British Journal of Anaesthesia 1996; 77: 3–10
Mechanisms of cell injury and death
J. P. COBB, R. S. HOTCHKISS, I. E. KARL AND T. G. BUCHMAN
Control of the rate of cell death relative to the rate of reserves. The associated changes in gene expression
cell division maintains organ integrity and physio- include decreased total protein synthesis, induction
logical homeostasis. Cell death is valuable for the of hypoxia-associated proteins (e.g. glyceraldehyde-
organism because it removes terminally injured or 3-phosphate dehydrogenase, a glycolytic enzyme),
unwanted cells that utilize valuable substrates and induction of the heat shock response (see below), and
nutrients. Likewise, cell death also has value for the induction of glucose-regulated proteins. If these
species, as it provides a mechanism for eliminating changes are inadequate to prevent ATP depletion,
terminally injured individuals who consume necess- membrane ion pumps fail and membrane integrity is
ary societal resources or harbour toxic pathogens. lost. Increased intracellular Ca2; occurs and a variety
Recent advances in cellular biology have contributed of degradative processes are initiated, leading to
substantially to our understanding of the processes cytoplasmic swelling and eventual cell death.
of cell injury and death, and have provided the
molecular tools necessary to control it. This paper OXIDATIVE STRESS RESPONSE 
reviews cell injury and adaptation; mechanisms of
cell death; the roles of cell injury and death in the Agents that provoke oxidative injury include pro-
pathophysiology of organ dysfunction; and implica- ducts of oxidative metabolism (especially from the
tions for prevention and therapy of multiple organ mitochondria) and those released from activated
dysfunction syndrome (MODS). phagocytes. Collectively, they are called reactive
oxygen species (ROS), and include superoxide, hy-
drogen peroxide, hydroxyl radical (the generation of
Cell injury and adaptation which depends on availability of ferrous ion and
Cell injury occurs as a result of physical, chemical or superoxide) and nitric oxide. Iron, which is essential
biological insults or as a result of vital substrate for DNA synthesis and oxidative metabolism, also
deficiency (table 1). The cellular response to these catalyses the Fenton and Haber-Weiss reactions,
injuries is adaptive, designed to restore homeostasis converting superoxide to molecular oxygen and
and protect the cell from further injury. Although hydrogen peroxide to the hydroxyl radical. Under
characteristic changes in gene transcription occur, it normal conditions, free iron is compartmentalized
is not the relative amount but the pattern of by the protein ferritin, which “protects” the cell by
transcription that changes, with emphasis directed keeping iron in a non-reactive crystallized core as
towards transcription of “vital” genes. The ferric ion (Fe3;). The results of the oxidative
responses induced by cellular injury fall into four reactions of ROS include de-energization of mito-
main patterns: the ischaemic/anoxic, oxidative, heat chondria and loss of energy stores, peroxidation and
shock and acute phase responses. These are reviewed disruption of lipid membranes, and direct DNA
briefly below. damage.
The adaptive response of the cell to oxidative
stress includes both enzymatic and non-enzymatic
ISCHAEMIC/ANOXIC STRESS RESPONSE  capacities and induction of oxidative stress response
proteins . Superoxide dismutase reduces super-
Because of the unusual high efficiency of the
cardiopulmonary system to transport oxygen, cells in oxide to molecular oxygen and hydrogen peroxide;
catalase catalyses the conversion of this hydrogen
higher animals have not developed elaborate cellular
peroxide to oxygen and water. Reduced glutathione
pathways to adapt to hypoxia and are thus relatively
sensitive to ischaemia [13, 18]. As a consequence, (which reacts with hydrogen peroxide in the presence
of glutathione peroxidase to form water and oxidized
lack of oxygen dramatically increases the need for
glutathione), vitamin C and vitamin E constitute the
anaerobic glycolysis to maintain intracellular ATP
(Br. J. Anaesth. 1996; 77: 3–10) J. PERREN COBB*, MD, TIMOTHY G. BUCHMAN, PHD, MD
(Department of Surgery); RICHARD S. HOTCHKISS, MD (Depart-
ment of Anesthesia); IRENE KARL, PHD (Department of Medicine);
Key words Washington University School of Medicine, St Louis, MO, USA.
Cells, apoptosis. Cells, necrosis. Cells, death. Complications, *Address for correspondence: Campus Box 8109, Department
sepsis. of Surgery, 660 South Euclid Ave, St Louis, MO 63110-1093,
4 British Journal of Anaesthesia
Table 1 Mechanisms of cell injury that function to maintain the homeostasis of the
organism. They include C-reactive protein, fibrino-
(a) ionizing radiation gen, complement, the metal binding proteins hapto-
(b) temperature globin and ferritin, and plasminogen activator in-
(c) mechanical trauma hibitor and many others. The acute phase response
(2) Chemical (activation) of endothelial cells includes increased
(a) drugs surface expression of adhesion, selectin and integrin
molecules that facilitate leucocyte adhesion and
release of IL-1, IL-6, IL-8 and platelet activating
(b) cytokines factor (PAF).
(c) viral infection
(4) Critical substrate deficiency Mechanisms of cell death
(b) glucose If the genetic and metabolic adaptive responses
described above are inadequate for a given injury,
the cell will die. Increased interest in the mechanisms
major intracellular reducing (non-enzymatic) agents. responsible for cell death, however, has made it clear
Several proteins are induced under oxidative stress, that morphological classification of cell death
the most important of which may be metallothionein, requires revision. At least two types of cell death
which binds not only heavy metals but also ROS via have been described. In the first, cell damage is
the free sulphydryl groups of its many cysteine manifested by cytoplasmic swelling, plasma mem-
residues. ROS also activate the transcriptional brane blebbing, dilation of the endoplasmic reticu-
factors AP-1 and NF B, both of which promote lum and mitochondria, dissolution of chromatin and,
transcription of cytokines and have been associated finally, interruption of membrane integrity. The
with induction of apoptotic cell death (see below). If other, less frequently observed type of cell death was
these adaptive responses are inadequate to prevent described by Kerr  and called shrinkage necrosis.
depletion of cellular glutathione, then cell protein It is manifested by cytoplasmic shrinkage, larger
thiol groups become the remaining reducing agents, plasma membrane buds and nuclear chromatin
leading to loss of critical enzymatic function and cell condensation. Both types of cell death result in the
death. generation of necrotic debris that is engulfed by
HEAT SHOCK RESPONSE [10, 20]
The highly conserved cellular response to heat,
known as the heat shock response, is associated with The morphological changes described above are not
induction of heat shock proteins (HSP). The most restrictive. Nuclear condensation and mitochondrial
extensively studied are the HSP 70 family, which swelling, for example, have been observed in both
includes stress-induced HSP 72. Interestingly, HSP swelling and shrinkage types of cell death. There is
also are induced by a variety of other cellular insults, also clear evidence of significant overlap between
including ischaemia/reperfusion, oxidative stress, them at the molecular level (see below) [11, 14, 18].
exposure to heavy metals (e.g. arsenite) and in- Moreover, there is considerable imprecision in the
fection. For this reason, the heat shock response is literature regarding the terminology of cell death.
called simply the “stress response”, and HSP are Historically, necrosis has been the term used to refer
known as “stress proteins”. Control of HSP tran- to cell death in general. The term apoptosis (coined
scription is mediated by heat shock element ac- by Kerr, Wyllie, and Currie from the Greek word
tivation in the heat shock protein promoter region. meaning “dropping off ”, as in leaves dropping from
HSP aid in the proper folding of newly translated a tree ) is now used specifically to describe death
proteins, and are referred to as “molecular chaper- manifested by cell shrinkage. Apoptosis is respon-
ones”. Increased production of HSP is believed to sible for the ordered, normal cell death of intestinal
provide an adaptive advantage to stressed cells by epithelial cells and blood neutrophils.
increasing the fidelity of protein synthesis and aiding Programmed cell death, which refers to the ordered
refolding of damaged or denatured proteins. death of cells during embryogenesis, however, is also
characterized by cell shrinkage. Apoptosis and
programmed cell death are frequently, but in-
correctly, used interchangeably. The question of
ACUTE PHASE RESPONSE 
what to call non-apoptotic cell death has been
Although “acute phase response” can refer to the problematic. Necrosis, a leading contender, is also
response of any tissue to injury, its use is commonly used to refer to the process of removal of the cellular
restricted to the dramatic change in the pattern of remains of apoptosis (so-called “post-apoptotic
hepatocyte protein synthesis. The most important necrosis” ) [11, 32]. This degree of imprecision
stimuli are interleukin 1 (IL-1), tumour necrosis led Farber recently to remark that “there is no field
factor (TNF), and IL-6, products of macrophage/ of basic cell biology and cell pathology that is more
monocyte activation. The hepatocyte response to confusing and unintelligible than is the area of
these cytokines is an outpouring of plasma proteins apoptosis versus necrosis ” . Consequently, several
Mechanisms of cell injury and death
Figure 1 Electron micrographs of murine thymocytes from normal (A, sham laparotomy) and septic (B, caecal ligation and puncture) mice. Note the differences in the pattern and
distribution of chromatin. Compared with controls (A), thymocytes from septic animals (B) demonstrate nuclear condensation and cell shrinkage, consistent with apoptosis.
6 British Journal of Anaesthesia
Figure 2 Micrographs ( 360 magnification) of murine thymocytes from normal (A, sham laparotomy) and septic
(B, caecal ligation and puncture) mice photographed using the fluorescent TUNEL (terminal deoxynucleotidyl
transferase-mediated dUTP nick end-labelling) technique. Cells are permeabilized and treated with fluorescein
labelled dUTP and terminal deoxynucleotide transferase. Note that in the control mice, all nuclei appear dark (A).
In contrast, nuclei of septic mice (B) are fluorescent, consistent with DNA strand breaks and apoptosis.
authors have reviewed this subject in an attempt to Death by suicide refers to the process of cell death
standardize terminology and separate the process in which injury activates a highly conserved pro-
from the morphology of cell death [11, 14, 15, 18]. gramme of “suicide” genes that engineer death of
the cell. This process typically results morpho-
logically in apoptosis. Interest in cell death by
PROCESS OF CELL DEATH
suicide (apoptosis) has gained considerable momen-
From a pathological standpoint, it is important to tum recently as the disorders associated with apop-
distinguish between the process of cells dying per se totic cell death have expanded to include cancer,
from the changes that occur in cells after death [11, autoimmunity, inflammation, infection, AIDS,
18]. Majno and Joris  have characterized the neurodegeneration and myelodysplasia . The
process of cell death as (1) cell death by ischaemia, (2) molecular trigger responsible for induction of apop-
cell death by accident, or (3) cell death by suicide. tosis is incompletely defined, but appears to be
Accidental cell death is used to describe death as a present in all mammalian cells at all times and is
result of an external agent or toxin. Both cell death conserved across species. Not surprisingly, induction
secondary to ischaemia and accident are usually of apoptosis is tightly controlled. Several regulatory
characterized morphologically by cell swelling. In genes have been identified, including the Bcl-2
this type of cell death, interference with ATP family, p53 and Fas [21, 25]. The molecular ma-
generation secondary to hypoxia or toxin-induced chinery responsible (the “executioner”) includes a
increases in plasma membrane permeability produce cysteine protease (CPP-32 in mammals) that may
membrane failure. Reversible consequences of injury inactivate DNA repair enzymes [19, 23, 35]. The
include cytoplasmic blebbing, nuclear chromatin cellular changes characteristic of apoptosis include a
condensation, dilation of the endoplasmic reticulum, “flip” of phosphatidylserine from the inside to the
condensation then swelling of mitochondria and outside surface of the cell membrane , cyto-
activation of stress response genetic programmes plasmic shrinkage, little or no swelling of organelles
(described above). Continued injury results in inter- (mitochondria), membrane budding and fragmen-
ruptions of membrane integrity, dissolution of tation that include mitochondria or nuclear frag-
chromatin, and calcifications within mitochondria, ments, and chromatin condensation consisting of
all of which are signs of irreversible cell injury and DNA fragments. These membrane changes lead to
death. Majno and Joris  have suggested the term rapid recognition and cell elimination by neigh-
oncosis, from the Greek word meaning “swelling”, bouring phagocytes, which may make apoptotic cells
for this type of cell death. Necrosis is the mor- difficult to locate using conventional microscopic
phological term used for the cellular debris re- techniques. The techniques that are used to detect
maining after either oncosis or apoptosis . apoptosis include light and electron microscopy (fig.
Mechanisms of cell injury and death 7
Figure 3 Normal cultured porcine aortic endothelial cells (A, 360 magnification) stained with nuclear binding
dye Hoechst 33342. The nuclei are smooth and ovoid. Nuclei from cells challenged with endotoxin followed by
arsenite are compact and fragmented (“apoptotic bodies”, B, 360 magnification).
Table 2 Comparison of characteristics of oncosis and apoptosis
Oncosis—death by swelling Apoptosis—death by shrinkage
(1) Swelling of organelles and cytoplasm (1) Shrinkage of cytoplasm
(2) Small dense chromatin clumps which are not sharply (2) Large, dense, often crescent-shaped aggregates of
defined chromatin and nuclear fragmentation
(3) Swelling and eventual disintegration of organelles (e.g. (3) Organelles maintain structural integrity
mitochondria and endoplasmic reticulum)
(4) Early focal disruption of the plasma membrane with (4) Plasma membrane maintains integrity early; later stage
blebbing characterized by budding of membrane, frequently
(5) DNA agarose gel electrophoresis demonstrates smear (5) DNA agarose gel electrophoresis demonstrates “ladder”
pattern indicative of randomized breakdown pattern of discrete internucleosomal breakdown
(6) Cells rupture and contents are released causing (6) Cells are either ingested whole by phagocytic cells, or they
inflammatory response break into membrane-bound fragments (apoptotic bodies)
which then are ingested
1), end-labelling of DNA fragments (fig. 2), DNA injury can result in cell death by either mode.
agarose gel electrophoresis and binding of nuclear- Indeed, Kerr’s original description of apoptosis
specific dyes (fig. 3). (“shrinkage necrosis”) was based upon differ-
Despite the relatively clear distinction which can entiation of shrunken necrotic cells from the more
be made morphologically (oncosis versus apoptosis common swollen necrotic cells in ischaemic liver
is compared in table 2), examination at the tissue .
molecular level demonstrates considerable overlap.
For example, both oncosis and apoptosis have been
associated with increases in intracellular Ca2;, which Pathophysiology of organ dysfunction
activate a number of enzymes including phospho- Studies of cellular responses in vivo indicate that
lipases, endonucleases, proteases and protein kinases. injury activates the programmes of stress gene
In addition, the adaptive response to ischaemic, expression reviewed above. For example, the hepato-
inflammatory, oxidant and heat-induced stress in- cellular response to ischaemic injury in a porcine
volve changes in gene expression that are shared by model of MODS includes activation of the acute
both types of cell death. Further, the same type of phase, oxidative, and heat shock responses . In
8 British Journal of Anaesthesia
contrast, neighbouring hepatic endothelial cells in responses, and may participate in determining the
this model did not stain for heat shock gene fate of the cell.
expression (in situ hybridization), suggesting that Apoptosis may also contribute to failure of organs
there are cell-specific differences in the genetic in other settings, in particular, septic shock. Injection
response to similar injury. A subsequent investi- of Gram-negative or Gram-positive bacteria ,
gation conducted in vitro under more controlled endotoxin [34, 36], or caecal ligation and puncture
conditions explored the time-course and interaction  induced apoptosis in rodent thymocytes. Zhang
of these cellular stress responses. Human hepato- and colleagues  reported that mice injected with
blastoma (HepG2) cell lines were treated with lipopolysaccharides had apoptosis not only in the
inducers of the acute phase response (IL-1 and thymus, but also in the spleen, bone marrow and
TNF) and heat shock responses separately and in endothelial cells. Norimatsu and associates injected
combination. The results indicated that shock- swine intravenously with 0.5 mg kg91 Escherichia coli
induced expression of these responses were distinct, endotoxin and noted that cells in both thymus and
exclusive and prioritized . Specifically, the heat mesenteric lymph nodes underwent apoptosis .
shock stress response, the most primitive and highly In a recent report, Rogers and colleagues demon-
conserved of stress gene responses, was capable of strated apoptosis in the liver of mice infected with
extinguishing expression of other genetic pro- Listeria monocytogenes . Apoptosis has also been
grammes [5, 28]. These data suggest that hepatocyte reported in rabbit heart  and rat kidney  after
injury of sufficient severity to trigger the heat shock ischaemia/reperfusion injury. Collectively, these
response can prevent production of system-stabil- investigations suggest that apoptotic cell death may
izing acute phase proteins and other adaptive be a principal mechanism responsible for organ
responses. The liver’s response to such a systemic dysfunction and death as a consequence of shock-
injury, from the host’s perspective, would appear to induced injury.
be inadequate and indicative of failure. Hepatic
dysfunction in this model of MODS, thus, would
result from execution of primitive, protective genetic
Conclusions—from basic science to therapy
responses that give individual cells priority over the and prevention
organism. Cell injury occurs as a result of physical, chemical or
The sequence of stress gene programme activation biological insults or from vital substrate deficiency.
also appears to be important. In one in vitro model, These insults induce expression of adaptive stress
the endothelial cell response to arsenite, an inducer response gene programmes that include the
of the heat shock response, and to endotoxin, an ischaemic/hypoxic stress, oxidative stress, heat
inducer of the acute phase response, were studied. shock and acute phase responses. If the severity of
The results indicated that induction of the heat the injury exceeds the ability of the cell to adapt,
shock response could protect against endotoxin- then cell death occurs. The processes of cell death
induced cytotoxicity, but reversing the order— include cell death by ischaemia, accident or suicide.
endotoxin challenge followed by induction of the Morphologically, ischaemic and accidental deaths
heat shock response—increased cell death by apop- are usually manifested by cytoplasmic swelling
tosis . The effect of the heat shock response was (oncosis) and suicidal cell death by cytoplasmic
not the result of a detrimental effect of the heat shock shrinkage (apoptosis). However, this terminology
proteins themselves, but rather to the heat shock- lacks precision, as some “accidental” causes of cell
induced inhibition of further protein synthesis . death, such as heat, can also induce apoptosis .
An important hypothesis drawn from these data is The molecular machinery responsible for cell death
that two independent programmes of stress gene and the boundaries between apoptosis and other
expression can interact, depending on the sequence, modes of cell death remain to be determined .
to either protect the cell or trigger cell death by The sequence and interaction of the acute phase,
suicide (apoptosis). This may explain the absence of heat shock and oxidative stress responses appear to
endothelial cells expressing heat shock proteins after be a determinant of the fate of the cell. The pattern
shock in vivo (, discussed above), as endothelial of cell responses is injury- and tissue-dependent and
cell apoptosis may have resulted in their subsequent may help to explain differences in the course and
removal by phagocytes before in situ staining. Thus, nature of organ failure. Specifically, it appears that
endothelial cell dysfunction and death in this model stimuli sufficient to trigger the heat shock response
result from the adverse interaction of two usually can precipitate cell (and organ) failure by blocking
beneficial patterns of stress responses. The mech- initiation of other programmes of stress gene ex-
anism responsible may involve alterations in the pression (e.g. the system stabilizing acute phase
cellular redox potential and changes in nuclear response of hepatocytes). In other cells (e.g. the
transcription factor activity [unpublished observa- endothelium), the sequence of acute phase followed
tions]. For example, in the cultured endothelial cell by heat shock response may result directly in
model, reducing agents such as N-acetyl-L-cysteine apoptotic cell death. The function of shock-induced
and dithiothreitol block induction of endotoxin/ apoptosis is not known, but it may contribute to
arsenite-induced endothelial cell apoptosis, impli- control of immune cell proliferation in thymus,
cating ROS in the induction of apoptotic cell death spleen, bone marrow, and lymph nodes and modu-
[1, 2]. This raises the possibility that the adaptive lation of the inflammatory response.
response produced by oxidative stress could modu- MODS is the result of cellular responses to a
late the interaction of the acute phase and heat shock stimulus of either enormous magnitude or distri-
Mechanisms of cell injury and death 9
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