Mus musculus
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ABSTRACT:
PROVIDER: PRJNA106173 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: Using an ortholog candidate gene approach, we previously identified GADD45a (growth arrest and DNA damage-inducible gene 45a) as a potential novel candidate involved in ventilator-induced lung injury (VILI). Objectives: We investigated whether genetically engineered mice with GADD45a deletion were more susceptible to ventilator- or endotoxin (LPS)-induced lung injury. We employed genomic strategies to explore the mechanistic involvement of GADD45a in inflammatory lung injury. Methods: Wild-type C57Bl/6 and GADD45a-/- mice were phenotyped for lung injury following exposure to high tidal volume ventilation (VILI) or intratracheal LPS. Whole lung homogenates were utilized for gene expression studies of ventilated animals and spontaneously breathing controls. To explore the consequences of GADD45a depletion on lung vascular permeability, electrical resistance was measured using human endothelial cells (EC) transfected with small interfering RNA (siRNA) specific for GADD45a or control sequence, or with active Akt1/PKBï¡ cDNA. Results: Mice harboring deletion of GADD45a were modestly susceptible to LPS-induced injury and profoundly susceptible to VILI, demonstrating increased inflammation and increased microvascular permeability. VILI-exposed GADD45a-/- mice manifested striking neutrophilic alveolitis and increased levels of BAL protein, IgG, and inflammatory cytokines. Expression profiling revealed strong dysregulation in the B cell receptor signaling pathway in GADD45a-/- mice, with involvement of several PI3K/Akt signaling components. Akt protein and phospho-Akt were reduced in GADD45a-/- lungs. Further, human EC with reduced GADD45a (siRNA) exhibited potentiated LPS-induced barrier dysfunction, which was attenuated by overexpressing active Akt1. Conclusions: GADD45a, which modulates Akt availability, is a significant participant in modulating vascular permeability and susceptibility to VILI. Experiment Overall Design: 4 experimental groups, each with 3 mouses. Wild type control group, VILI group, GADD-/- group, GADD-/- and VILI group.
2008-10-20 | E-GEOD-11662 | biostudies-arrayexpress
Project description:We explored the mechanistic involvement of the growth arrest and DNA damageinducible gene, GADD45a, in LPS- and ventilator-induced inflammatory lung injury (VILI). Multiple biochemical and genomic parameters of inflammatory lung injury indicated GADD45a-/- mice to be modestly susceptible to intratracheal LPS-induced lung injury and profoundly susceptible to high tidal volume ventilation-induced lung injury (VILI) with increases in microvascular permeability and levels of inflammatory cytokines in bronchoalveolar lavage. Expression profiling of lung tissues from GADD45a-/- mice revealed strong dysregulation in the B cell receptor signaling pathway suggesting involvement of PI3 kinase/Akt signaling components while the wild type controls depicted no observable changes. Western blot analyses of lung homogenates confirmed ~50% reduction in Akt protein levels in GADD45a-/- mice accompanied by marked increases in Akt ubiquitination. Electrical resistance measurements across human lung endothelial cell monolayers with either reduced GADD45a or Akt expression (siRNAs) revealed significant potentiation of LPS-induced human lung endothelial barrier dysfunction which was attenuated by overexpression of a constitutively active Akt1 transgene. These studies validate GADD45a as a novel candidate gene in inflammatory lung injury and a significant participant in vascular barrier regulation via effects on Akt-mediated endothelial signaling
2008-07-01 | GSE11662 | GEO
Project description:Background: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/ mitogen activated protein kinase kinase-3 and c-Jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3-/-) or c-Jun-NH2-terminal kinase-1 (jnk1-/-) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3-/- or jnk1-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GADD45a. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusions: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. Keywords: response to injury, genetically modified mouse
2007-05-08 | GSE7742 | GEO
Project description:Mouse gene expression profiling in ventilator-induced lung injury
| PRJNA140719 | ENA
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| PRJNA340962 | ENA
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| PRJNA251420 | ENA
Project description:Ventilator-induced lung injury in wild-type and jnk1 knockout mice
| PRJNA99853 | ENA