data were obtained at 1 and 6 months postinjury, as were neuropsychological and functional outcome measures. RESULTS: All patients survived. There were no episodes of harvest-related depression of systemic or cerebral hemodynamics. There was no detectable infusion-related toxicity as determined by PELOD score, hepatic enzymes, Murray lung injury scores, or renal function. cMRI imaging comparing gray matter, white matter, and CSF volumes showed no reduction from 1 to 6 months postinjury. Dichotomized Glasgow Outcome Score at 6 months showed 70% with good outcomes and 30% with moderate to severe disability. CONCLUSION: Bone marrow harvest and intravenous mononuclear cell infusion as treatment for severe TBI in children is logistically feasible and safe.

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Corrigendum to “ERK1/2/mTOR/Stat3 pathway-mediated autophagy alleviates traumatic brain injury-induced acute lung injury” [Biochim. Biophys. Acta 1864/5PA(2018) 1663–1674]

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2018.04.003 ◽

2018 ◽

Vol 1864 (6) ◽

pp. 2214

Author(s):

Xiupeng Xu ◽

Tongle Zhi ◽

Honglu Chao ◽

Kuan Jiang ◽

Yinlong Liu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Acute Lung Injury ◽

Brain Injury ◽

Lung Injury ◽

Stat3 Pathway

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The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation

Science Translational Medicine ◽

10.1126/scitranslmed.3009443 ◽

2014 ◽

Vol 6 (252) ◽

pp. 252ra124-252ra124 ◽

Cited By ~ 59

Author(s):

Daniel J. Weber ◽

Adam S. A. Gracon ◽

Matthew S. Ripsch ◽

Amanda J. Fisher ◽

Bo M. Cheon ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Acute Lung Injury ◽

Brain Injury ◽

Lung Injury ◽

Lung Transplantation ◽

Inflammatory Responses ◽

Pulmonary Dysfunction ◽

Wild Type ◽

Hmgb1 Protein ◽

Lung Dysfunction

Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs’ ability to expand), all of which were attenuated in RAGE−/−mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE−/−TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.

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Incidence and Outcomes of Acute Lung Injury in Patients With Isolated Traumatic Brain Injury

Iranian Journal of Neurosurgery ◽

10.32598/irjns.7.3.3 ◽

2021 ◽

Vol 7 (3) ◽

pp. 139-146

Author(s):

Siamak Rimaz ◽

◽

Seyyed Mahdi Zia Ziabari ◽

Neshat Jabbari ◽

Zahra Pourmohammadi ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Acute Lung Injury ◽

Brain Injury ◽

Lung Injury ◽

Brain Damage ◽

Study Data ◽

Cerebral Injury ◽

Age Group ◽

Cross Sectional ◽

Motorcycle Accident

Background and Aim: Traumatic Brain Injury (TBI) is an essential cause of morbidity and mortality worldwide. TBI patients frequently encounter lung complications, such as Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), which is associated with poor clinical outcome because hypoxia causes additional injury to the brain. This study aimed to evaluate the frequency of ALI in patients with TBI and its consequences. Methods and Materials/Patients: In this descriptive cross-sectional study, data from all records of patients admitted to Poursina Hospital’s ICU (emergency and neurosurgery ICU) in 20 18-2019 were used. The evaluated data included age, gender, type of head trauma mechanism, kind of brain injury based on CT scan findings, the severity of brain injury based on Glasgow Coma Scale (GCS), underlying diseases, mean head AIS score, the number of pack cell units injected, as well as bilateral pulmonary infiltration in favor of ALI and brain injury. Results: Only 81 of the 557 TBI cases met the inclusion criteria of the present study. The highest frequency of ALI following TBI was observed on the first day of hospitalization, in men (0.41%) in the age group of 40-50 years (7%) with severe brain damage (6%) and subdural hematoma (12%), following a motorcycle accident, cars, as well as on the third day of hospitalization were seen in men (43.8%) with the age group of 20-30 years (55%) with severe brain damage (42%) and intra-parenchymal bleeding (57%), following a motorcycle accident. In addition, no significant correlation was detected between the incidence of ALI and mortality, the duration of hospitalization, GCS, mean head AIS score, or the extent of received blood units in our study. Conclusion: According to the obtained findings, men aged between 20 and 30 years with severe cerebral injury, epidural hematoma and a motorcycle accident presented the highest rate of progression toward ALI in the first to third days of hospitalization.

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The Role of S100B/RAGE-Enhanced ADAM17 Activation in Endothelial Glycocalyx Shedding After Traumatic Brain Injury

10.21203/rs.3.rs-927255/v1 ◽

2021 ◽

Author(s):

Zhimin Zou ◽

Li Li ◽

Qin Li ◽

Kun Zhang ◽

Chengyong Liu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endothelial Cells ◽

Brain Injury ◽

Lung Injury ◽

Cultured Cells ◽

Cell Model ◽

Endothelial Glycocalyx ◽

Pharmacological Intervention ◽

Secondary Injury ◽

Rat Serum

Abstract Background: Traumatic brain injury (TBI) remains one of the main causes for disability and death worldwide. While the primary mechanical injury cannot be avoided, the prevention of secondary injury is the focus of TBI research. Present study aimed to elucidate the effects and mechanisms of S100B and its receptor RAGE on mediating secondary injury after TBI. Methods: This study established TBI animal model by fluid percussion injury in rats, cell model by stretch-injured in astrocytes, and endothelial injury model with conditioned medium stimulation. Pharmacological intervention was applied to interfere the activities of S100B/RAGE/ADAM17 signaling pathway, respectively. The expressions or contents of S100B, RAGE, syndecan-1 and ADAM17 in brain and serum, as well as in cultured cells and medium, were detected by western blot. The distribution of relative molecules was observed with immunofluorescence. Results: We found that TBI could activate the release of S100B, mostly from astrocytes, and S100B and RAGE could mutually regulate their expression and activation. Most importantly, present study revealed an obvious increase of syndecan-1 in rat serum or in endothelial cultured medium after injury, and a significant decrease in tissue and in cultured endothelial cells, indicating TBI-induced shedding of endothelial glycocalyx. The data further proved that the activation of S100B/RAGE signaling could promote the shedding of endothelial glycocalyx by enhancing the expression, translocation and activity of ADAM17, an important sheddase, in endothelial cells. The damage of endothelial glycocalyx consequently aggravated blood brain barrier (BBB) dysfunction and systemic vascular hyper-permeability, overall resulting in secondary brain and lung injury. Conclusions: TBI triggers the activation of S100B/RAGE signal pathway. The regulation S100B/RAGE on ADAM17 expression, translocation and activation further promotes the shedding of endothelial glycocalyx, aggravates the dysfunction of BBB, and increases the vascular permeability, leading to secondary brain and lung injury. Present study may open a new corridor for the more in-depth understanding of the molecular processes responsible for cerebral and systemic vascular barrier impairment and secondary injury after TBI.

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Fingolimod Attenuates Lung Injury and Cardiac Dysfunction after Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2019.6951 ◽

2020 ◽

Vol 37 (19) ◽

pp. 2131-2140

Author(s):

Yu Qian ◽

Chuang Gao ◽

Xiaonan Zhao ◽

Yiming Song ◽

Hongliang Luo ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Lung Injury ◽

Cardiac Dysfunction

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Human Lung Cell Pyroptosis Following Traumatic Brain Injury

Cells ◽

10.3390/cells8010069 ◽

2019 ◽

Vol 8 (1) ◽

pp. 69 ◽

Cited By ~ 4

Author(s):

Nadine Kerr ◽

Juan de Rivero Vaccari ◽

Oliver Umland ◽

M. Bullock ◽

Gregory Conner ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endothelial Cell ◽

Brain Injury ◽

Lung Injury ◽

Critical Role ◽

Gunshot Wounds ◽

Extracellular Vesicle ◽

Inflammasome Activation ◽

Trauma Patients ◽

Severe Tbi

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived EVs from severe TBI patients were analyzed for particle size, concentration, origin, and levels of the inflammasome component, an apoptosis-associated speck-like protein containing a caspase-recruiting domain (ASC). Serum ASC levels were analyzed from EV obtained from patients that presented lung injury after TBI and compared them to EV obtained from patients that did not show any signs of lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) to evaluate inflammasome activation and endothelial cell pyroptosis. TBI patients had a significant increase in the number of serum-derived EVs and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. Only EVs isolated from head trauma patients with gunshot wounds were of neural origin. Delivery of serum-derived EVs to HMVEC-L activated the inflammasome and resulted in endothelial cell pyroptosis. Thus, serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, supporting activation of an EV-mediated neural-respiratory inflammasome axis in TBI-induced lung injury.

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