title: Interaction of inflammation and hyperoxia in a rat model of neonatal white matter damage.
abstract: Intrauterine infection and inflammation are major reasons for preterm birth. The switch from placenta-mediated to lung-mediated oxygen supply during birth is associated with a sudden rise of tissue oxygen tension that amounts to relative hyperoxia in preterm infants. Both infection/inflammation and hyperoxia have been shown to be involved in brain injury of preterm infants. Hypothesizing that they might be additive or synergistic, we investigated the influence of a systemic lipopolysaccharide (LPS) application on hyperoxia-induced white matter damage (WMD) in newborn rats. Three-day-old Wistar rat pups received 0.25 mg/kg LPS i.p. and were subjected to 80% oxygen on P6 for 24 h. The extent of WMD was assessed by immunohistochemistry, western blots, and diffusion tensor (DT) magnetic resonance imaging (MRI). In addition, the effects of LPS and hyperoxia were studied in an in vitro co-culture system of primary rat oligodendrocytes and microglia cells. Both noxious stimuli, hyperoxia, and LPS caused hypomyelination as revealed by western blot, immunohistochemistry, and altered WM microstructure on DT-MRI. Even so, cellular changes resulting in hypomyelination seem to be different. While hyperoxia induces cell death, LPS induces oligodendrocyte maturity arrest without cell death as revealed by TUNEL-staining and immunohistological maturation analysis. In the two-hit scenario cell death is reduced compared with hyperoxia treated animals, nevertheless white matter alterations persist. Concordantly with these in vivo findings we demonstrate that LPS pre-incubation reduced premyelinating-oligodendrocyte susceptibility towards hyperoxia in vitro. This protective effect might be caused by upregulation of interleukin-10 and superoxide dismutase expression after LPS stimulation. Reduced expression of transcription factors controlling oligodendrocyte development and maturation further indicates oligodendrocyte maturity arrest. The knowledge about mechanisms that triggered hypomyelination contributes to a better understanding of WMD in premature born infants.
authors.affiliation: Department of Neonatology, Charité University Medical Center, Berlin, Germany. felix.brehmer@charite.de
authors.forename: Felix
authors.initials: F
authors.lastname: Brehmer
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.forename: Sebastian
authors.initials: S
authors.lastname: Prager
authors.forename: Yohan
authors.initials: Y
authors.lastname: van de Looij
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Reinboth
authors.forename: Julia
authors.initials: J
authors.lastname: Zimmermanns
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Schlager
authors.forename: Daniela
authors.initials: D
authors.lastname: Brait
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sizonenko
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: Bettina
authors.initials: B
authors.lastname: Gerstner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D056784:Leukoencephalopathies / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D008070:Lipopolysaccharides; D053148:Caspase 3