Am J Physiol Gastrointest Liver Physiol 286: G189–G196, 2004;
10.1152/ajpgi.00304.2003.
Invited Review
Apoptosis versus necrosis in acute pancreatitis
Madhav Bhatia
Department of Pharmacology, National University of Singapore, Singapore 117597
Submitted 13 July 2003; accepted in final form 8 September 2003
acute pancreatitis; pancreatic acinar cells
clinical condition, whose
incidence has been increasing over recent years (60, 75). In the
United States alone, ⬎300,000 patients are hospitalized annually with acute pancreatitis leading to 3,200 deaths. Acute
pancreatitis is a contributing factor in an additional 4,000
deaths annually. It also inflicts a heavy economic burden; the
direct cost in the United States alone is more than
$2,000,000,000 annually (75). In the majority of patients, the
condition is mild, but ⬃25% of patients suffer a severe attack,
and between 30 and 50% of these will die (8–10). Most cases
are secondary to biliary disease or excess alcohol consumption.
The events that regulate the severity of acute pancreatitis are,
for the most part, unknown. The exact mechanisms by which
diverse etiological factors induce an attack are still unclear, but
once the disease process is initiated, common inflammatory
and repair pathways are invoked. There is a local inflammatory
reaction at the site of injury; if marked, this leads to a systemic
inflammatory response syndrome, and it is this systemic response that is believed to be ultimately responsible for the
majority of the morbidity and mortality (8–10). Several recent
studies have, however, suggested that acinar cell response to
injury may, itself, be an important determinant of disease
severity. This review focuses on the contribution of pancreatic
acinar cell death as apoptosis vs. necrosis as a determinant of
ACUTE PANCREATITIS IS A COMMON
Address for reprint requests and other correspondence: M. Bhatia, Dept. of
Pharmacology, National Univ. of Singapore, Faculty of Medicine, Bldg MD2,
18 Medical Dr., Singapore 117597 (E-mail: [email protected]).
http://www.ajpgi.org
the severity of acute pancreatitis and our current understanding
of the mechanism of pancreatic acinar cell apoptosis.
Modes of Cell Death: Apoptosis and Necrosis
A distinction between the morphology of cells undergoing
physiological cell death and pathological cell death was observed more than 50 years ago (24). However, it was not until
the report by Kerr et al. (46) in 1972 that investigators adopted
the term “apoptosis” for a morphologically distinct form of cell
death. The perpetual flow of information in the past two
decades defining the effector and regulatory pathways that
result in apoptosis and necrosis (summarized in Fig. 1) has
raised further interest in the role of this mode of cell death in
various diseases and pathological conditions, including acute
pancreatitis.
Apoptosis is a highly coordinated process and is generally
believed to be mediated by active intrinsic mechanisms, although extrinsic factors can contribute (6, 16, 42, 70). Apoptosis is genetically controlled and is defined by cytoplasmic
and nuclear shrinkage, chromatin margination and fragmentation, and breakdown of the cell into multiple spherical bodies
that retain membrane integrity (14, 57). The factors contributing to necrosis are mostly extrinsic in nature, such as osmotic,
thermal, toxic, hypoxic-ischemic, and traumatic insults (14,
57). Necrosis is characterized by progressive loss of cytoplasmic membrane integrity, rapid influx of Na⫹, Ca2⫹, and water,
resulting in cytoplasmic swelling and nuclear pyknosis (4, 7,
94). The latter feature leads to cellular fragmentation and release
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Bhatia, Madhav. Apoptosis versus necrosis in acute pancreatitis. Am J Physiol
Gastrointest Liver Physiol 286: G189–G196, 2004; 10.1152/ajpgi.00304.2003.—
Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks, whereas others manifest a severe, highly morbid,
and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. It is generally believed that the earliest events
in acute pancreatitis occur within acinar cells and result in acinar cell injury. Other
processes, such as recruitment of inflammatory cells and generation of inflammatory mediators, are believed to occur subsequent to acinar cell injury, and these
“downstream” events are believed to influence the severity of the disease. Several
recently reported studies, however, have suggested that the acinar cell response to
injury may, itself, be an important determinant of disease severity. In these studies,
mild acute pancreatitis was found to be associated with extensive apoptotic acinar
cell death, whereas severe acute pancreatitis was found to involve extensive acinar
cell necrosis but very little acinar cell apoptosis. These observations led to the
hypothesis that apoptosis could be a favorable response to acinar cells and that
interventions that favor induction of apoptotic, as opposed to necrotic, acinar cell
death might reduce the severity of an attack of acute pancreatitis. Indeed, in an
experimental setting, the induction of pancreatic acinar cell apoptosis protects mice
against acute pancreatitis. Little is known about the mechanism of apoptosis in the
pancreatic acinar cell, although some early attempts have been made in that
direction. Also, clinical relevance of these experimental studies remains to be
investigated.
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of lysosomal and granular contents into the surrounding extracellular space, with subsequent inflammation (14, 57, 70, 77).
Apoptosis. Apoptosis is defined by distinct morphological
and biochemical changes mediated by a family of cysteine
aspartases (caspases), which are expressed as inactive zymogens and are proteolytically processed to an active state following an apoptotic stimulus. Early studies by Horvitz et al.
(38) first elucidated the existence of a genetically controlled
cell death program in which at least three gene products,
CED-3, CED-4, and CED-9, participate to cause selective
programmed cell death during Caernohabditis elegans development. Subsequent studies in other organisms revealed that
several cysteine proteases that share homology to CED-3 are
present in mammalian cells. Fourteen such cysteine proteases
have been identified so far, and they are identified as caspase-1
to caspase-14 (84, 85).
Caspases are the molecular executioners of apoptosis because they bring about most of the morphological and biochemical characteristics of apoptotic cell death. They are a
family of constitutively expressed proenzymes that undergo
proteolytic processing to generate its activated form (80, 84,
85). Functionally, the caspase family can be divided into two
major subfamilies. Caspases-1, -4, and -5 are involved in the
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maturation of cytokines such as interleukin-1␤ and interleukin-18 and promote proinflammatory functions. The other
members of the family function as part of the apoptotic
pathway, and they are subdivided into initiator (caspases-2, -8,
-9, and -10) and “executioner” or effector caspases (caspases-3,
-6, and -7) (80, 84). The “apical” or initiator caspases are
cleaved in response to apoptotic stimuli. The effector caspases
are activated through cleavage by initiator caspases (26). It has
recently been shown that the executioner caspases exist as
inactive dimers in their proforms and reside predominantly in
the cytosol. They are activated by cleavage at specific sites
between what will be the large and small subunits in the mature
enzymes, and it appears that this is the only way they can be
activated (13, 26). Unlike the executioner caspases, the initiator caspases cannot be activated by cleavage (such cleavage
occurs, but this does not cause the formation of an active site).
The initiator caspases exist in their proforms as monomers, and
it appears that they can only be activated by their enforced
dimerization. This activation occurs when adapter molecules
bind to protein-interaction domains near the NH2-terminal
prodomains of the initiator caspases. Such protein-interaction
domains are absent from the much shorter prodomains of the
executioner caspases (13, 26).
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Fig. 1. Overview of cell-death signaling pathways, apoptosis vs. necrosis. Components in red inhibit apoptosis, whereas those in
green promote apoptosis. Factors (in blue) such as mitochondrial permeability transition and reactive oxygen species (ROS) can
cause either apoptosis or necrosis, depending on other variables such as ATP supply. FLIP, FLICE-like inhibitory protein; IAP,
inhibitor of apoptosis proteins; Apaf, apoptotic protease activating factor; Cyt-c, cytochrome c; TNFR, TNF receptor; BH3, Bcl-2
homology-3.
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readily undergo apoptosis in response to receptor-mediated
apoptotic stimuli (43, 45).
The mechanism by which mitochondria release cytochrome
c during apoptosis is still controversial, and the mechanism of
release may differ depending on cell type, the cellular environment, and the apoptotic trigger (71). Cytochrome c is bound
to the inner mitochondrial membrane by its association with
the anionic phospholipid cardiolipin. Cardiolipin is unique to
mitochondria and is present predominantly, if not exclusively,
in the inner mitochondrial membrane. Evidence indicates that
the dissociation of cytochrome c from cardiolipin is a crucial
first step for cytochrome c release into the cytosol and for the
induction of apoptosis. The dissociation of cytochrome c is
facilitated by the peroxidation of cardiolipin, which results in a
decreased binding affinity for the hemoprotein. In addition,
Ca2⫹ can bind to cardiolipin in the inner mitochondrial membrane, leading to decreased lipid mobility, formation of cardiolipin-enriched domains, and protein aggregation. In turn, this
rearrangement leads to an increased production of reactive
oxygen species by the respiratory chain, which promotes the
oxidation of membrane phospholipids and proteins and, as a
result, an increase in membrane permeability (69). Recent
work has shown that cytochrome c is nitrosylated on its heme
iron during apoptosis (78). In vitro nitrosylation of cytochrome
c increases caspase-3 activation in cell lysates (78). Also, the
inhibition of intracellular cytochrome c nitrosylation is associated with a decrease in apoptosis, suggesting that cytochrome
c nitrosylation is a proapoptotic modification (78). A recent
paper (33) has also reported that mitochondrial aggregation is
an event upstream of cytochrome c release during apoptosis
and that changes in the localization of mitochondria participate
in the regulation of apoptosis through cytochrome c release.
Mitochondrial membrane permeabilization, which leads to
the release of proapoptotic mitochondrial proteins including
cytochrome c, is regulated by the opposing actions of pro- and
antiapoptotic Bcl-2 family members. The ever-growing mammalian Bcl-2 family of apoptotic regulators shares homology
with the C. elegans antiapoptotic molecule CED-9 (17, 50, 69).
On the basis of their structure and functional similarities, Bcl-2
family members are divided into the proapoptotic (Bax, Bak,
and Bok) and antiapoptotic (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and
A1) groups (43). A third class of death effector molecules
sharing homology only to the Bcl-2 homology-3 (BH3) domain
can activate proapoptotic Bcl-2 family members or inactivate
antiapoptotic members (39, 81). The family of BH3-only
proteins include Bin, Bid, Bad, Bik, BNIP3, Noxa, Puma, and
Hrk (39, 81). Recent studies have shown that micromolar to
submillimolar concentrations of selected BH3 peptides enable
the release of cytochrome c from either mitochondria or outer
mitochondrial membrane vesicles. This action, which is inhibited by Bcl-2 or Bcl-XL, is reduced when mutant peptides are
used (especially those mimicking apoptosis defects observed in
cells) (19, 71). In one study, BH3 peptide (0.1–60 ␮M)
released cytochrome c from mitochondria in the presence of
physiological concentrations of ions in a cell type-selective
manner, whereas a BH3 peptide with a single amino acid
substitution was ineffective. The release of cytochrome c by
BH3 peptide correlated with the presence of endogenous Bax
at the mitochondria and its integral membrane insertion. Cytochrome c release was accompanied by adenylate kinase
release, was not associated with mitochondrial swelling or
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During apoptosis, the effector caspases cleave numerous
proteins located in the cell membrane, nucleus, and cytoplasm,
and the significance of this proteolysis in the apoptotic process
is incompletely elucidated. The activation of caspase-activated
DNase to facilitate DNA degradation (62), cleavage of nuclear
lamins to facilitate nuclear shrinkage and budding (27, 72), and
activation of p21-activated kinase 2 to cause active blebbing in
apoptotic cells (74) are a few of the important functions
mediated by caspases in the apoptotic process.
Two separable pathways leading to caspase activation have
been characterized (26, 42, 92) (Fig. 1). The extrinsic pathway
is initiated by ligation of transmembrane death receptors
(CD95, TNF receptor, and TNF-related apoptosis-inducing
ligand receptor) to activate membrane-proximal (activator)
caspases, which, in turn, cleave and activate effector caspases.
This pathway can be regulated by c-FLICE-like inhibitory
protein, which inhibits upstream activator caspases, and inhibitor of apoptosis proteins (IAPs), which affect both activator
and effector caspases. The intrinsic pathway requires disruption of the mitochondrial membrane and the release of mitochondrial proteins including Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl), HtRA2 (high temperature requirement
protease A2), and cytochrome c. Cytochrome c functions with
apoptotic protease activating factor (Apaf)-1 to induce activation of caspase-9, thereby initiating the apoptotic caspase
cascade, whereas Smac/DIABLO and HtrA2 bind to and antagonize IAPs (26, 42, 64, 83).
The release of cytochrome c by mitochondria is almost a
universal feature found in response to various intracellular
stimuli, including DNA damage, glucocorticoids, oxidative
injury, and growth factor deprivation, although they may not
play a significant role in receptor-mediated apoptosis (3, 51).
Although classically considered the powerhouses of the cell, it
is now understood that mitochondria are also “gatekeepers”
that ultimately determine the fate of the cell. The mitochondrial
decision as to whether a cell lives or dies is complex, involving
protein-protein interactions, ionic changes, reactive oxygen
species, and other mechanisms that require further elucidation.
Once the death process is initiated, mitochondria undergo
conformational changes, resulting in the release of cytochrome
c, caspases, endonucleases, and other factors leading to the
onset and execution of apoptosis (3, 51). The activation of
caspase-9 is mediated by a macromolecular complex, the
apoptosome, that is formed in response to a cellular commitment to apoptotic death. Formation of the apoptosome is
initiated on release of certain mitochondrial proteins, such as
cytochrome c, from the mitochondrial intermembrane space.
Released cytochrome c binds to monomers of Apaf-1 in the
cytosol, inducing a conformational change that enables stable
association with (deoxy)adenosine triphosphate. Apaf-1 monomers then assemble into the heptameric apoptosome, which, in
turn, binds to procaspase-9. Once recruited, procaspase-9 acquires catalytic competency, is proteolytically cleaved, and
activates the effector caspases, a process that culminates in
apoptotic cell death (64).
Cytochrome c-deficient embryonic stem cells have been
shown to be resistant to ultraviolet light and staurosporineinduced apoptosis and partially resistant to apoptotic stimuli
from serum deprivation. However, cytochrome c-deficient cells
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the cell to extrinsic death ligands. Although the extrinsic and
intrinsic signals are considered to take two distinct pathways to
execute cell death, receptor-initiated cell death can involve the
mitochondrial pathway through the BH3-only protein Bid. In
hepatocytes, for example, activation of caspase-8 by Fas leads
to cleavage of Bid to its active form t-Bid. t-Bid translocates to
mitochondria and associates with Bcl-2-like proteins to disrupt
mitochondrial integrity (93). It should be noted, however, that
the cross-talk between the two pathways is minimal under most
conditions. A recent report (53) indicates that cytotoxic stressinduced mitochondrial permeability and release of various
apoptogenic factors is mediated by caspase-2 in human fibroblasts transfected with adenoviral oncogene E1A. Small interfering RNA-mediated silencing of caspase-2 expression prevented cisplatin, etoposide, and ultraviolet light-induced apoptosis in these cells. It is argued that in this setting, mitochondria
are amplifiers of caspase activity rather than initiators of
caspase activation (53).
Necrosis. Necrosis is the prominent mode of cell death that
occurs in various neurodegenerative conditions and as a consequence to ischemic injury in various organs including the
brain and heart. Although progress has been made in the last
decade in understanding the molecular mechanisms of apoptosis, the biochemical pathways leading to necrotic cell death
remain poorly understood (58). Necrosis has long been thought
to be a “passive” process occurring as a consequence of acute
ATP depletion. Several ATP-dependent ion channels become
ineffective, leading to ion dyshomeostasis, disruption of the
actin cytoskeleton, cell swelling, membrane blebbing, and
eventual collapse of the cell (15, 67, 68). Recent reports
suggest that in addition to the passive mechanisms, “active”
mechanisms, such as Na⫹ overloading, Ca2⫹ accumulation,
and changes in mitochondrial permeability, may also participate in the necrotic process (Fig. 2) (5, 55, 56, 70).
In ischemic or hypoxic injury, energy depletion occurs by
defective ATP production combined with the rapid consumption of ATP by ion pumps and through hydrolysis and leakage.
The necrotic volume increase associated with necrotic cell
death is initiated by an influx of Na⫹ and release of ATP due
to membrane leakage (70). The increased Na⫹ level in the
cytosol activates Na⫹-K⫹-ATPase, resulting in dissipation of
ATP. In the beginning stages of the injury, a simultaneous
efflux of K⫹ maintains ion homeostasis. Severe depletion of
Fig. 2. Sequence of biochemical events that may lead to
necrotic cell death based on current information in the
literature.
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substantial loss of electrical potential across the inner membrane, and was unaffected by inhibitors of the permeability
transition pore. Cytochrome c release was, however, inhibited
by Bcl-2. Although energy-coupled respiration was inhibited
after the release of cytochrome c, mitochondria maintained
membrane potential in the presence of ATP due to the reversal
of the ATP synthase (71).
Pro- and antiapoptotic members of the Bcl-2 family can
homodimerize or heterodimerize, thus forming a large number
of combinations within a cell. Heterodimerization between a
proapoptotic member and an antiapoptotic member can nullify
the functions of each (73). The outcome of a cell that received
an apoptotic stimulus is thought to depend partly on the ratio of
the death promoter to the death suppressor (1, 2). The precise
mechanisms by which the Bcl-2 family members modulate
apoptosis are still not completely elucidated, but their key
functions revolve around the release of proapoptotic factors,
especially cytochrome c from the mitochondrial intermembrane compartment into the cytosol (66, 82). Multidomain
proapoptotic Bcl-2 proteins (e.g., Bak and Bax) can be activated directly following interaction with the BH3-only Bcl-2
protein Bid. Alternatively, binding of other BH3-only proteins
(e.g., Noxa, Puma, Bad, and Bim) to antiapoptotic Bcl-2
proteins (e.g., Bcl-2 and Bcl-XL) results in activation of Bax
and Bak (1, 39). Whether Bcl-2 proteins control mitochondrial
membrane permeability by directly forming pores in the outer
membrane and/or by regulating the opening and closing of the
permeability transition pore remains the topic of much debate
(59). The net effect, however, is the regulated release of
proapoptotic factors from the mitochondria, induction of
downstream caspases, and potential loss of mitochondrial function. According to a recent report (95), Bid may activate
mitochondria by two mechanisms; one is related to permeability transition, and the other is related to Bak oligomerization.
Bid can further affect mitochondria potentials by indirectly
regulating caspase activity (95).
There is considerable cross-talk between the extrinsic and
intrinsic pathways. For example, caspase-8 can proteolytically
activate Bid, which can then facilitate cytochrome c release
(26, 42). This apparently amplifies the apoptotic signal following death receptor activation, and different cell types may be
more reliant on this amplification pathway than others (21).
Conversely, activators of the intrinsic pathway can sensitize
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Apoptosis and Necrosis in Acute Pancreatitis
Clinical as well as experimental acute pancreatitis is characterized by progressive cell death, the mechanisms of which
remain poorly understood. Necrosis has classically been considered the major form of cell death in acute pancreatitis (48,
63), whereas apoptosis was suggested to mediate atrophy in the
organ (88, 89). However, careful biochemical and morphological examination of experimental models of acute pancreatitis
has shown that severe acute pancreatitis (e.g., that induced by
pancreatic duct ligation in the opossum, by choline-deficient
and ethionine-supplemented diet in the mouse, and by caerulein hyperstimulation in the mouse) is associated primarily
with necrosis but little apoptosis, whereas mild acute pancreatitis (e.g., that induced by pancreatic duct ligation and by
caerulein hyperstimulation in the rat) is associated primarily
with apoptotic cell death and little necrosis (30, 44).
The mechanisms of acinar cell apoptosis and necrosis in
acute pancreatitis remain poorly understood, although several
recent studies have contributed significantly in this direction
(Fig. 3). An early study in this direction using the caeruleinhyperstimulation model of acute pancreatitis showed that caerulein stimulates pancreatic production of platelet activating
factor (PAF). PAF mediates both apoptosis and neutrophil
chemotaxis in the pancreas. Neutrophils in turn may convert
acinar cells undergoing apoptosis into necrotic cells (76). A
subsequent study by the same group has shown the evidence of
the death receptor (TNF-␣ receptor) on pancreatic acinar cells.
In this study, it was shown that pancreatic acinar cells produce,
release, and respond (by apoptosis) to TNF-␣ (29). In a later
study (31), these authors showed a potential role of NF-␬B in
cell death, possibly by activation of TNF-␣ transcription.
Another study (79) has shown that duct ligation-induced apoptosis of the pancreatic acinar cells is p53 dependent. A recent
report (28) has shown the role of the intrinsic pathway in acinar
cell apoptosis. The results show that CCK stimulates death
signaling pathways in rat pancreatic acinar cells, including
caspase activation, cytochrome c release, and mitochondrial
depolarization, leading to apoptosis. The mitochondrial dysfunction is mediated by upstream caspase(s). CCK causes
mitochondrial alterations through both permeability transition
pore (PTP)-dependent (cytochrome c release) and -independent
(mitochondrial depolarization) mechanisms. In addition to apoptosis, caspases also regulate other processes in the pancreatic
acinar cell that play key roles in pancreatitis; in particular,
caspases negatively regulate necrosis and intra-acinar cell activation of trypsin (28). Caspase-mediated protection against
necrosis and trypsin activation can explain the inverse correlation between the extent of apoptosis on the one hand and
necrosis and the severity of the disease on the other hand
observed in experimental models of pancreatitis. Indeed, these
signaling mechanisms may play an important role in acinar cell
injury and death in pancreatitis.
In addition to CCK, other inducers of pancreatic acinar cell
apoptosis have been used to investigate cell death in relation to
acute pancreatitis. Examples of these compounds are menadione and crambene (1-cyano-2-hydroxy-3-butene). Menadione
is a quinone that is metabolized by flavoprotein reductase to
semiquinone, which can be oxidized back to quinone in the
presence of molecular oxygen. In this redox cycle the superoxide anion radical, hydrogen peroxide, and other reactive
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ATP leads to failure of the pump-leak balance mechanism,
leading to an influx of Na⫹ and water that results in swelling
and collapse of the cell. Thus the overload of Na⫹ concomitant
with severe ATP depletion seems to be the major determinant
of a necrotic outcome (15).
Cytosolic Ca2⫹ plays a role in linking ATP depletion and
necrosis in some cell types (4), but several other cell types
including hepatocytes and renal tubules can undergo necrotic
cell death in its absence (40). The reactive oxygen speciesmediated necrotic volume increase and Na⫹ influx are suggested to be initiated by the binding of the free radicals to ion
channels including nonselective Ca2⫹ channels (5, 36, 37, 49).
The increased levels of Na⫹ activate Na⫹-K⫹-ATPase and
consume ATP, which, in turn, activates nonselective Ca2⫹
channels, resulting in massive cytosolic Ca2⫹ accumulation.
High levels of Ca2⫹ can participate in ATP depletion by
activating Ca2⫹-ATPase and mitochondrial depolarization.
The increased levels of Ca2⫹ activate endonucleases to degrade
DNA and activate cellular proteases such as calpain to degrade
several structural and signaling proteins (91).
Mitochondria participate in necrotic as well as apoptotic cell
death by opening the mitochondrial permeability transition
pore. Indeed, despite the presumed fundamental difference
between apoptosis and necrosis, growing evidence supports an
essential role of the mitochondrial permeability transition
(MPT) in the release of cytochrome c and initiation of apoptosis in many models, including hepatocytes exposed to TNF-␣
and Fas ligation (35). Several second messengers and proapoptotic proteins including Bcl-2 family members can induce the
permeabilization of the MPT pore (18, 52). BNIP3 is a member
of the Bcl-2 family that is loosely associated with mitochondria
in the normal state but gets fully integrated into the mitochondrial outer membrane after a death stimulus. BNIP3-transfected cells are found to undergo cell death independently of
Apaf-1, caspase activation, cytochrome c release, and nuclear
translocation of apoptosis-inducing factor. The cells exhibited
morphology typical of the necrotic form of cell death with
plasma membrane permeability, mitochondrial damage, extensive cytoplasmic vacuolation, and mitochondrial autophagy. It
is proposed that BNIP3 can mediate necrosislike cell death
through mitochondrial permeability transition pore opening
and mitochondrial dysfunction (87). The expression of BNIP3
is shown to be induced in several cell lines in response to
hypoxic injury. Overexpression of the hypoxia-inducible factor-1␣ has also been shown to induce the expression of BNIP3,
resulting in a necrotic form of cell death (32). Moreover,
although ischemia-reperfusion is usually associated with necrotic cell death (86), more recent studies have shown that
apoptosis also occurs after ischemia-reperfusion in cells from
liver and other organs (22, 25). In a recent study (47), it has
been shown that the balance between ATP depletion after the
MPT and ATP generation by glycolysis operates a switch
determining whether the fate of the cell would be necrosis or
apoptosis after simulated ischemia-reperfusion-induced onset
of the MPT. These findings also highlight the importance of
apoptotic commitment and of common pathways, such as
MPT, which initiate events that culminate in either apoptosis or
necrosis, depending on other variables, such as ATP supply
(47). Thus death/toxic signals, through common mechanisms,
can cause both apoptosis and necrosis, depending on variables
such as ATP supply.
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Fig. 3. Factors that determine the cellular fate of pancreatic
acinar cell. This figure summarizes the information currently
available in the literature. More research is needed to characterize the pathways responsible for acinar cell death in the form
of necrotic and apoptotic cell death.
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apoptosis by an extract of Artemisia asiatica (DA-9601) was
beneficial in caerulein-induced pancreatitis in rats (34).
Transition to the Clinic
Many of today’s medical illnesses can be attributed directly
or indirectly to problems with cell death. Disorders in which
defective regulation of cell death contributes to disease pathogenesis or progression can involve either cell accumulation, in
which cell eradication or cell turnover is impaired, or cell loss,
in which the cell-death program is inappropriately triggered.
Identification of the genes and gene products that are responsible for cell death, together with emerging information about
the mechanisms of action and structures of regulatory and
effector proteins, has laid a foundation for the discovery of
therapies for several clinical conditions (73).
Both apoptotic and necrotic forms of cell death are seen in
clinical as well as experimental acute pancreatitis. The mechanisms of pancreatic acinar cell death, apoptosis and necrosis,
in acute pancreatitis are just beginning to be identified. The
vast array of molecules involved in both the apoptotic and
necrotic cell death pathways offers several potential targets for
therapeutic intervention. The extent of pancreatic acinar cell
apoptosis has been shown to be inversely related to the severity
of the disease, suggesting that apoptosis is a teleologically
beneficial form of cell death in acute pancreatitis. Indeed, in
animal models, induction of apoptosis has been found to have
a protective action against acute pancreatitis. It is, therefore,
reasonable to speculate that selective induction of pancreatic
acinar cell apoptosis may be of value in clinical acute pancreatitis. As a first step, the effect of prophylactic induction of
apoptosis in individuals with a high risk of pancreatitis (such as
those undergoing endoscopic retrograde cholangiopancreatography) should be investigated. More basic research into the
mechanisms of apoptosis of pancreatic acinar cells and how it
benefits against acute pancreatitis is, however, needed before one
could take these studies into the clinic. Active research in this
direction will facilitate a transition of our knowledge of pancreatic
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oxygen species are generated (61). Menadione can cause elevations in the cytosolic Ca2⫹ concentration contributing to cell
death (23). In a recent study, menadione has been shown to
evoke repetitive cytosolic Ca2⫹ spikes, partial mitochondrial
depolarization, cytochrome c release, and apoptosis of pancreatic acinar cells in vitro (23). Crambene is a stable plant nitrile
found in many cruciferous vegetables. Crambene is a potent
inducer of “phase II” detoxification enzymes, including certain
glutathione S-transferases and quinone reductase, which are
important enzymes associated with conjugation and elimination of reactive chemical intermediates and carcinogens (65,
90). Also, it has been shown to cause cell cycle arrest of the
Hep G2 cells or colonic adenocarcinoma cells in G2/M phase
(41). We have earlier shown that on intravenous administration, crambene induces apoptosis of the pancreatic acinar cells
(11, 12). The mechanism of induction of pancreatic acinar cell
apoptosis by crambene is not yet clear. However, induction of
pancreatic acinar cell apoptosis with crambene protects mice
against acute pancreatitis induced by caerulein (11, 12). This is
despite the fact that crambene does not alter the interaction of
CCK to its receptor on pancreatic acinar cells (12). The
maximal protective effect of crambene against acute pancreatitis is observed when the pancreatic acinar cells have become
committed to apoptosis (11, 12). Studies are in progress to
investigate the mechanism of induction of pancreatic acinar
cell apoptosis by crambene. A possible role of the gap junction
communication (GJC) and connexin gene Cx32 in crambeneinduced apoptosis has been suggested by a recent study (20).
Mice deficient in Cx32 gene were found to be resistant to
apoptosis induced by crambene and were more susceptible to
acute pancreatitis than their wild-type counterparts (20). Although the role of GJC in apoptosis is still unclear, the data in
this study (20) indicate that defective GJC in Cx32-deficient
mice prevented acinar cell apoptosis at a step upstream of
caspase-3 activation. A protective effect of induction of pancreatic acinar cells against acute pancreatitis was substantiated
in another study in which it was shown that induction of
Invited Review
APOPTOSIS VERSUS NECROSIS IN ACUTE PANCREATITIS
acinar cell death in the form of necrosis vs. apoptosis from bench
to bedside.
GRANTS
I acknowledge grant support from the National Medical Research Council,
the Biomedical Research Council, and the Academic Research Fund.
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