Figure 3

Initiation, execution and propagation of regulated cell death. The term ‘execution’ has largely been used to indicate the processes that (were thought to) mediate regulated cell death (RCD), such as the massive activation of CASP3 in the course of apoptosis. Conversely, the word ‘initiation’ has generally been used to refer to the signal transduction events that trigger executioner mechanisms, such as the activation of CASP8 or CASP9, both of which normally impinge on CASP3. Upon an attentive re-evaluation of the available literature, the NCCD recommends caution in attributing a specific process a bona fide causative value in the execution of cell death. In addition, the NCCD proposes to use the term ‘initiation’ with a pragmatic connotation, that is, to indicate the steps in the cascades of events leading to RCD that are truly reversible, and the term ‘propagation’ to indicate the processes that link primary RCD to the insult-independent initiation of a secondary wave of RCD, that is, the release of cytotoxic and proinflammatory factors, including damage-associated molecular patterns (DAMPs), by dying cells and their consequences. Based on this conceptual construction, only pharmacologic and genetic interventions that target the initiation phase exert bona fide cytoprotective effects, that is, truly inhibit primary RCD rather than just delaying its course or changing its morphologic or biochemical correlates. Robust cytoprotection can also be achieved in vivo by the administration of anti-inflammatory agents and by measures that block DAMPs or their receptors. These maneuvers, however, appear to be efficient as they prevent the propagation of primary RCD or the initiation of secondary RCD