SCientiFiC REPORtS | (2018) 8:4499 | DOI:10.1038/s41598-018-22556-7
Intranasal Delivery of Copper Oxide
Nanoparticles Induces Pulmonary
Toxicity and Fibrosis in C57BL/6
, Hu Zhao
, Yong Zhang
, Kai Guo
, Yuqiao Xu
, Suning Chen
& Jian Zhang
Copper oxide nanoparticles (CuO NPs) are widely used as catalysts or semiconductors in material elds.
Recent studies have suggested that CuO NPs have adverse genotoxicity and cytotoxicity eects on
various cells. However, little is known about the toxicity of CuO NPs following exposure to murine
lungs. The purpose of this fundamental research was to investigate whether CuO NPs could induce
epithelial cell injury, pulmonary inammation, and eventually brosis in C57BL/6 mice. Our studies
showed that CuO NPs aggravated pulmonary inammation in a dose-dependent manner. CuO NPs
induced apoptosis of epithelial cells as indicated by TUNEL staining, ow cytometry and western blot
analysis, which was partially caused by increased reactive oxygen species (ROS). In addition, CuO NPs
exposure promoted collagen accumulation and expression of the progressive brosis marker α-SMA in
the lung tissues, indicating that CuO NP inhalation could induce pulmonary brosis in C57BL/6 mice. All
data provide novel evidence that there is an urgent need to prevent the adverse eects of CuO NPs in
the human respiratory system.
Nanoparticles, whose sizes range from 1 nm to 100 nm, are widely used in almost all elds due to their unique
physicochemical characteristics, including their high surface area to volume ratio, diversity of surface structures,
and quantum eect
. ese particular characteristics make nanoparticles suitable for various applications in
. With growing demand and the employment of nanoparticles, our modern life has changed
greatly. However, one thing that should not be ignored is that they also bring challenges to the environment and to
. With sizes smaller than cellular organelles, nanoparticles can easily penetrate through basic biological
Copper oxide nanoparticles (CuO NPs) have attracted attention and have been commonly used in industrial
and commercial elds for their photovoltaic and photoconductive properties
. CuO NPs are mostly used in sem-
iconductors, solar cells, catalysts, electronic chips, lithium batteries, additives in inks, plastics, skin products and
face masks, etc
. In the production process and the employment of CuO NPs, CuO NPs are prone to diusion in
the ambient air as aerosols and are retained in the lungs for a long time aer inhalation
. erefore, the eect of
CuO NP exposure on the respiratory system has become a major concern for the public and for scientists.
In vitro studies have proven that CuO NPs induce the cytotoxic, genotoxic, and oxidative stress response in
several cultured human lung epithelial cells
. Compared with SiO
NPs, CuO NPs
showed the greatest cytotoxicity in a dose-dependent manner
. For in vivo studies, Yokohira et al. established a
method through intratracheal instillation in F344 male rats to simulate nanoparticle inhalation in human being
and found that CuO NPs induced pulmonary neoplastic lesions aer intratracheal instillation
. Sandhya Rani
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military
Medical University, Xi’an, 710032, P.R. China.
Fujian Provincial Key Laboratory of Transplant Biology, Fuzhou
General Hospital, Xiamen University, Fuzhou, Fujian, 350025, P.R. China.
Department of Respiratory Medicine,
Xijing Hospital, the Fourth Military Medical University, Xi’an, 710032, P.R. China.
Department of Orthopedics, Xijing
Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, 710032, P.R. China.
State Key Laboratory of Cancer
Biology, Department of Pathology, the Fourth Military Medical University, Xi’an, 710032, P.R. China.
Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, 710032, P.R. China. Xiaofeng Lai,
Hu Zhao and Yong Zhang contributed equally to this work. Correspondence and requests for materials should be
addressed to S.C. (email: firstname.lastname@example.org) or J.Z. (email: email@example.com)
Received: 7 September 2017
Accepted: 26 February 2018
Published: xx xx xxxx