Abstract
Brain injuries caused by an explosive blast or blunt force is typically presumed to associate with mechanical trauma to the brain tissue. Recent findings from our laboratory suggest that shockwaves produced by a blast can generate micron-sized bubbles in the tissue. The collapse of microbubbles (i.e., microcavitation) may induce a mechanical trauma and compromise the integrity of the blood-brain endothelium (BBE). To test our hypothesis, we engineered a BBE model to determine the effect of microbubbles on the structural and functional changes in the BBE. Using monolayers of mouse primary brain microvascular endothelial cells, the permeability coefficient was measured following simulated blast-induced microcavitation. This event down-regulated the expression of tight junction markers, disorganized the cell-cell junction, and increased permeability. Since poloxamers have been shown to rescue damaged cells, the cells were treated with the FDA-approved poloxamer 188 (P188). The results indicate P188 recovered the permeability, restored the tight junctions, and suppressed the expressions of matrix metalloproteinases. The biomimetic interface we developed appears to provide a systematic approach to replicate the structure and function of BBE, determine its alteration in response to traumatic brain injury, and test potential therapeutic treatments to repair the damaged brain endothelium.
Highlights
Brain injuries caused by an explosive blast or blunt force is typically presumed to associate with mechanical trauma to the brain tissue
Since we have demonstrated the microcavitation-induced upregulation of the superoxide level in multiple cell types including astrocytes and muscle cells, we measured the superoxide levels in brain endothelial cells (Fig. 11)
Changes in the biotransport properties were experimentally quantified in response to a mechanical trauma such as microcavitation, and the potential restorative effects of poloxamer 188 (P188) were established
Summary
Brain injuries caused by an explosive blast or blunt force is typically presumed to associate with mechanical trauma to the brain tissue. Since a monolayer of mouse brain endothelial cells has been demonstrated to resemble the in vivo BBB phenotype, express excellent characteristics of the BBB, and form the functional barriers[22], it offers a model system to elucidate the potential damage mechanisms that are associated with microcavitation. Brain trauma is increasingly better understood, it remains elusive whether reparative treatments are plausible This is rather important because a recent study suggests that approximately 320,000 soldiers may have experienced mild TBI during the Iraq and Afghanistan wars and that such injuries most often lead to cognitive degeneration and post-traumatic stress disorder[23]. We cultured a monolayer of brain endothelial cells on a well-characterized synthetic membrane and quantitatively determined changes in the permeability and disorganized tight junctions in response to the blast-induced microcavitation. Our results show that microcavitation functionally and mechanically disrupts the BECs, and that treatment of brain endothelial cells with P188 mitigates the BBE disruption by alleviating the loss of tight junctions
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