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Proliferation of lung epithelial cells is regulated by the mechanisms of autophagy upon exposure of soots

By Rituraj Niranjan, Kaushal Prasad Mishra, Ashwani Kumar Thakur

Posted 20 Sep 2020
bioRxiv DOI: 10.1101/2020.09.19.304725

Soots are known to cause many diseases in humans but their underlying mechanisms of toxicity are still not known. Here, we report that, soots induce cell proliferation of lung epithelial cells via modulating autophagic pathways. Fullerene soot and diesel exhaust particles (DEP) induced cell proliferation of lung epithelial, A549 cells, via distinct autophagic mechanisms and did not cause cell death. Exposure of fullerene soot protected cell death of A549 cells, caused by hydrogen peroxide and inhibited LPS-induced autophagy. Fullerene soot co-localize with the autophagic proteins and inhibited starvation-induced autophagy (downregulated ATG-5, beclin-1, p62 and LC3 expressions) independent of its antioxidant properties. Similarly, it decreased expression profile of autophagic genes and upregulated proliferation responsive gene, Ki-67, in mice. We observed that, expressions of fullerene soot responsive genes (Beclin-1, ATG-5 and p62) were reverted by Akt Inhibitor X, indicating an important role of Akt pathway. On the other hand, DEP up-regulated expressions of autophagy genes. Akt Inhibitor X and Etoricoxib, did not attenuate DEP-induced cell proliferation and autophagic response. However, autophagic inhibiter 3-MA and chloroquine has significantly inhibited DEP-induced cell roliferation. In conclusion, distinct autophagic mechanisms are operational in cell proliferation of lung epithelial cells in response to soots and may have implication in diseases. The proliferation inducing potential of fullerene soot may be utilized as a regenerative agent in autophagy-associated disorders. ### Competing Interest Statement The authors have declared no competing interest. * DEP : Diesel exhaust particles; COX-2 : Cyclooxygenase-2; DCF-DA : dichloro-dihydro-fluorescein diacetate; LPS : Lipo-polysaccharide; Akt : Protein kinase B; LC3 : Light chain 3; ATG-5 : Autophagy protein-5; p62/SQSTM1 : Sequestosome 1; AMPK : Adenosine monophosphate-activated protein kinase; GF : Glucose free; GP : Glucose plus; AD : aerodynamic diameter; PAHs : polycyclic aromatic hydrocarbons; ROS : Reactive oxygen species; HRP : Horse Radis Peroxidase; PM : particulate matter; OCEC : Organic Carbon/Elemental Carbon Analyser; HBSS : Hank’s balanced salt solution; 3-MA : 3-Methyladenine; DMEM : Dulbecco′s Modified Eagle′s Medium.

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