title: Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit.
abstract: Understanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. It is through the filter of the blood-brain barrier that the brain responds to outside influences, and the blood-brain barrier is a critical point of failure in neuroinflammation. It is important to note that this interaction is not a static response, but one that evolves over time. While current models have provided invaluable information regarding the interaction between cytokine stimulation, the blood-brain barrier, and the brain, these approaches-whether in vivo or in vitro-have often been only snapshots of this complex web of interactions.
  
  
  
  We utilize new advances in microfluidics, organs-on-chips, and metabolomics to examine the complex relationship of inflammation and its effects on blood-brain barrier function ex vivo and the metabolic consequences of these responses and repair mechanisms. In this study, we pair a novel dual-chamber, organ-on-chip microfluidic device, the NeuroVascular Unit, with small-volume cytokine detection and mass spectrometry analysis to investigate how the blood-brain barrier responds to two different but overlapping drivers of neuroinflammation, lipopolysaccharide and a cytokine cocktail of IL-1β, TNF-α, and MCP1,2.
  
  
  
  In this study, we show that (1) during initial exposure to lipopolysaccharide, the blood-brain barrier is compromised as expected, with increased diffusion and reduced presence of tight junctions, but that over time, the barrier is capable of at least partial recovery; (2) a cytokine cocktail also contributes to a loss of barrier function; (3) from this time-dependent cytokine activation, metabolic signature profiles can be obtained for both the brain and vascular sides of the blood-brain barrier model; and (4) collectively, we can use metabolite analysis to identify critical pathways in inflammatory response.
  
  
  
  Taken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure.
authors.affiliation: Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.|Center for Innovative Technology, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Simona G
authors.initials: SG
authors.lastname: Codreanu
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Shi
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.|Center for Innovative Technology, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Stacy D
authors.initials: SD
authors.lastname: Sherrod
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Markov
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.|Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: M Diana
authors.initials: MD
authors.lastname: Neely
authors.affiliation: Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.
authors.forename: Clayton M
authors.initials: CM
authors.lastname: Britt
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.
authors.forename: Orlando S
authors.initials: OS
authors.lastname: Hoilett
authors.affiliation: Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Reiserer
authors.affiliation: Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Samson
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: McCawley
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.|Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.|Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA.|Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.affiliation: Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.|Center for Innovative Technology, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: McLean
authors.affiliation: Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, 6301 Stevenson Center, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA. john.wikswo@vanderbilt.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Wikswo
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D062507:Claudin-5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D056656:Lab-On-A-Chip Devices; D008070:Lipopolysaccharides / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D062507:Claudin-5; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein
keywords: Brain-on-chip; Cytokine; IL-1β; Lipopolysaccharide; MCP1,2; Mass spectrometry; Metabolomics; Micro-organ; TNF-α; Tight junctions