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Fate of airway epithelial cells exposed to titanium dioxide nanoparticles: NGF regulated apoptotic death.

Chakraborty-S; Piedimonte-G; Ding-M; Castranova-V; Othumpangat-S
Am J Respir Crit Care Med 2011 May; 183(Meeting Abstracts):A2121
Recent studies revealed that nano-sized TiO2 can cause inflammatory response in airways of rats and mice, fibrosis or lung tumors in rats and DNA damage in Chinese hamster ovary (CHO) cells, Syrian hamster embryo fibroblasts and human lymphoblastoid cells. The primary human airway bronchial epithelial cells exposed to nanoparticles elicit high levels of neurotrophins, which has a significant role in modulating the cell cycle, cell proliferations and inflammatory responses. Nerve Growth Factor (NGF) can bind to tyrosine kinase A (trkA) and with p75NTR depending the physiological state of the cell. It has also been reported that unprocessed NGF precursor, proNGF, binds p75NTR preferentially over trkA, and this selective binding of proNGF to p75NTR leads to apoptotic death of cells. The cytotoxicity observed on TiO2 treatment was differed with cell type of the airway niche and particle size. Here we try to explore the possible molecular mechanism that leads to the toxicity of TiO2 and the downstream targets of NGF pathway. TiO2 mediated induction of NGF, was dependent on cell type, particle size and dose. To evaluate the mechanism of TiO2 mediated toxicity, the bronchial epithelial cells were exposed to TiO2 (10 microg/mL) and the apoptosis and necrosis were measured. Annexin-V and propidium iodide (PI) staining demonstrated that TiO2-NP induced cell death through apoptosis was highest in bronchial cells (22.0+/-2.6%) compared to nasal epithelial cells (14.0+/-0.5%; p<0.001). However, nasal epithelial cells following TiO2 fine particle exposure were more diverted to necrotic death (7.4+/-1.4% in bronchial vs. 18.6+/-1.0% in nasal; (p<0.0004). We observed significant up-regulation of p75NTR (protein and mRNA) along with lowered co-expression of trkA in bronchial epithelial cells. To further understand the NGF mediated apoptotic pathway, we blocked the low affinity receptor p75NTR expression using p75NTRspecific antibody resulted significant reduction in apoptosis induced by TiO2. We also measured the p75NTR downstream stress kinase p-JNK during mitochondrial induced apoptotic cell death. Immunoprecipitation experiments further confirmed significant binding of NGF to p75NTR receptor protein. In conclusion, our study clearly elucidates that the TiO2 mediated differential expression of neurotrophins along the respiratory tract modulates cellular responses that lead to apoptosis and is modulated by NGF.
Nanotechnology; Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Airway-obstruction; Humans; Lung-cells; Dioxides; Neurophysiological-effects; Immune-reaction; Cytotoxic-effects; Cytotoxicity; Immunotoxins; Laboratory-testing; Cell-cultures; Exposure-assessment; Dose-response; Cell-damage; Cellular-reactions; Molecular-biology; Toxic-dose; Toxic-effects; Proteins; Ribonucleic-acids; Antibody-response
S. Chakraborty, West Virginia University, Morgantown, WV
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American Journal of Respiratory and Critical Care Medicine