Overactivation of the
N-methyl-d-aspartate (
NMDA) receptor promotes oxidative stress, aggravates the inflammatory response and induces excitotoxic
lung injury.
NMDA is a synthetic agonist that selectively activates the
NMDA receptor.
Oleanolic acid (OA) is a natural anti-inflammatory and
antioxidant compound. This study investigated the effect and possible mechanism of OA on
NMDA-induced
acute lung injury (ALI) in mice. OA pretreatment alleviated
NMDA-induced histological lung changes and ameliorated pulmonary oedema and pulmonary permeability. At the same time, OA inhibited inflammatory cell infiltration and decreased the levels of tumour
necrosis factor (TNF)-α,
interleukin (IL)-6 and IL-1β in the lung and bronchoalveolar lavage fluid (BALF). OA markedly decreased
malondialdehyde (MDA) production and increased the
superoxide dismutase (SOD) and
glutathione (GSH) contents of the lung in vivo. Meanwhile, we first found that
NMDA increased LDH activity and decreased cell viability, and induced oxidative stress and apoptosis in mouse lung epithelial (MLE)-12 cells. By employing
SRT1720 and
sirtinol, the activator and inhibitor of
sirtuin 1 (
SIRT1), we found that
SRT1720 partially eliminated the increase in ROS,and
sirtinol further promoted the increase in ROS caused by
NMDA. OA increased MLE-12 cells viability and attenuated oxidative stress after
NMDA challenge in vitro. OA suppressed
NMDA-induced MLE-12 cells apoptosis, while
sirtinol inhibited the effect of OA. In addition, OA significantly upregulated the levels of
SIRT1, nuclear-related factor 2(Nrf2) and Bcl-2
protein and downregulated the levels of acetylated
nuclear factor-kappa B (NF-κB), NLRP3 and
Bax protein. In conclusion, OA attenuated
NMDA-induced excitotoxic
lung injury, potentially through its anti-inflammatory, antioxidative stress and anti-apoptotic effects. The mechanism may be related to activating
SIRT1 and reducing NF-κB acetylation.