Pathological hemodynamic changes and leukocyte transmigration disrupt the blood–spinal cord barrier after spinal cord injury

Abstract

Background Blood–spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. Methods A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. Results Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. Conclusions Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.

Serum glucose/potassium ratio as a clinical risk factor for predicting the severity and prognosis of acute traumatic spinal cord injury

“…Therefore, further research is needed to develop diagnostic and predictive prognostic models for acute TSCI, and a framework for identifying valuable biomarkers is also necessary to improve the accuracy of prognostic prediction. It has been shown that the blood-spinal cord barrier (BSCB) is disrupted by TSCI, leukocyte tra cking is also increased (21,22). Some in ammatory biomarkers, such as C-reactive protein (CRP ), IL-6 or monocyte chemotactic protein-1, can participate in the systemic in ammatory response and can be transported into the blood or cerebrospinal uid(8, 23,24).…”

Teriparatide: an innovative and promising strategy for protecting the blood-spinal cord barrier following spinal cord injury

“…After the disruption of the blood-spinal cord barrier, significant leakage can occur, reaching its peak at 24 h post-injury and showing a second peak on the fifth day ( Chang and Cao, 2021 ). It was found that most of the leakage occurs in the pericellular space, and intercellular pathways are less common, with TJ proteins being the main component connecting BSCB cells ( Zhou et al, 2023 ). The study of He et al (2023) indicates that spinal cord injury can induce lysosomal damage, leading to disruption of the endothelial cell autophagic flow and dysfunction of the autophagy-lysosomal pathway (ALP).…”

“…Studies have shown that there is no significant decrease in TJ proteins in the early stages of spinal cord injury, specifically at the 1st and 3rd hours. However, a significant reduction can be observed from the 8th to the 24th hour ( Zhou et al, 2023 ). The decrease in TJ expression, along with changes in TJ localization or post-transcriptional modifications, are the main reasons leading to an increased permeability of the BSCB ( Deli et al, 2005 ; Chio et al, 2019 ; Zhou et al, 2023 ).…”

“…However, a significant reduction can be observed from the 8th to the 24th hour ( Zhou et al, 2023 ). The decrease in TJ expression, along with changes in TJ localization or post-transcriptional modifications, are the main reasons leading to an increased permeability of the BSCB ( Deli et al, 2005 ; Chio et al, 2019 ; Zhou et al, 2023 ). Chang and Cao (2021) indicates that spinal cord anterior horn damage often leads to more severe lower limb symptoms and blood-spinal cord barrier (BSCB) disruption.…”

Tetramethylpyrazine-loaded electroconductive hydrogels promote tissue repair after spinal cord injury by protecting the blood–spinal cord barrier and neurons

“…3 These exudates trigger a cascade of complex pathological processes including neurotoxic product generation, oxidative stress response, and inflammatory cell infiltration, resulting in the programmed death of neurons at lesions and interface of the injury site that may even lead to permanent neurological deficits. 3,4 Notably, the loss of BSCB integrity is detrimental to the maintenance of homeostasis of the internal environment of the spinal cord, and it also impacts the generation of blood vessels that act as a scaffold for axonal regeneration. 5,6 Thus, it is significant to target BSCB repair at an early stage of SCI to mitigate peri-lesional cellular perturbations and thereby modulate neuronal network homeostasis.…”