Proliferation of Lung Epithelial Cells Is Regulated by the Mechanisms of Autophagy Upon Exposure of Soots

Rituraj Niranjan,Kaushal Prasad Mishra,Ashwani Kumar Thakur,Sachchida Nand Tripathi

doi:10.3389/fcell.2021.662597

Abstract

BackgroundSoots 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 autophagy pathways.ResultsFullerene 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 the cell death of A549 cells, caused by hydrogen peroxide, and inhibited LPS-induced autophagy. Fullerene soot co-localized 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 the expression profile of autophagic genes and upregulated the 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 the Akt pathway. At an elemental level, we found that elemental carbon of fullerene soot may be converted into organic carbon, as measured by OCEC, which may point fullerene soot as a source of carbon. On the other hand, DEP upregulated the expressions of autophagy genes. Akt Inhibitor X did not attenuate DEP-induced cell proliferation and autophagic response. However, an autophagic inhibitor, chloroquine, and significantly inhibited DEP-induced cell proliferation.ConclusionIt can be said that distinct autophagic mechanisms are operational in cell proliferation of lung epithelial cells due to soots, which may be responsible for different diseases. Understanding the mechanism of these pathways provides some important targets, which can be utilized for the development of future therapeutics.

Highlights

Soots are known to cause many diseases in humans, but their underlying mechanisms of toxicity are still not known
Soot consists of carbonaceous particles and free and fused polycyclic aromatic hydrocarbons (PAHs) which are formed after the incomplete combustion of gasoline, diesel, and other petroleum fuels (Boffetta et al, 1997; Niranjan and Thakur, 2017)
In order to assess the toxic effect of fullerene soot, we tested its effect on the cell viability or cell proliferation of A549 cells

Summary

Introduction

Soots are known to cause many diseases in humans, but their underlying mechanisms of toxicity are still not known. The carbon particles from wood smoke and road traffic produce allergic adjuvant effects and exacerbate lung-associated disorders (Samuelsen et al, 2008). Other model soots, such as fullerene soot (carbon black and nanocaged structure), share the same kind of toxicological responses with environmental soot. Environmental soot (like diesel exhaust particles, DEP) significantly induces reactive oxygen species (ROS) in the lungs of humans along with experimental animals (Hussain et al, 2009, 2010). We found that in the presence of fullerene soot, lung epithelial cells show proliferation by reducing autophagy This effect was found to be dependent on the Akt pathway. We have shown that soot-induced cell proliferation can cause a hyperplasia-like tissue development, which may in turn lead to tissue remodeling and lung diseases

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