Figure 8: Hypothetic model for the mechanism of the antiapoptotic effect of PM2.5. Exposure of bronchial epithelial cells to PM2.5, leads to particles endocytosis and PAH desorption. Then, intracellular PAH can target and activate the aryl hydrocarbon receptor (AhR). It is noteworthy, that AhR translocates to the nucleus to bind to specific xenobiotic responsive elements (XRE) in the promoter of its target genes; some of them might be mitochondrial MMP regulators (dotted arrow), thus might protect the cell from apoptosis induced by A23187, staurosporin (STS) or oligomycin (Omy). Moreover, the water-soluble compounds of PM2.5 also have antiapoptotic activity, but the pathway involved is still under investigation (dotted arrow). Illustration carried out thanks to Servier Medical Art.

Mentions: In summary, Parisian PM2.5 are not cytotoxic in four cellular models of bronchial epithelial cells. However, PM2.5 exposure rapidly triggers an antiapoptotic effect at the mitochondrial level, which seems to be linked to the water-soluble and some PAH components adsorbed on particles. Finally, the AhR pathway partially contributes to the antiapoptotic effect of fine particles. Altogether, our results allow us to propose the hypothetic model in which desorbed PAH may activate the AhR leading to the regulation of genes involved in the mitochondrial checkpoint of apoptosis (Figure 8). In parallel, the water-soluble fraction seems to have similar effect on mitochondria by regulating unknown pathways. Our results are the first evidence of a missing link in the connection between adverse health effects of fine particles and exacerbation of cancerous pathologies, via the cell death impediment in their presence. Furthermore, the antiapoptotic effect of PM2.5 associated with the well-documented inflammatory response might also explain the maintenance of a prolonged inflammation state in vivo induced after pollution exposure.

Ferecatu I, Borot MC, Bossard C, Leroux M, Boggetto N, Marano F, Baeza-Squiban A, Andreau K - Part Fibre Toxicol (2010)

Bottom Line: Conversely, a 4 hour-pretreatment with PM2.5 prevent mitochondria-driven apoptosis triggered by broad spectrum inducers (A23187, staurosporine and oligomycin) by reducing the mitochondrial transmembrane potential loss, the subsequent ROS production, phosphatidylserine externalization, plasma membrane permeabilization and typical morphological outcomes (cell size decrease, massive chromatin and nuclear condensation, formation of apoptotic bodies).Experiments performed with different compounds of PM2.5 suggest that endotoxins as well as carbon black do not participate to the antiapoptotic effect of PM2.5.Finally, the activation or silencing of the aryl hydrocarbon receptor (AhR) showed that it is involved into the molecular mechanism of the antiapoptotic effect of PM2.5 at the mitochondrial checkpoint of apoptosis.The PM2.5-antiapoptotic effect in addition to the well-documented inflammatory response might explain the maintenance of a prolonged inflammation state induced after pollution exposure and might delay repair processes of injured tissues.

Affiliation: Université Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) CNRS EAC 4413, Laboratory of Molecular and Cellular Responses to Xenobiotics, Bâtiment Buffon, case courrier 7073, 5 rue Thomas Mann, 75013 Paris, France.

Abstract: Nowadays, effects of fine particulate matter (PM2.5) are well-documented and related to oxidative stress and pro-inflammatory response. Nevertheless, epidemiological studies show that PM2.5 exposure is correlated with an increase of pulmonary cancers and the remodeling of the airway epithelium involving the regulation of cell death processes. Here, we investigated the components of Parisian PM2.5 involved in either the induction or the inhibition of cell death quantified by different parameters of apoptosis and delineated the mechanism underlying this effect.In this study, we showed that low levels of Parisian PM2.5 are not cytotoxic for three different cell lines and primary cultures of human bronchial epithelial cells. Conversely, a 4 hour-pretreatment with PM2.5 prevent mitochondria-driven apoptosis triggered by broad spectrum inducers (A23187, staurosporine and oligomycin) by reducing the mitochondrial transmembrane potential loss, the subsequent ROS production, phosphatidylserine externalization, plasma membrane permeabilization and typical morphological outcomes (cell size decrease, massive chromatin and nuclear condensation, formation of apoptotic bodies). The use of recombinant EGF and specific inhibitor led us to rule out the involvement of the classical EGFR signaling pathway as well as the proinflammatory cytokines secretion. Experiments performed with different compounds of PM2.5 suggest that endotoxins as well as carbon black do not participate to the antiapoptotic effect of PM2.5. Instead, the water-soluble fraction, washed particles and organic compounds such as polycyclic aromatic hydrocarbons (PAH) could mimic this antiapoptotic activity. Finally, the activation or silencing of the aryl hydrocarbon receptor (AhR) showed that it is involved into the molecular mechanism of the antiapoptotic effect of PM2.5 at the mitochondrial checkpoint of apoptosis.The PM2.5-antiapoptotic effect in addition to the well-documented inflammatory response might explain the maintenance of a prolonged inflammation state induced after pollution exposure and might delay repair processes of injured tissues.