title: Prolonged White Matter Inflammation After Cardiopulmonary Bypass and Circulatory Arrest in a Juvenile Porcine Model.
abstract: BACKGROUND
  White matter (WM) injury is common after neonatal cardiopulmonary bypass (CPB). We have demonstrated that the inflammatory response to CPB is an important mechanism of WM injury. Microglia are brain-specific immune cells that respond to inflammation and can exacerbate injury. We hypothesized that microglia activation contributes to WM injury caused by CPB.
  
  
  METHODS
  Juvenile piglets were randomly assigned to 1 of 3 CPB-induced brain insults (1, no-CPB; 2, full-flow CPB; 3, CPB and circulatory arrest). Neurobehavioral tests were performed. Animals were sacrificed 3 days or 4 weeks postoperatively. Microglia and proliferating cells were immunohistologically identified. Seven analyzed WM regions were further categorized into 3 fiber connections (1, commissural; 2, projection; 3, association fibers).
  
  
  RESULTS
  Microglia numbers significantly increased on day 3 after CPB and circulatory arrest, but not after full-flow CPB. Fiber categories did not affect these changes. On post-CPB week 4, proliferating cell number, blood leukocyte number, interleukin (IL)-6 levels, and neurologic scores had normalized. However, both full-flow CPB and CPB and circulatory arrest displayed significant increases in the microglia number compared with control. Thus brain-specific inflammation after CPB persists despite no changes in systemic biomarkers. Microglia number was significantly different among fiber categories, being highest in association and lowest in commissural connections. Thus there was a WM fiber-dependent microglia reaction to CPB.
  
  
  CONCLUSIONS
  This study demonstrates prolonged microglia activation in WM after CPB. This brain-specific inflammatory response is systemically silent. It is connection fiber-dependent which may impact specific connectivity deficits observed after CPB. Controlling microglia activation after CPB is a potential therapeutic intervention to limit neurologic deficits after CPB.
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Korotcova
authors.affiliation: George Washington University School of Medicine and Health Science, Washington, DC.
authors.forename: Sonali
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Kota
authors.initials: K
authors.lastname: Agematsu
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC; George Washington University School of Medicine and Health Science, Washington, DC.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jonas
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC; George Washington University School of Medicine and Health Science, Washington, DC. Electronic address: nishibas@childrensnational.org.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishibashi
mesh_terms: D000367:Age Factors; D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D005260:Female; D017628:Microglia / Q000473:pathology; D011897:Random Allocation; D013552:Swine; D013997:Time Factors; D066127:White Matter