Abstract W P105: Lipopolysaccharide Exacerbates Stroke Severity and Compromises Mitochondrial Function in Cerebral Endothelium
Stroke is the fourth leading cause of death in the U.S, with many cases leading to severe disabilities. Statistics reports present that more than 40% of ischemic stroke patients have recent prior infections. Acute infections initiate rapid inflammation and can be a trigger for acute ischemic stroke in people. Ischemia-reperfusion injury following ischemic stroke induces blood-brain barrier (BBB) breakdown, hyperpermeability and brain edema. Cerebral vascular endothelial cells (CVEC) lining the BBB play a key role in fluid leakage into the brain tissue. The expression of toll-like receptor 4 (TLR4, specific for bacteria-sourced lipopolysaccharide, LPS) on CVEC implicates that acute bacterial infections may directly target CVEC and regulate BBB permeability and integrity. High mitochondrial contents in BBB capillaries suggest mitochondrial mechanisms are important to maintain BBB integrity.
In order to test the hypothesis that bacterial infections regulate BBB permeability via mitochondrial mechanisms in stroke, we designed a series of studies both in vivo and in vitro. First, we used LPS challenged mice, then evaluated stroke outcomes including: infarct size, neurological deficits, BBB permeability and infiltration of neutrophils in the brain after transient middle cerebral artery occlusion (tMCAO). Second, we treated cultured CVEC with various concentrations of LPS and evaluated their mitochondrial function. Third, we impaired mitochondrial function in CVEC and investigated the BBB permeability in vitro.
Our results demonstrated that LPS (100ug/kg) prior to tMCAO administration significantly exacerbates stroke infarct volume, BBB permeability and neutrophil infiltration in the brain, and worsens neurological deficits in murine experimental stroke in vivo. In vitro, LPS significantly impaired mitochondrial oxidative phosphorylation and decreased maximal respiration and spare capacity in CVEC. Finally, pharmacological inhibition of mitochondria respiration disrupted tight junctions in CVEC monolayers and increased CVEC monolayer permeability in vitro.
These data are particularly important because they suggest a novel mitochondrial mechanism of the interactions between stroke and infections on BBB integrity.
Author Disclosures: X. Ren: None. D.N. Doll: None. H. Hu: None. J. Sun: None. S.E. Lewis: None. S.L. Rellick: None. J.W. Simpkins: None.
- © 2015 by American Heart Association, Inc.