Naringenin attenuates inflammation, apoptosis, and ferroptosis in silver nanoparticle-induced lung injury through a mechanism associated with Nrf2/HO-1 axis: In vitro and in vivo studies.

With the wide application of silver nanoparticles (AgNPs), their potential damage to human health needs to be investigated. Lung is one of the main target organs after inhalation of AgNPs. Naringenin has been reported to have anti-inflammatory and anti-oxidative properties. This study aims to evaluate the protective effects of naringenin against AgNPs-induced lung injury and determine the underlying mechanism. In in vivo experiments, AgNPs were intratracheally instilled into ICR mice (l mg/kg) to establish a lung injury model. These mice were then treated with naringenin by oral gavage (25, 50, 100 mg/kg) for three days. Naringenin treatment decreased the levels of white blood cells, neutrophils, and lymphocytes in the blood, ameliorated lung injury, suppressed the release of pro-inflammatory cytokines, normalized ferroptotic markers and prevented oxidative stress with elevating Nrf2 and HO-1 protein expressions in lung. In in vitro experiments, BEAS-2B cells were firstly treated with AgNPs (320 μg/mL) and then naringenin (25, 50, and 100 μM), respectively. Naringenin attenuated AgNPs-induced oxidative stress and inflammatory response. Moreover, naringenin attenuated AgNPs-induced apoptosis with modulated low BAX, CytC, cleaved Caspase9, cleaved Caspase3 but high Bcl2. Furthermore, naringenin effectively decreased ferroptotic markers and increased the protein expressions of Nrf2 and HO-1, as well as increased the nuclear translocation of Nrf2. Importantly, the anti-apoptotic and anti-ferroptotic effects of naringenin in BEAS-2B cells were found to be at least partially Nrf2-dependent. These results indicated that naringenin exerted anti-inflammation, anti-apoptosis, and anti-ferroptosis effects and protected against AgNPs-induced lung injury at least partly via activating Nrf2/HO-1 signaling pathway.