Figure 2.

A complex regulatory network of initiation of silica-induced apoptosis or pyroptosis. Normally, when silica invades the alveoli, mtROS is produced and augments the formation of the cas-9-Apaf-1 complex. Furthermore, cas-3 is activated to crack PARP, leading to cell apoptosis finally. In such a mitochondrial-dependent apoptotic pathway, the increased ratio of Bax/Bcl-2 aggravates the cas-3 activation. Moreover, the Fas/FasL signaling pathway, induced by upstream factor Annexin A5, also mediates silica-induced apoptosis. p53 induces apoptosis, not via the inhibition of uPA and induction of PAI-1, but via p53 trans-activation. Another member of the p53 family, PPP1R13B, promotes over-activation of ER stress via the PERK/eIF2α/CHOP signaling pathway, further initiating silica-induced apoptosis. Similarly, it also can be activated by ER stress-related protein cas-12. Silica-induced apoptosis is still induced by the IL-1β-iNOS-NO cascade reaction. Notably, TNF-α activation aggravates cell apoptosis. However, TNF-α also stimulates the NF-κB signaling pathway to alleviate cell apoptosis against silica invasion. The bidirectional role of TNF-α deserves further discussion. It is worth noting that NAC and DHA have potential anti-apoptotic effects activated by silica. In addition to apoptosis, silica can stimulate the interaction of NALP3 and ASC, and subsequent NALP3-ASC complex activates cas-1. The cas-1 activation leads to the transformation from pro-IL-1β to IL-1β, further executing cell pyroptosis. BMSCs might mitigate cell pyroptosis via inhibition of NALP3.