American Journal ofPathology, Vol. 146, No. 1, January 1995 Copyright ) American Societyfor Investigative Pathology Review Apoptosis, Oncosis, and Necrosis An Overview of Cell Death Guido Majno and Isabelle Joris of this rapid advance, new concepts, such as apop- From the Department ofPathology, University of tosis, appeared on the scene, and ancient terms such Massachusetts Medical School, Worcester, Massachusetts as necrosis came to be used in a new context. In- evitably, some conceptual and semantic strains de- veloped; a recent reviewer saw fit to conclude that The historical development of the ceU death con- "there is no field of basic cell biology and cell pa- cept is reviewed, with special attention to the ori- thology that is more confusing and more unintelligible gin of the terms necrosis, coagulation necrosis, than is the area of apoptosis versus necrosis."1 The autolysis, physiological ceU death, programmed purpose of this paper is to offer a critical and, we ceU death, chromatolysis (the first name of ap- hope, constructive overview of the terms and con- optosis in 1914), karyorhexis, karyolysis, and cepts related to cell death. ceU suicide, of which there are three forms: by It will be useful to begin by tracing the main steps lysosomes, by free radicals, and by a genetic that led us to where we now stand. mechanism (apoptosis). Some ofthe typicalfea- tures of apoptosis are discussed, such as bud- ding (as opposed to blebbing andzeiosis) and the Development of the Cell Death Concept infZammatory response. For ceU death not by ap- optosis the most satisfactory term is accidental The fact that cells can perish is discussed in Lecture ceU death. Necrosis is commonly used but it is not XV of Virchow's Cellular Pathology among "passive appropriate, because it does not indicate aform processes and degenerations."2 Understandably, no of ceU death but refers to changes secondary to microscopic description of cell death is included, as ceU death by any mechanism, including apopto- histological stains were not used in 1858. Thus, topics sis. Abundant data are available on oneform of related to cell death are treated in this lecture at a accidental ceUl death, namely ischemic ceU death, gross level, under names such as degeneration, soft- which can be considered an entity of its own, ening, necrosis, and mortification, which was synony- caused by failure of the ionic pumps of the mous with gangrene. For our present purposes it is plasma membrane. Because ischemic ceU death relevant to note that Virchow uses necrosis to mean (in known models) is accompanied by sweUing, an advanced stage of tissue breakdown, similar to the name oncosis is proposedfor this condition. what we would now call gangrene: "In necrosis we The term oncosis (derivedfrom 6nkos, meaning swelling) was proposed in 1910 by von Reckling- hausenprecisely to mean ceUdeath with sweUing. Supported in part by National Institutes of Health Grant DK 32520 Oncosis leads to necrosis with karyolysis (IJ). and stands in contrast to apoptosis, which leads Accepted for publication August 10, 1994. to necrosis with karyorhexis and ceU shrink- Address reprint requests to Dr. Guido Majno, Department of Pa- thology, University of Massachusetts Medical Center, 55 Lake Av- age. (AmJPathol 1995, 146:3-15) enue North, Worcester, MA 01655-0125. We dedicate this paper to the memory of Dr. Marcel Bessis, pio- neer in the study of cell death, eminent clinician, and founder of Knowledge in the field of cell death has greatly in- the first Institute of Cellular Pathology, who passed away in Paris creased during the past 20 years or so. In the course on March 28, 1994. 3 4 Majno and Joris AJPJanuary 1995, Vol. 146, No. 1 conceive the mortified [gangrenous] part to be pre- theritic pseudomembrane was at work also in pro- served more or less in its external form" (p. 358). This ducing what we now call white infarcts. He even re- had been the traditional usage of the term necrosis, ferred to the typical wedge-shaped white infarcts as not only in the textbook of Virchow's teacher Rokitan- fibrin wedges (Fibrinkeile).9 Julius Cohnheim, another sky3 but also, as necrosis, in ancient Greek texts at disciple of Virchow, accepted this view and intro- least since Galen.4 duced, in the 1877 edition of his textbook, the term Virchow's Lecture XV also creates a special cat- coagulation necrosis.10 Soon the fibrin component egory of regressive processes under the name necro- was found to be unrelated to the coagulation of the biosis, a term he borrowed from a contemporary au- tissue11; today Weigert's concept survives only in thor, K. H. Schultz. Included among the necrobiotic what we call fibrinous necrosis. However, an impor- processes, for example, were the "softenings." tant byproduct of Weigert's studies was the observa- Necrobiosis is thus defined, perhaps, to fit the model tion that necrotic cells lose their nuclei.b of brain softening: "The part vanishes, so that we can The role of protein denaturation in the genesis of no longer perceive it in its previous form. We have no coagulation necrosis was vaguely hinted in necrosed fragment at the end of the process." A foot- Cohnheim's textbook10; it could not escape the pa- note extends the definition (emphasis original): thologists' attention that necrotic tissue looked like "Necrobiosis is death brought on by (altered) life - a "coagulated albumen."12 Interestingly, the notion that spontaneous wearing out of living parts - the destruc- protein denaturation may participate in cell death was tion and annihilation consequent upon life - natural as first proposed in 1886 by a botanist, G. Berthold. 13,14 opposed to violent death (mortification)." The use of This is just one of the many contributions made by necrobiosis throughout Virchow's book and later in- plant pathology to animal pathology, the latest one dicates that this term was sometimes meant to imply being the tetrazolium method for detecting dead tis- also "slow death" or "death of tissues within the living sue on gross specimens, originally used by botanists body." Needless to say, necrobiosis was a vague and for identifying nonviable seeds (reviewed in reference ambiguous term. After a long career it is finally dis- 15). appearing. Another term from Virchow's Lecture XV Weigert's notion of coagulation necrosis had the that needs rethinking is degeneration. Virchow's "fatty virtue of triggering, after 1880, many experimental degeneration" still clings on5; it should be banished, studies on cell death,16 produced by ligating the renal because cells can die but certainly cannot degener- artery, by maintaining tissue fragments septically or ate into something else. In our opinion, there are few aseptically in vitro,11 or by introducing them into the defensible uses of this term in general pathology; we peritoneal cavity of experimental animals.17 Much of can think of two: for the breakdown of axons, as in the present terminology of cell death, besides coagu- Wallerian degeneration, and for the breakdown of car- lation necrosis, stems from that era. Autolysis was tilage matrix in degenerative osteoarthritis. proposed in 1900, although the concept was known The next step, around 1877, was the identification earlier.13'16'18 Pyknosis was in use around 1890.19 of coagulation necrosis by Carl Weigert and Julius Karyolysis and karyorhexis were proposed in 187920 Cohnheim. Today this term evokes a rather obvious by Edwin Klebs of Klebsiella fame (he spelled his and noncontroversial lesion, mainly the white infarct, Karyorhexis right, but the erroneous Karyorrhexis ap- but this was not true in the beginning, when it applied peared in the title of an 80-page paper in 189019 and to a condition that in our view has virtually nothing to has lasted ever since). Chromatin margination (Rand- do with coagulation necrosis. stellung) was described in 1890.17 Some terms born When Carl Weigert (1845-1904) was training under in those days changed meaning, such as chroma- Virchow, diphtheria was a common cause of death, as tolysis (1885),21 and others disappeared, such as the vaccine was not available before 1880. Diphtheria plasmarhexis,20, chromatopyknosis, and deconstitu- causes necrosis of the tracheobronchial epithelium, tion.22 which becomes impregnated with fibrin and leuko- Spontaneous cell death as a physiological event cytes and tends to slough off as a leathery, whitish was discussed almost as soon as stains became pseudomembrane (diphth6ra is Greek for tanned available. It was born with a bang in 1885 in a paper21 hide). Weigert, who was especially interested in fibrin by the same Walther Flemming who created the terms (witness the fibrin stain of his name), became im- chromatin and mitosis.23 Flemming studied ovarian pressed by this combination of epithelial necrosis and follicles in mammals and noticed that the epithelial fibrin.6-9 He held the current view that dead leuko- lining of regressing follicles was littered with cells the cytes cause fibrinogen to coagulate and proposed nuclei of which were breaking up (Figure 1).21 His that the same mechanism that produced the diph- careful camera lucida drawings illustrate the half- Apoptosis, Oncosis, and Necrosis 5 AJPJanuary 1995, Vol. 146, No. 1 Figure 1. A40ptosis as observed in 1885 by Flemming,21 who called it chromatolysis. Top left: Normal rabbit ovarian follicle near matu- nity, 1 mm in diameter. Numerous epithelial mitoses. Top right: Early stage of involution in a nearbyfollicle. Many epithelial cells are in van- ous stages of death by chromatolysis; some are shed into the lumen. Bottom: detail of the same involuting follicle. Most epithelial cells in con- tact with the ovum are normal (one is in mito- sis); those farther removed are undergoing chromatolysis. Note the half-moons of chroma- tin typical of apoptosis.