n e w e ng l a n d j o u r na l
m e dic i n e
Mechanisms of Disease
Richard S. Hotchkiss, M.D., Andreas Strasser, Ph.D., Jonathan E. McDunn, Ph.D., and Paul E. Swanson, M.D.
From the Departments of Anesthesiology (R.S.H., J.E.M.), Medicine (R.S.H.), and Surgery (R.S.H.), Washington University School of Medicine, St. Louis; the Department ofMolecular Genetics of Cancer, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia (A.S.); and the Department of Pathology, University of Washington School of Medicine, Seattle (P.E.S.). Address reprint requests to Dr. Hotchkiss at the Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, or at hotch@ wustl.edu. N Engl J Med2009;361:1570-83.
Copyright © 2009 Massachusetts Medical Society.
ll multicellular organisms require apoptosis, the controlled death of cells. Without apoptosis, 2 tons of bone marrow and lymph nodes and a 16-km intestine would probably accumulate in a human by the age of 80.1 Investigations into apoptosis have revealed complex interconnections between various cell-death programs, and thesenetworks could affect the treatment of a wide range of diseases.2-10
Cl a ssific at ion of Cel l De ath
The most widely used classification of mammalian cell death recognizes two types: apoptosis and necrosis.3,4,11 Autophagy, which has been proposed as a third mode of cell death, is a process in which cells generate energy and metabolites by digesting their own organelles andmacromolecules.12-15 Autophagy allows a starving cell, or a cell that is deprived of growth factors, to survive.12-15 However, cells that do not receive nutrients for extended periods ultimately digest all available substrates and die (autophagy-associated cell death). Distinctions between apoptosis, necrosis, and autophagy entail differences in the mode of death and morphologic, biochemical, and molecularattributes (Fig. 1).3,4,11 Programmed cell death is an important concept. Cell death is “programmed” if it is genetically controlled. Apoptosis and autophagy-associated cell death are the two fundamental types of programmed cell death.3,12 The recognition that cell death can occur by genetically controlled processes has enabled advances in unraveling the mechanisms of many diseases, and this newknowledge has facilitated the development of pharmacologic agents that initiate or inhibit programmed cell death.6-8,16 Moreover, there is now evidence that necrosis, traditionally considered an accidental form of cell death, can in certain instances be initiated or modulated by programmed control mechanisms.17-21
A p op t osis
Apoptosis is derived from an ancient Greek word thatsuggests “leaves falling from a tree.”22-24 In contrast to the swelling of the cell and its organelles that defines necrosis, the principal morphologic feature of apoptosis is shrinkage of the cell and its nucleus (Fig. 2 and 3, and Fig. 1 through 4 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The distinction between necrosis and apoptosis is due inpart to differences in how the plasma membrane participates in these processes. In necrosis, early loss of integrity of the plasma membrane allows an influx of extracellular ions and fluid, with resultant swelling of the cell and its organelles.17-20,25,26 In apoptosis, plasma-membrane integrity
n engl j med 361;16
october 15, 2009
The New England Journal of MedicineDownloaded from nejm.org on February 16, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.
mechanisms of disease
persists until late in the process. A key feature of apoptosis is cleavage of cytoskeletal proteins by aspartate-specific proteases, which thereby collapses subcellular components.2,5,8,23 Other...
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