CAREER: Mitochondrial Regulation of Hyperoxic Cell Death

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Exposure of normal animals to 100 percent oxygen for 48-72 hours causes death from respiratory failure. Histologic examination of the lungs of these animals reveals a pattern of lung injury similar to that seen in patients with the acute respiratory distress syndrome (ARDS). While several genetic and pharmacologic strategies have been shown to attenuate hyperoxic injury in animal models, the mechanisms that underlie hyperoxic death at the cellular level are unknown. The proposed research will test the hypothesis that mitochondrial generation of reactive oxygen species triggers closure of the voltage dependent anion channel (VDAC) in the outer mitochondrial membrane leading to cell death, and that BCI-XL prevents hyperoxic cell death by preventing closure of VDAC. Firstly, the role of the mitochondrial generation of reactive oxygen species in the pathway leading to cell death following hyperoxic exposure will be determined using transfected cells over-expressing both manganese superoxide dismutase (MnSOD) and catalase in the mitochondrial membrane, and cells without functioning electron transport chains (p' cells). Secondly, the mechanism by which BCI-XL prevents mitochondrial membrane depolarization and subsequent cell death following exposure to hyperoxia will be determined by comparing the cell death pathway after exposure to hyperoxia in cells over-expressing BCI-XL, and p' cells. Thirdly, the effect of Akt and MAP kinase activation on the cell death pathway following exposure to hyperoxia will be determined by genetic and pharmacologic manipulation of these pathways. Collectively, these studies will confirm or refute existing hypotheses regarding the mechanisms of cellular injury during hyperoxic exposure. If oxygen therapy exacerbates lung injury, strategies to minimize hyperoxic exposure might improve outcomes in patients with acute lung injury.
StatusFinished
Effective start/end date8/1/017/31/06

Funding

  • National Heart, Lung, and Blood Institute (5 K08 HL067835-05)

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