Cranial Venous Outflow Obstruction Promotes Neuroinflammation And Edema Via ADAM17/solTNF-α/NF-κB Pathway In A Rat Subdural Hematoma Model

Abstract Background: Traumatic brain injury (TBI) is recognized as a common cause of death and disability worldwide. Cerebrovascular reaction, as an important cause of secondary injury, can cause secondary bleeding, venous sinus thrombosis, and malignant brain swelling. Intracranial venous return disorder is closely related to patient prognosis. Treatment strategies after craniocerebral injury have primarily focused on the recanalization of cerebral arteries and capillaries and the protection of insulted neurons. In this study, we used an acute subdural hematoma (ASDH) model with cranial venous outflow obstruction (CVO) to explore the mechanism by which CVO aggravates the pathological process after TBI, especially for inflammation and tissue damage.Methods: Based on a rat ASDH model using the modified Miller method, an intracranial venous circulation obstruction intervention was given to form a compound model. A sham operation group (sham), a CVO group, an ASDH group and an ASDH+CVO group were constructed. A neurobehavioural assessment and the determination of brain water content were performed. The content was determined by Evans blue staining. Expression levels of inflammatory factors and metalloproteinases ADAM17 and MMP9 were detected by immunofluorescence assay, ELISA and Western blot. The rats in the ASDH+CVO group were treated with XPro1595 to compare the changes in the NF-κB/MMP9 pathway before and after the inhibition of solTNF.Results: CVO aggravated neurological function defects and damage to the blood-brain barrier in ASDH rats. CVO significantly increased the expression level of ADAM17, and localization of ADAM17 in intracranial cells occurred mainly in microglia or macrophages (positive for IBA-1), accompanied by increased secretion of solTNF. Activation of the ADAM17/solTNF/NF-κB pathway increased the subsequent inflammatory response and tissue damage.Conclusions: The results of this study suggest that intracranial venous return disorder after TBI significantly promotes the expression of ADAM17, which is mainly located in microglia or macrophages, and that the secretion of solTNF-α is increased. The ADAM17/solTNF-α/NF-κB pathway plays an important role in the subsequent inflammatory response and tissue injury. Our study reveals a molecular basis for the finding that CVO aggravates inflammation and tissue damage.