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Gp91(phox )(NOX2) in classically activated microglia exacerbates traumatic brain injury

BACKGROUND: We hypothesized that gp91(phox )(NOX2), a subunit of NADPH oxidase, generates superoxide anion (O(2)(-)) and has a major causative role in traumatic brain injury (TBI). To evaluate the functional role of gp91(phox )and reactive oxygen species (ROS) on TBI, we carried out controlled corti...

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Detalles Bibliográficos
Autores principales: Dohi, Kenji, Ohtaki, Hirokazu, Nakamachi, Tomoya, Yofu, Sachiko, Satoh, Kazue, Miyamoto, Kazuyuki, Song, Dandan, Tsunawaki, Shohko, Shioda, Seiji, Aruga, Tohru
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917406/
https://www.ncbi.nlm.nih.gov/pubmed/20659322
http://dx.doi.org/10.1186/1742-2094-7-41
Descripción
Sumario:BACKGROUND: We hypothesized that gp91(phox )(NOX2), a subunit of NADPH oxidase, generates superoxide anion (O(2)(-)) and has a major causative role in traumatic brain injury (TBI). To evaluate the functional role of gp91(phox )and reactive oxygen species (ROS) on TBI, we carried out controlled cortical impact in gp91(phox )knockout mice (gp91(phox-/-)). We also used a microglial cell line to determine the activated cell phenotype that contributes to gp91(phox )generation. METHODS: Unilateral TBI was induced in gp91(phox-/- )and wild-type (Wt) mice (C57/B6J) (25-30 g). The expression and roles of gp91(phox )after TBI were investigated using immunoblotting and staining techniques. Levels of O(2)(- )and peroxynitrite were determined in situ in the mouse brain. The activated phenotype in microglia that expressed gp91(phox )was determined in a microglial cell line, BV-2, in the presence of IFNγ or IL-4. RESULTS: Gp91(phox )expression increased mainly in amoeboid-shaped microglial cells of the ipsilateral hemisphere of Wt mice after TBI. The contusion area, number of TUNEL-positive cells, and amount of O(2)(- )and peroxynitrite metabolites produced were less in gp91(phox-/- )mice than in Wt. In the presence of IFNγ, BV-2 cells had increased inducible nitric oxide synthase and nitric oxide levels, consistent with a classical activated phenotype, and drastically increased expression of gp91(phox). CONCLUSIONS: Classical activated microglia promote ROS formation through gp91(phox )and have an important role in brain damage following TBI. Modulating gp91(phox )and gp91(phox )-derived ROS may provide a new therapeutic strategy in combating post-traumatic brain injury.