# Role of mitochondrial dysfunction in hyperoxia-induced pulmonary vascular endothelial injury

> **NIH VA I01** · CLEMENT J. ZABLOCKI VA MEDICAL CENTER · 2020 · —

## Abstract

More than 250,000 veterans are placed on mechanical ventilation annually. These patients often require high
fractions of oxygen (hyperoxia) which significantly exacerbates the injury that triggered mechanical ventilation
initially. Pulmonary endothelial cells (PECs) are particularly sensitive to hyperoxia, exhibiting increased
production rates of mitochondrially-derived reactive oxygen species (mtROS), mitochondrial (mt) dysfunction,
pulmonary edema and ultimately increased morbidity/mortality in critically ill patients, but mechanisms are
incompletely understood. Cells adapt to stress by increasing both mitochondrial fission and fusion. Our data
identify for the first time hyperoxia-enhanced mt-fragmentation in PECs, and decreased expression of mt-
fusion and increased expression of mt-fission promoting proteins which underlie the increased mt-
fragmentation. In addition, we show that mitochondrial targeted endonuclease repair protein (mt-ENDO-III)
protects from hyperoxic PEC loss. Finally, we have demonstrated that inhaled 2% hydrogen gas (H2) can
protect against hyperoxia-induced lung injury, and that this protection can be identified by single photon
emission computed tomography (SPECT) imaging. The molecular basis of hyperoxia-associated mt-
fragmentation and subsequent pulmonary microvascular permeability is the focus of this proposal.
Our hypothesis is that hyperoxia-induced pulmonary edema results from mtDNA damage which signals a shift
to pro-fission protein expression and mt-fragmentation, leading to increased microvascular permeability and
edema. Furthermore, we believe that 2% H2 in atmospheric gases will counteract hyperoxia-evoked
pulmonary edema with diminished mtDNA damage and mt-fragmentation. Using novel tools including Dendra-
2 mice, which express a fluorescent protein targeted to the mitochondrial membrane in endothelial cells to
quantify mt-fragmentation in intact tissue, recombinant adeno- and lentivirus, siRNA, unique genetically
modified rodents, vertical experimental designs from cultured cells to intact animals and human tissue, our
work will determine mechanisms linking hyperoxia-induced mtDNA damage, mt-fragmentation and pulmonary
edema. Specific Aims: 1) To determine if hyperoxia-induced pulmonary endothelial mtDNA damage modifies
expression/activation ratios of specific mt-fission and fusion proteins, thereby enhancing mt-fragmentation, and
increasing microvascular permeability. We will use mt-ENDO-III to repair mtDNA damage in cultured PECs and
in vivo and measure hyperoxia-induced changes in pro-fission or fusion protein expression, mt-fragmentation,
mt-function, monolayer transendothelial electrical resistance (TEER) or filtration coefficient (Kf) as
measures of endothelial permeability. 2) To test if pulmonary endothelial mt-fragmentation, independent of
mtDNA damage, increases microvascular permeability. Using genetically modified rodents, siRNA and
overexpression of pro-fission or fusion protein in cultured PE...

## Key facts

- **NIH application ID:** 9852294
- **Project number:** 5I01BX003833-02
- **Recipient organization:** CLEMENT J. ZABLOCKI VA MEDICAL CENTER
- **Principal Investigator:** ELIZABETH R JACOBS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852294

## Citation

> US National Institutes of Health, RePORTER application 9852294, Role of mitochondrial dysfunction in hyperoxia-induced pulmonary vascular endothelial injury (5I01BX003833-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9852294. Licensed CC0.

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