Autophagy deficiency exacerbates acute lung injury induced by copper oxide nanoparticles

Abstract

Copper oxide nanoparticles (CuONPs) are one of the widely used metal nanoparticles in the industrial and commercial fields. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome and has been linked to nanoparticles-induced toxicity. In particular, the roles of autophagy in response to CuONPs have been explored in vitro, although the conclusions are controversial. To clarify the role of autophagy in CuONPs-induced acute lung injury, microtubule-associated protein 1 light chain 3 beta (Map1lc3b or lc3b) knockout mice and their corresponding wild type mice are applied. Our results showed that single-dose intratracheal instillation of CuONPs with dosages of 1.25, 2.5 or 5 mg/kg caused acute lung injury 3 days after treatment in a dose-dependent manner, as evidenced by deteriorative lung histopathology, more infiltration of macrophage cells, increased oxidative stress and copper ions. Loss of lc3b resulted in aggravated lung injury induced by CuONPs, which was probably due to the blockade of mitophagy and consequently the accumulation of aberrant mitochondria with overloaded copper ions. Our study provides the first in vivo evidence that autophagy deficiency exacerbates CuONPs-induced acute lung injury, and highlights that targeting autophagy is a meaningful strategy against CuONPs-associated respiratory toxicity.

PINK1/TAX1BP1-directed mitophagy attenuates vascular endothelial injury induced by copper oxide nanoparticles

“…Physical properties of CuONPs have been reported in our previous study [ 16 , 37 ]. Briefly, transmission electron microscopy (TEM) analysis showed that CuONPs were spherical NPs with a diameter size of about 50 nm.…”

“…To determine the protective role of UA against vascular injury in CuONPs-treated mice, we established CuONPs pulmonary exposure mouse model as described in our previous study [ 37 ]. The mice experimental design was illustrated in the Fig.…”

“…These data indicate that PINK1-dependent mitophagy facilitates removal of damaged mitochondria to appropriately mitigate oxidative stress and cell death in CuONPs-treated EA.hy926 cells. Recently, we reported that CuONPs exposure increased intracellular copper ions concentration both in vitro and in vivo model [ 16 , 37 ]. Copper is an essential metal regulator of autophagy initial kinases ULK1/2, which directly interacts with ULK1/2 and enhances these kinases activity, consequently promotes autophagic flux [ 71 ].…”

“…The physical–chemical characteristics of CuONPs were described in our previous study [ 37 ]. For preparation of CuONPs suspension, CuONPs were firstly diluted in serum solution (composed of 2% heat-inactivated sibling mouse serum in MilliQ water) to the concentration of 2 mg/mL.…”

Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

“…CuONPs are highly toxic NPs compared to many other metal oxide NPs [ 14 ]. In our previous studies, we revealed that pulmonary inhaled CuONPs triggered oxidative stress and acute lung injury in mice [ 15 ]. Pulmonary exposure to CuONPs also caused neurotoxicity because of inflammation, oxidative damage and mitochondrial dysfunctions in the cerebral cortex [ 16 ].…”