Fig. 2.5 Therelationshipamongcellularfunction,celldeath,andthemorphologicchangesofcellinjury.Notethatcellsmayrapidlybecomenonfunctionalaftertheonsetofinjury,althoughtheyarestillviable,withpotentiallyreversibledamage;withalongerdurationofinjury,irreversibleinjuryandcelldeathmayresult.Notealsothatcelldeathtypicallyprecedesultrastructural,lightmicroscopic,andgrosslyvisiblemorphologicchanges.
by therapeutic agents or genetic mutations, it is said to be “regulated” cell death. The morphologic appearance of most types of regulated cell death is apoptosis (see
Table 2.1 ). In some instances, regulated cell death shows features of both necrosis and apoptosis, and has been called necroptosis. The discovery of these previously unrecognized forms of cell death that were regulated by identifiable genes and signaling pathways showed that cell death can be a controlled process. The idea of regulated cell death also raises the possibility that specific molecular pathways can be targeted therapeutically to prevent the loss of cells in pathologic conditions. Apoptosis is a process that eliminates cells with a variety of intrinsic abnormalities and promotes clearance of the fragments of the dead cells without eliciting an inflammatory reaction. This “clean” form of cell suicide occurs in pathologic situations when a cell’s DNA or proteins are damaged beyond repair or the cell is deprived of necessary survival signals. But unlike necrosis, which is always an indication of a pathologic process, apoptosis also occurs in healthy tissues. It serves to eliminate unwanted cells during normal development and to maintain constant cell numbers, so it is not necessarily associated with pathologic cell injury. These types of physiologic cell death are also called programmed cell death.
It is important to point out that cellular function may be lost long before cell death occurs, and that the morphologic changes of cell injury (or death) lag far behind loss of function and viability (
Fig. 2.5 ). For example, myocardial cells become noncontractile after 1 to 2 minutes of ischemia, but may not die until 20 to 30 minutes of ischemia have elapsed. Morphologic features indicative of the death of ischemic myocytes appear by electron microscopy within 2 to 3 hours after the death of the cells, but are not evident by light microscopy until 6 to 12 hours later.
Necrosis is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell (
Fig. 2.3 ). Necrosis elicits a local host reaction, called inflammation, that is induced by substances released from dead cells and which serves to eliminate the debris and start the subsequent repair process (Chapter 3). The enzymes responsible for digestion of the cell are derived from lysosomes and may come from the dying cells themselves or from leukocytes recruited as part of the inflammatory reaction. Necrosis often is the culmination of reversible cell injury that cannot be corrected.
The biochemical mechanisms of necrosis vary with different injurious stimuli. These mechanisms include: failure of energy generation in the form of ATP because of reduced oxygen supply or mitochondrial damage; damage to cellular membranes, including the plasma membrane and lysosomal membranes, which results in leakage of cellular contents including enzymes; irreversible damage to cellular lipids, proteins, and nucleic acids, which may be caused by reactive oxygen species (ROS); and others. These biochemical mechanisms are discussed later when we consider the individual causes of cell necrosis.
Figs.2.3 2.4C