<div>Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway</div>
Authors: Suning Li
Xuanhao Fu
Yiyi Huang
Gan Zhao
Zefeng Lai
Yue Qin
Xiaojing Cheng
Jinbin Wei
Xueping Xie
Huagang Liu
Journal: International Journal of Nanomedicine (2016)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: NF-κB; capillary embolization; carbon nanotubes; inflammation; lung fibrosis.
Affiliations: Pharmaceutical College, Guangxi Medical University., Department of Pharmacy, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region., Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, People's Republic of China.

Abstract:  Numerous studies have demonstrated promising application of single-walled carbon nanotubes (SWNTs) in drug delivery, diagnosis, and targeted therapy. However, the adverse health effects resulting from intravenous injection of SWNTs are not completely understood. Studies have shown that levels of "pristine" or carboxylated carbon nanotubes are very high in mouse lungs after intravenous injection. We hypothesized that long-term and repeated intravenous administration of carboxylated SWNTs (c-SWNTs) can result in persistent accumulation and induce histopathologic changes in rat lungs. Here, c-SWNTs were administered repeatedly to rats via tail-vein injection for 90 days. Long-term intravenous injection of c-SWNTs caused sustained embolization in lung capillaries and granuloma formation. It also induced a persistent inflammatory response that was regulated by the nuclear factor-kappa B signaling pathway, and which resulted in pulmonary fibrogenesis. c-SWNTs trapped within lung capillaries traversed capillary walls and injured alveolar epithelial cells, thereby stimulating production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and pro-fibrotic growth factors (transforming growth factor-beta 1). Protein levels of type-I and type-III collagens, matrix metalloproteinase-2, and the tissue inhibitor of metalloproteinase-2 were upregulated after intravenous exposure to c-SWNTs as determined by immunohistochemical assays and Western blotting, which suggested collagen deposition and remodeling of the extracellular matrix. These data suggest that chronic and cumulative toxicity of nanomaterials to organs with abundant capillaries should be assessed if such nanomaterials are applied via intravenous administration. 

Retracted: No

PubPeer comments:
 Figure 6A appears to have an irregular splicing or overlap in the WB band. Could the authors please provide an explanation? ![file] , 
 Thanks for your questions. Sorry for the late reply. Please find the attachment for our raw data of Western blot that we did more than five years ago. Ladders were included in the image. For the tubulin control image, when we were doing the transfer step for Western blot, we broke the gel, and then we covered the membrane on the broken gel for the transfer step. So this may cause the irregular splicing shown in the membrane image. You can see there was a narrow gap in the membrane image (attachment) as well. For the c-SWNTs sample, there was no obvious splicing in the image, and the irregular shape of the band may be caused by the stacking gel. We made the SDS-PAGE gel by ourselves for all of our Western blot studies. Running voltages and stacking gels may result in different shapes of bands in different samples. I hope our explanation could answer your questions. Please feel free to contact us if you have any questions. Thank you so much! ![file] ,