Fig. 2.

Mechanisms of cell death. Three potential pathways of hepatocellular cell death are illustrated: apoptosis, necrosis and necroptosis. Apoptosis is characterized by cell shrinking and blebbing, as well as fragmentation of the nucleus and DNA. Apoptosis proceeds under regulation from mitochondria and/or receptor signaling, particularly the receptors for TNFα and Fas. Apoptosis is considered to be the least inflammatory mode of cell death, as there is little release of cellular contents (DAMPs) that would activate inflammatory and chemotactic responses. Necrotic cell death is due to acute injury; cells swell and burst, leading to a release of cytoplasmic contents into the extracellular space. These DAMPs trigger pathways termed sterile inflammation that can lead to further hepatocellular injury [41]. MIF, which is present in pre-formed pools in cells, can also be released by necrotic cells, likely contributing to the sterile inflammatory response evoked by necrotic cells. Necroptosis, or programmed necrosis, morphologically resembles necrosis; however, it is RIP3-mediated process and has been indicated as a mediator of ethanol-induced liver injury in mice [13].