Mechanisms of cell necrosis.

Work in the area of apoptosis (or “programmed cell death”) over the last few decades has defined a series of its morphologic and biochemical events. In contrast to apoptosis, necrosis has received less attention and was dismissed as an accidental and unregulated form of cell death. A key difference between the two forms of cell death is that during necrosis, the membrane integrity breaks down and cytosolic constituents are released into the extracellular space through the damaged plasma membrane, whereas during apoptosis cells shrink and their nuclei condense, resulting in their encapsulation into well-enclosed apoptotic bodies followed by consumption by macrophages. Studies in the area of apoptosis have concluded that apoptosis during embryogenesis is an evolutionarily conserved mechanism of cell elimination. This concept was reinforced by the discovery (in Caenorhabditis elegans) of multiple genes and gene products responsible for biochemical mechanisms of apoptosis, mitochondrial “death factors,” and caspases (1, 2). The importance of gene expression and protein synthesis in the process of apoptosis has been established. Subsequently, the concept emerged that apoptosis not only is important in embryogenesis but may also represent a key death pathway mediating tissue injury in various pathophysiologic states. Even to date, this notion holds sway in the pathomechanistic thinking of many investigators. The overextension of the concept of apoptosis into many diseases (including myocardial infarction, stroke, liver failure, and others) fails to take into account the obvious clinical experience demonstrating that necrosis is a common and highly visible feature of disease. Early on in medical school, we learn that myocardial specific enzymes (creatine kinase, troponin) are diagnostic markers of myocardial infarction, and these enzymes correlate with the degree of myocardial damage. These enzymes can be detected in the plasma due to the fact that the internal content of the myocyte is released. This is a feature of necrosis, not apoptosis. Similarly, plasma levels of many “liver enzymes” are elevated due to the death and lysis of hepatocytes. Thus, there is clear evidence of necrosis in many diseases, including stroke, myocardial infarction, various forms of reperfusion injury (hepatic, gastrointestinal, renal), and hemorrhagic shock (a wholebody ischemia-reperfusion disease). The concept that apoptosis is a key component of cell death in these diseases does not fit with the concept that apoptosis relies on novel protein synthesis (considering that ischemic and hypoxic tissues or cells exposed to toxic oxidants and free radicals decrease their protein synthesis). Finally, the fact that pharmacologic inhibition of caspases (the main executioners of apoptosis) does not eliminate tissue damage and pathology in many disease states, including stroke, myocardial infarction, and circulatory shock (3– 6), must refocus our attention to cell death pathways other than apoptosis. The distinction of apoptosis and necrosis is somewhat blurred, as many cellular pathways (e.g., DNA fragmentation, mitochondrial dysfunction) may occur in both conditions (1, 2, 7–9). This is the reason why assays detecting DNA fragmentation—such as the popular terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling assay—are by no means specific to detect apoptosis. There exists a spectrum of suicidal programs in cells, and “classic” necrosis and apoptosis are the extremes of this continuum.