Gastroenterology

Gastroenterology

Volume 125, Issue 4, October 2003, Pages 1246-1257
Gastroenterology

Special reports and reviews
Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury

https://doi.org/10.1016/S0016-5085(03)01209-5Get rights and content

Abstract

Warm and cold hepatic ischemia followed by reperfusion leads to necrotic cell death (oncosis), which often occurs within minutes of reperfusion. Recent studies also suggest a large component of apoptosis after ischemia/reperfusion. Here, we review the mechanisms underlying adenosine triphosphate depletion—dependent oncotic necrosis and caspase-dependent apoptosis, with emphasis on shared features and pathways. Although apoptosis causes internucleosomal DNA degradation that can be detected by terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling and related assays, DNA degradation also occurs after oncotic necrosis and leads to pervasive terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling staining far in excess of that for apoptosis. Similarly, although apoptosis can occur in a physiological setting without inflammation, in pathophysiological settings apoptosis frequently induces inflammation because of the onset of secondary necrosis and stimulation of cytokine and chemokine formation. In liver, the mitochondrial permeability transition represents a shared pathway that leads to both oncotic necrosis and apoptosis. When the mitochondrial permeability transition causes severe adenosine triphosphate depletion, plasma membrane failure and necrosis ensue. If adenosine triphosphate is preserved, at least in part, cytochrome c release after the mitochondrial permeability transition activates caspase-dependent apoptosis. Mitochondrial permeability transition-dependent cell death illustrates the concept of necrapoptosis, whereby common pathways lead to both necrosis and apoptosis. In conclusion, oncotic necrosis and apoptosis can share features and mechanisms, which sometimes makes discrimination between the 2 forms of cell death difficult. However, elucidation of critical cell death pathways under clinically relevant conditions will show potentially important therapeutic intervention strategies in hepatic ischemia/reperfusion injury.

Section snippets

Oncotic necrosis (oncosis) in ischemia/reperfusion injury

The primary stress in ischemia to liver and most other solid tissues is loss of mitochondrial adenosine triphosphate (ATP) production. The resulting ATP depletion leads to cellular swelling, rounding and swelling of mitochondria, dilatation of the endoplasmic reticulum, and formation of plasma membrane protrusions called blebs.26, 27 Blebs are a consequence of ATP depletion and likely represent a response to disrupted cellular volume control and cytoskeletal disturbances. After briefer periods

Morphological features of apoptosis

The original description of apoptotic cell death was based on morphology.32 The classic morphological features of apoptosis include cellular shrinkage, nuclear condensation, chromatin margination, and fragmentation of both the nucleus and cytoplasm into apoptotic bodies, which are phagocytosed and degraded by phagocytes, neighboring cells, or both (Figure 1). The original definition of apoptosis describes the cytoplasmic organelles of apoptotic cells as remaining normal in appearance, in

Signaling mechanisms in hepatocellular apoptosis

We first briefly review some basic background information on apoptotic signaling pathways in hepatocytes to place into context the discussion of whether postischemic cell death is caused by apoptosis. During the last decade, dramatic progress has been made in the elucidation of the intracellular signaling mechanisms of apoptosis.35, 36, 37, 38, 39 A variety of mediators, including tumor necrosis factor (TNF)-α, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),

Assessment of apoptotic cell death

As a result of an increasing understanding of the mechanisms and pathways to apoptotic cell death, more and more biochemical and immunologic assays are being developed and used to characterize apoptosis (Table 1). Today, apoptosis can be monitored in vitro and in vivo by such diverse techniques as enzyme assays for activated caspases, Western blot analyses for caspase processing, annexin V labeling for phosphatidyl serine externalization, cleavage of poly (adenosine diphosphate—ribose)

Apoptotic cell death during hepatic ischemia/reperfusion

The first report of apoptotic cell death during hepatic ischemia/reperfusion appeared in 1996.24 Similar reports of postischemic apoptosis have appeared for heart, brain, and other organs.23, 62, 63 In liver after 60 minutes of warm ischemia, the number of apoptotic hepatocytes evaluated by nuclear morphology increases during the first 24 hours of reperfusion.24 Using the TUNEL assay, another study identified apoptotic hepatocytes in human allografts after transplantation.64 Subsequent studies

Necrapoptosis

Part of the confusion concerning the roles of apoptosis and necrosis in ischemia/reperfusion and other forms of hepatic injury arises from the assumption that apoptotic and necrotic mechanisms are distinct and separate when, in fact, these mechanisms can be shared. In particular, the MPT plays an important role in oncotic necrosis, as well as in apoptosis. In ischemia, anaerobic glycolysis and ATP hydrolysis during ischemia rapidly decrease tissue pH, which protects strongly against necrotic

Conclusions

In liver, oncotic necrosis and apoptosis share features and mechanisms. DNA degradation after necrosis causes TUNEL labeling, which may be incorrectly interpreted as apoptotic cell death. During apoptosis in pathophysiological settings, inflammatory responses and enzyme release occur that resemble a necrotic process. Frequently, oncotic necrosis and apoptosis coexist after toxic, hypoxic, and inflammatory liver injury. The coexistence of the 2 patterns of cell death likely reflects shared

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    Supported in part by National Institutes of Health grants ES06091 and AA12916 (to H.J.) and DK37034, DK59340, and AG13637 (to J.J.L.).

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