Surgical Stress and Liver Response: Injury, Regeneration, and Protection

Liver surgery commonly involves the resection of the liver (loss of liver mass) and the temporary blockage of blood flow to the liver (liver ischemia). The liver immediately responds to overcome any surgical insult by recovering liver mass and function (liver regeneration). Major liver responses include cell proliferation, growth, and death, which are induced and regulated by various intrahepatic and extrahepatic factors. The central molecular machinery that regulates cell proliferation and growth during regeneration of the liver is driven mainly by interleukin-6/janus kinase/signal transducers and activators of transcription-3 and hepatocyte growth factor/phosphoinositide 3-kinase/phosphoinositide-dependent protein kinase 1/v-akt murine thymoma viral oncogene homolog signaling pathways in hepatocytes, respectively. These surgical procedures also induce a deleterious response by hepatocytes, which generate excessive amounts of reactive oxygen species, resulting in certain types of programmed or nonprogrammed cell death (e.g., necroptosis, apoptosis, parthanatos, and necrosis). The janus kinase/signal transducers and activators of transcription-3 and phosphoinositide 3-kinase/phosphoinositide-dependent protein kinase 1/v-akt murine thymoma viral oncogene homolog signals are activated instantly after surgical stress. At the same time, these signals play crucial roles in suppressing cellular oxidative stress and programmed cell death, thereby supporting liver regeneration after surgery. Such molecular machineries work harmoniously and efficiently to induce rapid and reliable liver regeneration that is necessary for life support. This review describes the various molecular and cellular responses of hepatocytes to surgical stress.