Liver cell necrosis: cellular mechanisms and clinical implications.
Based on our current understanding, we have developed a provisional model for hepatocyte necrosis that may be applicable to cell necrosis in general (Figure 6). Damage to mitochondria appears to be a key early event in the progression to necrosis. At least two pathways may be involved. In the first, inhibition of oxidative phosphorylation in the absence of the MMPT leads to ATP depletion, ion dysregulation, and enhanced degradative hydrolase activity. If oxygen is present, toxic oxygen species may be generated and lipid peroxidation can occur. Subsequent cytoskeleton and plasma membrane damage result in plasma membrane bleb formation. These steps are reversible if the insult to the cell is removed. However, if injury continues, bleb rupture and cell lysis occur. In the second pathway, mitochondrial damage results in an MMPT. This step is irreversible and leads to cell death by as yet uncertain mechanisms. It is important to note that MMPT may occur secondary to changes in the first pathway (e.g. oxidative stress, increased Cai2+, and ATP depletion) and that all the "downstream events" occurring in the first pathway may result from MMPT (e.g., ATP depletion, ion dysregulation, or hydrolase activation). Proof of this model's applicability to cell necrosis in general awaits further validation. In this review, we have attempted to highlight the advances in our understanding of the cellular mechanisms of necrotic injury. Recent advances in this understanding have allowed scientists and clinicians a better comprehension of liver pathophysiology. This knowledge has provided new avenues of therapy and played a key role in the practice of hepatology as evidenced by advances in organ preservation. Understanding the early reversible events leading to cellular and subcellular damage will be key to prevention and treatment of liver disease. Hopefully, disease and injury specific preventive or pharmacological strategies can be developed based on this expanding data base.
Rosser
B G
BG
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota.
Gores
G J
GJ
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology; D009336:Necrosis; D009626:Terminology as Topic