PURPOSE: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II antioxidant enzyme which has been shown to be induced in murine lung in response to hyperoxia by Nrf2 to protect against lung injury. Previous studies in our lab have shown that NQO1 may play a key role in hyperoxia induced epithelial cell injury and reactive oxygen species formation. We have also found that NQO1 polymorphisms are associated with increased susceptibility to acute lung injury after blunt trauma. Here, we report that the loss of NQO1 results in increased susceptibility to hyperoxia while NQO1 overexpression results in protection from hyperoxic injury in mice.
METHODS: Nqo1+/+, Nqo1−/− and Nqo1OE mice (Nqo1+/+ mice fed dimethyl fumarate to induce expression of NQO1) were exposed to air and hyperoxia (95% O2) for 48 and 72 hours. Bronchoalveolar lavage (BAL) was then performed to determine protein levels (a measure of lung permeability), total and differential cell counts, and lactate dehydrogenase activity. Lungs were also fixed in zinc formalin for histopathologic analysis.
RESULTS: Significantly greater hyperoxia-induced lung hyperpermeability and BAL inflammatory cells were found in Nqo1−/− mice compared to wild type mice. Compared to wild type mice exposed to hyperoxia, significantly decreased levels of protein and inflammatory cells in BAL fluid were found in Nqo1OE mice. Histologic analysis also showed increased levels of peribronchial and perivascular inflammation, edema and bronchoalveolar epithelial proliferation in Nqo1−/− mice compared to Nqo1+/+ mice exposed to hyperoxia.
CONCLUSION: Loss of NQO1 caused increased hyperoxia induced lung injury in vivo, while overexpression of NQO1 protected against hyperoxic lung injury in mice. Our results indicate that antioxidant responses mediated by NQO1 are essential in pulmonary protection from oxidative injury.
CLINICAL IMPLICATIONS: Further investigation into the mechanism of NQO1 may lead to important insights into the care of patients with acute lung injury and acute respiratory distress syndrome.
DISCLOSURE: Anita Reddy, None.