Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy

Abstract

As a complex multicellular structure of the vascular system at the central nervous system (CNS), the blood-brain barrier (BBB) separates the CNS from the system circulation and regulates the influx and efflux of substances to maintain the steady-state environment of the CNS. Lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, can damage the barrier function of BBB and further promote the occurrence and development of sepsis-associated encephalopathy (SAE). Here, we conduct a literature review of the direct and indirect damage mechanisms of LPS to BBB and the relationship between these processes and SAE. We believe that after LPS destroys BBB, a large number of inflammatory factors and neurotoxins will enter and damage the brain tissue, which will activate brain immune cells to mediate inflammatory response and in turn further destroys BBB. This vicious circle will ultimately lead to the progression of SAE. Finally, we present a succinct overview of the treatment of SAE by restoring the BBB barrier function and summarize novel opportunities in controlling the progression of SAE by targeting the BBB.

Keywords: blood-brain barrier; central nervous system; inflammation; lipopolysaccharide; oxidative stress; sepsis-associated encephalopathy.

Figure 1

Cellular responses of BBB evoked by LPS. lipopolysaccharide (LPS) activates Ras homolog family member A (RHOA) and Nuclear factor-k-gene binding (NF-κB), and destroys the tight junctions (TJs) protein by triggering the production of cyclooxygenase-2 (Cox-2); LPS inhibits the expression of Nuclear factor-erythroid 2-related factor 2 (Nrf2), thereby increasing the expression of Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)1 and destroying the TJs protein;LPS increases the phosphorylation of p38 mitogen-activated protein kinase (MAPK), activates c-Jun amino-terminal kinase (JNK), triggers the expression of matrix metalloproteinase (MMP)-2, and destroys the TJs protein; LPS reduces the expression of TJs protein by inducing secreted protein acidic and rich in cysteine (SPARC); LPS activates Tumour Necrosis Factor-α (TNF-α) and endothelin (ET)-1 after binding to Toll-like receptor 4 (TLR4), and reduces the activity of P-glycoprotein(P-gp); LPS increases the phosphorylation of caveolin-1(cav-1); LPS inhibits endothelial nitric oxide synthase (eNOS) and Guanosine triposphate cyclohydrolase 1 (GTPCH1) and increases the activity of Caspase3/7 to trigger cell apoptosis; LPS trigger cell apoptosis by inhibiting the expression of Ki-67; LPS activates dynamin-related protein-1(Drp1) or activates myeloid differentiation factor 88 (MyD88) after binding to TLR4 to reduce ATP produced by mitochondria; LPS inhibits the production of ATP by inhibiting complex I, III and IV LPS inhibits the expression of Superoxide Dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) to increase the level of reactive oxygen species (ROS); LPS trigger the translocation of NF-κB into the nucleus to promote the secretion of inflammatory factors such as Interleukin(IL)-6 and TNF-α; LPS inhibits the expression of Monocarboxylate transporter-1(MCT-1) and inhibits lactic acid influx; LPS trigger the secretion of MMP-2/9 in endothelial cells and directly degrades extracellular matrix (ECM) and digest basement membrane (BM); LPS increases the activity of Cathepsin B and cleave type IV collagen; LPS triggers the translocation of NF-κB to the nucleus in pericytes; LPS trigger the increase of the levels of Vascular cell adhesion molecule-1(VCAM-1) and Intercellular adhesion molecule-1(ICAM-1) in blood vessels, as well as the combination of neutrophils and C-X-C Motif Chemokine Receptor 2 (CXCR2) to trigger the infiltration of the brain; LPS trigger the secretion of vascular endothelial growth factor A (VEGF-A) in astrocytes and destroys TJs protein by activating eNOS; LPS binds to TLR4 on microglia and trigger the production of TNF-α and ROS through the NOX pathway; LPS produces MMP-9 through the phosphoinositide 3-kinase (PI3K)γ pathway and acts on the BM.

Figure 2

Mechanisms of action of drugs that may target the BBB to treat SAE. Dexmedetomidine activates α2A adrenoceptors on astrocytes to inhibit the extracellular release of high mobility group box protein 1 (HMGB1) and reduce the levels of Interleukin(IL)-6 and IL-1β in brain tissue; Insulin inhibits the activity of Nuclear factor-k-gene binding (NF-κB) in astrocytes and mitogen-activated protein kinase (MAPK)s in microglia after lowering blood sugar; Citrate-covered gold nanoparticles (Cit-AuNP) or targeted inhibition of Poldip2 inhibits the nuclear translocation process of Nuclear factor-k-gene binding (NF-κB) in endothelial cells to reduce the secretion of Intercellular adhesion molecule-1(ICAM-1) and cyclooxygenase-2 (Cox-2); TPPU(N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea) inhibits Cluster of differentiation (CD)40 by inhibiting soluble epoxide hydrolase (SEH), and reduces the secretion of Tumour Necrosis Factor-α (TNF-α), IL-1β and IL-6; 4-aminobenzoic acid hydrazide (ABAH) or Fish oil (FO) maintain the steady state of Sphingolipid by inhibiting Myeloperoxidase (MPO); P110(an inhibitor of dynamin-related protein-1(Drp1)-Fission 1(Fis1) interaction) inhibits the Drp1-Fis1 interaction; UCF-101(an inhibitor of Omi/HtrA2) inhibits the translocation of Omi/high-temperature requirement serine protease A2 (HtrA2) from mitochondria to cytoplasm, antagonizes the Caspase-dependent apoptosis pathway and reduces poly (ADP-ribose) polymerase (PARP) levels, while also protecting the tight junctions (TJs) protein; Injection of immunoglobulin G or a combination of immunoglobulin A and M inhibits complement(C)5a.