LUNG CELLULAR HYPOXIA AND OXIDANT STRESS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the applicant's abstract): Lung tissue ischemia
and cellular hypoxia due to interruption of blood flow and ventilation such
as during lung transplantation, atelectasis, or thromboembolism, result in
acute lung injury during reoxygenation which is indistinguishable from acute
respiratory distress syndrome. Both mitochondrial manganese-containing
superoxide dismutase (MnSOD) and cytosolic, copper zinc containing
superoxide dismutase (CuZnSOD) are critical intracellular antioxidants.
MnSOD is concentrated in alveolar epithelial Type II cells and protects the
lung from oxidant injury by induction in response to oxidant stress. MnSOD
protein is relatively abundant in Type II cells and a decrease in MnSOD, by
itself, increases sensitivity of alveolar cells to oxidant stress, including
that produced by hyperoxia and TNF-alpha. The hypothesis that will be
tested by this application is that hypoxia decreases SOD expression in
alveolar Type II cells and that decreased alveolar Type II cell SOD activity
is a predisposing factor for oxidant injury during reoxygenation and other
types of oxidant stress. The specific aims to be addressed are: 1) define
the biological importance of the hypoxia-induced decreases in alveolar Type
II cell SOD expression; 2) identify the mechanisms by which hypoxia reduces
SOD expression in alveolar Type II cells; and 3) determine whether repletion
of MnSOD by gene transfer reverses the increased sensitivity to oxidant
stress. These studies will be done by using a combination of isolated Type
II cells from rabbits and in vivo experiments on transgenic mice to
investigate the impact of the reduction in SOD expression on the cellular
responses to oxidant stress in the lung. Heterozygous MnSOD knockout mice
will be used to define the importance of specific decreases in MnSOD
expression. Since the effects of hypoxia on alveolar Type II cell SOD
expression has not been fully investigated, this study will fill gaps in our
knowledge of alveolar Type II cell biology and the effects of hypoxia on
antioxidant defenses. The potential exists for generating specific new
information regarding the biological importance of hypoxia-induced SOD
depletion from alveolar Type II cells and the mechanisms by which hypoxia
decreases SOD in Type II cells and the potential therapeutic efficacy of
restoring SOD activity to pre-hypoxia levels for restoring resistance to
oxidant stress.
StatusFinished
Effective start/end date7/8/976/30/01

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

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