NEDD4 attenuates phosgene-induced acute lung injury through the inhibition of Notch1 activation

Abstract

Phosgene gas leakage can cause life-threatening acute lung injury (ALI), which is characterized by inflammation, increased vascular permeability, pulmonary oedema and oxidative stress. Although the downregulation of neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) is known to be associated with inflammation and oxidative damage, its functions in phosgene-induced ALI remain unclear. In this study, rats with phosgene-induced ALI were intravenously injected with NEDD4-overexpressing lentiviruses to determine the functions of NEDD4 in this inflammatory condition. NEDD4 expression was decreased in the lung parenchyma of phosgene-exposed control rats, whereas its expression level was high in the NEDD4-overexpressing rats. Phosgene exposure increased the wet-to-dry lung weight ratio, but NEDD4 abrogated this effect. NEDD4 overexpression attenuated phosgene-induced lung inflammation, lowering the high lung injury score (based on total protein, inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid) and also reduced phosgene-induced oxidative stress and cell apoptosis. Finally, NEDD4 was found to interact with Notch1, enhancing its ubiquitination and thereby its degradation, thus attenuating the inflammatory responses to ALI. Therefore, we demonstrated that NEDD4 plays a protective role in alleviating phosgene-induced ALI, suggesting that enhancing the effect of NEDD4 may be a new approach for treating phosgene-induced ALI.

Keywords: NEDD4; Notch1; phosgene; pulmonary inflammation.