Cranial venous-outflow obstruction promotes neuroinflammation via ADAM17/solTNF-α/NF-κB pathway following experimental TBI.

Traumatic brain injury (TBI) is a global public health problem. As an important cause of secondary injury, cerebrovascular reaction can cause secondary bleeding, venous sinus thrombosis, and malignant brain swelling. Recent clinical studies have confirmed that intracranial venous return disorder is closely related to the prognosis of patients, yet the specific molecular mechanism involved in this process is still unclear. This study used an acute subdural hematoma (ASDH) model with cranial venous outflow obstruction (CVO) to explore how CVO aggravates the pathological process after TBI, especially for inflammation and tissue damage. The results suggest that intracranial venous return disorder exacerbates neurological deficits and brain edema in rats with ASDH by aggravating the destruction of endothelial cell tight junctions (TJs) proteins and promoting the expression of inflammatory factors, the activation of microglia and expression of recombinant A disintegrin and metalloprotease 17 (ADAM17) as well as the secretion of solTNF-α, a soluble form of tumor necrosis factor-alpha (TNFα), which in turn increase IκB-α ((inhibitor of the transcription factor nuclear factor-κB) and NF-κB p65. Our study revealed a molecular basis of how CVO aggravates inflammation and tissue damage.

Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling.

The transformation of microglia to a pro-inflammatory phenotype at the site of traumatic brain injury (TBI) drives the progression of secondary neurodegeneration and irreversible neurological impairment. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to suppress this phenotype transformation, thereby reducing neuroinflammation following TBI, but the molecular mechanisms are unknown. We found that Omega-3 PUFA suppressed the expression of disintegrin metalloproteinase (ADAM17), the enzyme required to convert tumor necrosis factor-α (TNF-α) to the soluble form, thereby inhibiting the TNF-α/NF-κB pathway both in vitro and in a mouse model of TBI. Omega-3 PUFA also prevented the reactive transformation of microglia and promoted the secretion of microglial exosomes containing nerve growth factor (NGF), activating the neuroprotective NGF/TrkA pathway both in culture and TBI model mice. Moreover, Omega-3 PUFA suppressed the pro-apoptotic NGF/P75NTR pathway at the TBI site and reduced apoptotic neuronal death, brain edema, and disruption of the blood-brain barrier. Finally, Omega-3 PUFA preserved sensory and motor function as assessed by two broad-spectrum test batteries. The beneficial effects of Omega-3 PUFA were blocked by an ADAM17 promotor and by a NGF inhibitor, confirming the pathogenic function of ADAM17 and the central neuroprotective role of NGF. Collectively, these findings provide a strong experimental basis for Omega-3 PUFA as a potential clinical treatment for TBI.

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury.

Secondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The neurovascular unit maintains blood-brain barrier and vascular integrity through interactions among glial cells, pericytes and endothelial cells. Trauma-induced neuroinflammation and oxidative stress may act as initiating factors for pathological damage after TBI, which in turn impairs cerebral microcirculatory function. Studies have shown that the tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates inflammation and oxidative damage, but its role in pericyte-mediated cerebral microcirculation are currently unknown. Herein, we assessed TNF-α/NF-κB signaling and inducible nitric oxide synthase (iNOS), and the effects of the TNF-α inhibitor infliximab after TBI. Whether pericyte damage is dependent on the TNF-α/NF-κB/iNOS axis was also evaluated to explore the mechanisms underlying disturbances in the microcirculation after TBI. Microglia are activated after TBI to promote inflammatory factors and free radical release, and upregulate NF-κB and iNOS expression. After lipopolysaccharide treatment, the activity of TNF-α/NF-κB/iNOS in BV2 cells was also upregulated. Inhibition of TNF-α using infliximab reduced NF-κB phosphorylation and nuclear translocation and downregulated iNOS expression, which attenuated the inflammation and oxidative damage. Meanwhile, inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and microcirculation perfusion after TBI. In conclusion, our study suggests that microglia released TNF-α after TBI, which promoted neuroinflammation and oxidative stress by activating downstream NF-κB/iNOS signals, and this led to pericyte-mediated disturbance of the cerebral microcirculation.

Predictive role of shock index in the early formation of cerebral infarction in patients with TBI and cerebral herniation.

Background and purpose: Traumatic brain injury (TBI) with brain herniation predisposes to posttraumatic cerebral infarction (PTCI), which in turn seriously affects the prognosis of patients. At present, there is a lack of effective indicators that can accurately predict the occurrence of PTCI. We aimed to find possible risk factors for the development of PTCI by comparing the preoperative and postoperative clinical data of TBI patients with brain herniation. Methods: The clinical data of 120 patients with craniocerebral trauma and brain herniation were retrospectively analyzed. Among them, 54 patients had cerebral infarction within 3-7 days after injury. The two groups of patients were compared through univariate and multivariate logistic regression analysis, and a classification tree model and a nomogram model were constructed. Finally, receiver operating characteristic curve analysis and decision curve analysis were conducted to analyze the clinical utility of the prediction model. Results: Logistic regression analysis showed that factors like the Glasgow Coma Scale (GCS) score (P = 0.002), subarachnoid hemorrhage (SAH) (P = 0.005), aspiration pneumonia (P < 0.001), decompressive craniectomy (P < 0.05), intracranial pressure (ICP) monitoring (P = 0.006), the shock index (SI) (P < 0.001), the mean arterial pressure (MAP) (P = 0.005), and blood glucose (GLU) (P < 0.011) appeared to show a significant statistical correlation with the occurrence of infarction (P < 0.05), while age, sex, body temperature (T), D-dimer levels, and coagulation tests were not significantly correlated with PTCI after cerebral herniation. Combined with the above factors, Classification and Regression Tree was established, and the recognition accuracy rate reached 76.67%. Conclusions: GCS score at admission, no decompressive craniectomy, no ICP monitoring, combined SAH, combined aspiration pneumonia, SI, MAP, and high GLU were risk factors for infarction, of which SI was the primary predictor of PTCI in TBI with an area under the curve of 0.775 (95% CI = 0.689-0.861). Further large-scale studies are needed to confirm these results.

Cerebral venous hemodynamic responses in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is a serious public health problem that endangers human health and is divided into primary and secondary injuries. Previous work has confirmed that changes in cerebral blood flow (CBF) are related to the progression of secondary injury, although clinical studies have shown that CBF monitoring cannot fully and accurately evaluate disease progression. These studies have almost ignored the monitoring of venous blood flow; however, as an outflow channel of the cerebral circulation, it warrants discussion. To explore the regulation of venous blood flow after TBI, the present study established TBI mouse models of different severities, observed changes in cerebral venous blood flow by laser speckle flow imaging, and recorded intracranial pressure (ICP) after brain injury to evaluate the correlation between venous blood flow and ICP. Behavioral and histopathological assessments were performed after the intervention. The results showed that there was a significant negative correlation between ICP and venous blood flow (r = -0.795, P < 0.01), and both recovered to varying degrees in the later stages of observation. The blood flow changes in regional microvessels were similar to those in venous, and the expression of angiogenesis proteins around the impact area was significantly increased. In conclusion, this study based on the TBI mouse model, recorded the changes in venous blood flow and ICP and revealed that venous blood flow can be used as an indicator of the progression of secondary brain injury.

Effect of high concentration of ammonium on production of n-caproate: Recovery of a high-value biochemical from food waste via lactate-driven chain elongation.

Ammonium accumulation is inevitable during the fermentation of food waste (FW), challenging the application of chain elongation process upgrading FW into the high-value biochemical n-caproate, which is a medium chain carboxylate. This study is the first to investigate ammonium inhibition of lactate-driven chain elongation process. The short-term exposure of a Clostridium IV-dominated chain elongating reactor microbiome at an ammonium concentration of 1-4 g L-1 linearly decreased n-caproate production by 25-80%. High levels of ammonium (≥5 g L-1) could cause failure of chain elongation, shifting the product from n-caproate to propionate. The involved mechanisms revealed that ammonium reshaped the microbial community from Clostridium IV domination to Clostridium IV and Propionibacterium co-domination (based on 16S rRNA sequencing) and reduced the activities of key enzymes involved in the reversed ß-oxidization pathway. We propose an effective strategy from our study, which is the first one to do in our knowledge, to upgrade raw FW without dilution to n-caproate: lowering the ammonium accumulation to 1.0 g L-1 at the setup phase for adaptation and prolonging the hydraulic retention time (10 days) during the operation phase for the colonization of chain-elongation bacteria. These findings lay a foundation for the implementation of the LCE process on FW, providing an alternative way to alleviate the global FW crisis.