title: Propofol's effects on phagocytosis, proliferation, nitrate production, and cytokine secretion in pressure-stimulated microglial cells.
abstract: BACKGROUND
  Intracranial hypertension complicates severe traumatic brain injury frequently and might be associated with poor outcomes. Traumatic brain injury induces a neuroinflammatory response by microglial activation and upregulation of proinflammatory cytokines, such as interleukin-1β, tumor necrosis factor alpha, and interleukin-6. To elucidate the effect of increased intracranial pressure on microglial function, we studied the effects of increased extracellular pressure on primary human microglial cell phagocytosis, proliferation, cytokine secretion, and total nitrate production. In addition, because many patients receive propofol during anesthesia or intensive care unit sedation, we evaluated whether propofol alters the effects of pressure.
  
  
  METHODS
  Human microglial cells were pretreated with (2.5-20 μg/mL) propofol or Intralipid as a vehicle control were incubated at ambient atmospheric pressure or at 15 or 30 mm Hg increased pressure for 2 h for phagocytosis assays or 24 h for proliferation, cytokine secretion, and total nitrate production studies. Phagocytosis was determined by incorporation of intracellular fluorescent latex beads. Tumor necrosis factor alpha, interleukin-1β, and interleukin-6 were assayed by sandwich enzyme-linked immunosorbent assay and total nitrate by Greiss reagent.
  
  
  RESULTS
  Increased extracellular pressure stimulated phagocytosis versus untreated microglial cells or cells treated with an Intralipid vehicle control. Propofol also stimulated microglial phagocytosis at ambient pressure. Increased pressure, however, decreased phagocytosis in the presence of propofol. Pressure also increased microglial tumor necrosis factor-α and interleukin-1β secretion and propofol pretreatment blocked the pressure-stimulated effect. Interleukin-6 production was not altered either by pressure or by propofol. Pressure also induced total nitrate secretion, and propofol pretreatment decreased basal as well as pressure-induced microglial nitrate production.
  
  
  CONCLUSIONS
  Extracellular pressures consistent with increased intracranial pressure after a head injury activate inflammatory signals in human primary microglial cells in vitro, stimulating phagocytosis, proliferation, tumor necrosis factor-α, interleukin-1β, and total nitrate secretion but not affecting interleukin-6. Such inflammatory events may contribute to the worsened prognosis of traumatic brain injury after increased intracranial pressure. Because propofol alleviated these potentially proinflammatory effects, these results suggest that the inflammatory cascade activated by intracranial pressure might be targeted by propofol in patients with increased intracranial pressure after traumatic brain injury.
authors.affiliation: Department of Anesthesiology, Wayne State University, Detroit, MI, USA.
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Yu
authors.forename: Michael
authors.initials: M
authors.lastname: Dymond
authors.forename: Lisi
authors.initials: L
authors.lastname: Yuan
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Chaturvedi
authors.forename: Hiroe
authors.initials: H
authors.lastname: Shiratsuchi
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Durairaj
authors.forename: H Michael
authors.initials: HM
authors.lastname: Marsh
authors.forename: Marc D
authors.initials: MD
authors.lastname: Basson
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019586:Intracranial Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects*; D011312:Pressure; D015742:Propofol / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018686:Anesthetics, Intravenous; D016207:Cytokines; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen; D015742:Propofol