title: Hypoxia induces nitric oxide production in mouse microglia via p38 mitogen-activated protein kinase pathway.
abstract: In vitro exposure of microglial cells to hypoxia induces cellular activation. Also, in vivo studies of glial activation following ischemic hypoxia have shown that neuronal cell death is followed by microglial activation. Thus, it is likely that toxic inflammatory mediators produced by activated microglial cells under hypoxic conditions may exacerbate neuronal injury following cerebral ischemia. Nitric oxide (NO), which is known to be produced by activated microglia, may participate in this process. In the current work, we sought to determine whether and how the production of NO and the expression of inducible NO synthase (iNOS) are triggered by hypoxia in microglial cells. Exposure of established microglial cell lines as well as primary mouse microglial cultures to mild hypoxia (8 h) followed by reoxygenation (24 h) induced the production of NO and TNFalpha, indicating that hypoxia could lead to the inflammatory activation of microglia. Hypoxic induction of NO was accompanied by iNOS induction. Moreover, hypoxia induced the activation of p38 MAPK, but not ERK or JNK/SAPK, in BV-2 mouse microglial cells. SB203580, a specific inhibitor of p38 MAPK, blocked the hypoxic induction of NO and iNOS. Taken together, our results indicated that hypoxia could induce inflammatory activation of microglia, and the hypoxic induction of NO production in microglia is mediated through p38 MAPK pathway. Thus, during cerebral ischemia, hypoxia may not only directly damage neurons, but may also promote neuronal injury indirectly via microglial activation.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Gyeongsang National University, 92 Chilam-dong, Jinju, Kyungnam 660-751, South Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.forename: Heasuk
authors.initials: H
authors.lastname: Lee
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Hur
authors.forename: Sun Yeou
authors.initials: SY
authors.lastname: Kim
authors.forename: Hocheol
authors.initials: H
authors.lastname: Kim
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Cha
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases