1. health and fitness
2. disease

C 2004)
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004), pp. 1359–1377 (°
REVIEW
Ischemia–Reperfusion Injury of the Intestine
and Protective Strategies Against Injury
ISMAIL HAMEED MALLICK, MRCS, MSc,* WENXUAN YANG, MD, PhD,* MARC C. WINSLET, MS, FRCS,*†
and ALEXANDER M. SEIFALIAN, MSc, PhD*
Ischemia–reperfusion injury of the intestine is a significant problem in abdominal aortic aneurysm
surgery, small bowel transplantation, cardiopulmonary bypass, strangulated hernias, and neonatal
necrotizing enterocolitis. It can also occur as a consequence of collapse of systemic circulation,
as in hypovolemic and septic shock. It is associated with a high morbidity and mortality. This
article is a comprehensive review of the current status of the molecular biology and the strategies to
prevent ischemia–reperfusion injury of the intestine. Various treatment modalities have successfully
been applied to attenuate reperfusion injury in animal models of reperfusion injury of the intestine.
Ischemic preconditioning has been found to be the most promising strategy against reperfusion injury
during the last few years, appearing to increase the tolerance of the intestine to reperfusion injury.
Although ischemic preconditioning has been shown to be beneficial in the human heart and the liver,
prospective controlled studies in humans involving ischemic preconditioning of the intestine are
lacking. Research focused on the application of novel drugs that can mimic the effects of ischemic
preconditioning to manipulate the cellular events during reperfusion injury of the intestine is required.
KEY WORDS: intestine; ischemia; intestinal transplantation; reperfusion injury.
Ischemia–reperfusion injury (IRI) of the intestine is an
important factor associated with a high morbidity and
mortality in both surgical and trauma patients (1). It is
of importance in situations such as the interruption of
blood flow to the gut as in abdominal aortic aneurysm
surgery, cardiopulmonary bypass, strangulated hernias,
neonatal necrotizing enterocolitis, and intestinal transplantation (2). IRI of the intestine also occurs in septic
and hypovolemic shock (3, 4).
Interruption of blood supply results in ischemic injury
which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissue
initiates a cascade of events that may lead to additional
Manuscript received April 1, 2004; accepted June 13, 2004.
From the *GI & Hepatobiliary Research Unit, University Department
of Surgery, Royal Free and University College Medical School, University College London, London NW3 2PF, UK., and †Department of Surgery, Royal Free Hampstead NHS Trust Hospital, London NW3 2QG, UK.
Address for reprint requests: A.M. Seifalian, PhD, University Department of Surgery, Royal Free and University College Medical School,
University College London, Rowland Hill Street, London NW3 2PF,
UK; [email protected].
cell injury known as reperfusion injury. This reperfusion
damage frequently exceeds the original ischemic insult
(5). On restoration of the blood supply, the molecular and
biochemical changes that occur during ischemia predispose to free radical-mediated damage. The reduction of
blood supply results in damage to the intestinal mucosa.
Among the internal organs, the intestine is probably the
most sensitive to IRI (6, 7). The intestine is composed of
labile cells that are easily injured by episodes of ischemia.
Subsequent reperfusion of the intestine results in further
damage to the mucosa (8). It has been shown that the
enterocytes that are located at the tips of the villi are more
sensitive to the effect of ischemia. Earlier studies attributed
this increased sensitivity of the enterocyte at the tips of the
villi to the location which is at the end of the distribution of
a central arteriole which can lead to lower oxygen tension
compared to the crypts (8, 9). However, a recent study in a
rat model demonstrated that the sensitivity of an enterocyte
is dependent on its state of differentiation (10).
There is substantial evidence that the mucosa of the
intestine becomes the site for the production of various
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
C 2004 Springer Science+Business Media, Inc.
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acute-phase proteins (11, 12), gut hormones (13), and
cytokines (14, 15). These not only influence the intestine
but also may affect the function and integrity of distant organs. The initial site of abnormality in ischemia has been
emphasized on the cellular mitochondria, which is particularly important in producing adenosine triphosphate
(ATP) for organ recovery (16). The damage, however,
is dramatically magnified by a large number of events,
such as oxygen free radical formation, release of iron
storage, damage of the microvasculature of IR organs,
inflammatory cytokines, complement activation, and neutrophil infiltration at the site of injury (17). The enterocyte, in particular, has been shown to produce increased
amounts of cytokines during sepsis, endotoxemia, hemorrhagic shock, and trauma (18) .
SEARCH METHODS
All studies were identified by PubMed, ISIS, and
CAS searches with the following key words: intestine, ischemia, intestinal transplantation, reperfusion injury, xanthine oxidase, nitric oxide, endothelins, nuclear
factor- kappa B, neutrophils, cytokines, and preconditioning. All references were reviewed to retrieve additional
articles.
CONSEQUENCES OF INTESTINAL IRI
Alteration of Absorptive Function of the Intestine
Several studies have demonstrated an alteration of absorptive function of the intestine following IRI of the
intestine (19–21) . This could lead to deficient absorption of nutrients. In severe cases such as infarction of the
bowel, short-bowel syndrome can occur (22) . Sileri et
al. demonstrated in a rat model that IRI of the intestine
causes both acute and chronic alterations of intestinal absorptive function, which was associated with significant
mortality (23).
Bacterial Translocation
Bacterial translocation is the passage of viable bacteria from the gastrointestinal tract through the epithelial
mucosa to extraintestinal sites such as mesenteric lymph
nodes, liver, and spleen (24). Subsequently the bacteria can
disseminate throughout the body, producing sepsis, shock,
or multiple organ failure (MOF). Bacterial translocation
has been reported to occur in 44% of pediatric patients undergoing small bowel transplantation (25). The increase
in intestinal hyperpermeabilty occurring in IRI of the intestine is one of the factors causing bacterial translocation
(26–28). The other factors are overgrowth of bacteria in the
small intestine and differences in host immune defenses
(29).
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Injury to Distant Organs
IRI to the intestine results in production of molecules
such as hydrogen peroxide, superoxide, and inflammatory cytokines that may harm distant organs. This leads to
the development of systemic inflammatory response syndrome (SIRS), which can progress to MOF (30). Intestinal IRI also causes pulmonary infiltration of neutrophils,
which contributes to the development of acute respiratory
distress syndrome (ARDS) (31, 32). Hence, the gut has
been referred to as “the motor of MOF” (33).
MEDIATORS INVOLVED IN IRI
OF THE INTESTINE
Xanthine Oxidase and Oxygen Free Radicals
Xanthine oxidase (XO) is a highly versatile enzyme
which plays an important role in the catabolism of purines.
The intestine is the richest initial source of free radicals
that can cause further tissue damage (34). In mammals
xanthine dehydrogenase (XDH) can be converted to XO
either reversibly or irreversibly (35). During the ischemic
period, cellular ATP is catabolized to yield hypoxanthine
(36). The hypoxic stress also triggers the conversion of
XDH to the oxygen radical-producing XO. ATP depletion
results in loss of ATP-dependent ion channel regulation,
producing passive ion shifts across cell membranes: K+
and Mg2+ diffuse out, but Na+ , Ca2+ , and H2 O diffuse in,
causing cell swelling. Increased cellular Ca2+ is harmful,
one of its important consequences being the activation of a
calcium-dependent protease, which cleaves XDH to XO.
During reperfusion, molecular oxygen is reintroduced into
the tissue, where it reacts with hypoxanthine and XO to
produce a burst of oxygen free radicals—superoxide anion
(O−
2 ) and hydrogen peroxide (H2 O2 ) (37) (Figure 1).
Under physiological conditions, the damaging effects of
O−
2 are prevented by superoxide dismutase (SOD), which
converts O−
2 to H2 O2 (37). However, during reperfusion of
ischemic tissues, these natural defenses may be overcome.
Fig 1. Mechanism of xanthine oxidase-mediated free radical injury.
Modified from Granger et al. (6).
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
ISCHEMIA–REPERFUSION INJURY OF THE INTESTINE
O−
2 itself is a relatively low-energy radical, but it is responsible for production of the highly reactive and damaging
hydroxyl radical (OH• ). Typically OH• causes biological
damage by stimulating the free chain reaction known as
lipid peroxidation, in which OH• attacks the fatty acid
side chains of the membrane phospholipids and causes
organelle and cell disruption (38).
Endothelins (ETs)
ETs are potent peptide vasoconstictors derived from
the vascular endothelium (39). Among the three active
isoforms (ET-1, ET-2, and ET-3) , ET-1 is the most powerful endogenous vasoconstrictor substance known to date
(40, 41). The vasoconstrictive effects of ET-1 are predominantly mediated via ET-A receptors present on vascular
smooth muscle cells. The ET-B receptors mediate vasoconstriction (ET-B2 ) and vasodilatation (ET-B1 ) (42). ET
receptor antagonists provide significant protection against
IRI of the intestine (43–47). The major beneficial effects
of ET inhibition include a decrease in mucosal lesions, an
increase in blood flow, an increase in mucosal ATP, and a
decrease in leukocyte adhesion (48).
Heat Shock Proteins
Heat shock proteins (HSPs) are intracellular stress proteins that have been shown to accumulate after ischemia
(49).The concept of sublethal whole-body hyperthermia
conferring tolerance to ischemia and endotoxin exposure
is known as hyperthermic preconditioning and has been
associated with HSP accumulation (50, 51). In the rat intestine, tolerance to ischemic injury has been associated
with the production of various inducible HSPs: HSP-70
(52), HSP-72 (53), and HSP-73 (54). The exact mechanism whereby HSPs confer protection of the intestine
against IRI is not known. Stojadinovic and coworkers
showed that a probable mechanism involves the inhibition
of leukotriene-B4 production and subsequent prevention
of neutrophilic activation and chemotaxis (53).
Polymorphonuclear Neutrophils (PMNs)
There is a growing body of evidence that incriminates
PMNs in the pathophysiology of IRI (55–58). In a model of
small bowel transplantation, Massberg et al. showed that
the manifestation of IRI is primarily due to leukocyte–
endothelial cell interactions in the submucosal venules of
the transplanted intestine (59).
PMN-depleted blood in the reperfusate has been shown
to ameliorate IRI in the human small bowel (60). Intravital microscopic studies of tissues exposed to IRI reveal an
acute inflammatory response that is characterized by increased adhesion and emigration of PMNs in postcapillary
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
venules and enhanced protein efflux (61). Indirectly, the
assessment of neutrophil migration into the small intestine is performed by measuring myeloperoxidase (MPO)
activity in the small intestine (62).
The emigration of PMNs from the postcapillary venules
to areas of inflammation is a complex and highly coordinated three-step process, namely, rolling, adhesion, and
extravasation (63) (Figure 2). First, the leukocytes roll
along the endothelial cell surface. This initial reaction is
mediated by the upregulation of adhesion molecules such
as P-selectin and E-selectin on the surface of the endothelium and their interaction with L-selectin, which is expressed constitutively by the leukocytes. This weak leukocyte tethering to the endothelium brings the leukocyte
into close proximity to chemoattractants (e.g., leukotriene
B4 , C5a, and PAF) and chemokines (64). Chemokines
bind to receptors on leukocytes to activate β2 integrins
(CD11a, CD11b, and CD 11c/CD18). The activated integrins bind to the adhesion molecules such as intercellular adhesion molecule (ICAM-1) and vascular cellular
adhesion molecule (VCAM-1) expressed on endothelial
cells. This interaction strengthens the adhesion between
the leukocyte and the endothelial cells, thereby allowing
extravasation of the leukocyte out of the circulation and
into the interstitium (65). Riaz et al. showed that following
IRI of the mouse intestine, both P- and E-selectins were
expressed (66). Pretreatment with anti-P-selectin antibody
reduced PMN rolling and adhesion, thereby attenuating
the injury (66). PMNs can cause tissue damage in several ways including secretion of proteolytic enzymes such
as elastase from cytoplasmic granules (67), production of
free radicals via a respiratory burst (68), and physical impairment of the microcirculation and thereby extension
of ischemia (69). Nalini and colleagues showed that it is
PMNs and not XO that are the initial source of free radicals
in a rat model of IRI of the intestine (70).
Nitric Oxide (NO)
NO is a free radical and a highly reactive substance.
NO is synthesized from L-arginine by a family of enzymes
known as NO synthases (NOS). Three isoforms of NOS
have been identified and cloned: endothelial NOS (eNOS),
neuronal NOS (nNOS), and inducible NOS (iNOS) (71).
Whereas eNOS and nNOS are constitutively expressed,
iNOS is only expressed in response to cytokines and
growth factors. nNOS is the predominant NOS in the normal intestine and this suppresses the expression of iNOS
(72). Possible sources of NO in the intestine include intrinsic intestinal tissue (epithelium, mast cells, smooth
muscle, and neural plexus) and leukocytes (PMNs and
monocytes) (75).
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Fig 2. Sequence of events in emigration of neutrophils. First, the endothelial selectins are upregulated and interact with the
oligosaccharides on the surface of leukocytes. This then brings the leukocytes into close proximity to chemoattractants such
as chemokines, which activates the integrins. Integrins (CD11/CD18) bind to the endothelial receptors (ICAM-1), resulting
in strong adhesion, followed by extravasation of the neutrophil. Reproduced from Collard and Gelman (2).
The role of NO in IRI is still a matter of considerable
controversy. NO plays a dichotomous role as both a cytotoxic and a cytoprotective molecule in intestinal IRI,
whereas inhibition of NO causes tissue dysfunction in certain models of IRI and inhibition of NO provides benefit
in others. The constitutive forms of NO synthase (nNOS
and eNOS) are critical to normal physiology and inhibition of these enzymes causes tissue damage (76). The
induction of iNOS produces large amounts of NO and peroxynitrite, leading to tissue injury, and therefore specific
inhibition of this enzyme is considered beneficial (76).
Additionally, iNOS knockout mice exhibitedsignificant
resistance to mucosal barrier dysfunction and bacterial
translocation after intestinal IRI, further supporting a role
for iNOSas an important mediator of reperfusion injury in
the intestine (77). On the contrary, Cuzzocrea et al. provided evidence that the production of peroxynitrate was
not related to the induction of iNOS, whereas it was associated with the inhibition of eNOS (78). In a recent
study, Wu et al. demonstrated that the formation of iNOS
after IRI of the intestine enhanced mucosal apoptosis,
leading to IRI of the intestine (79). Virlos et al. showed
that pulmonary injury following intestinal IRI was associated with decreased eNOS expression in the lung (80).
Expression of iNOS occurred during the later stages of
reperfusion, with overproduction of NO and nitrosylation
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of protein tyrosine residues, thus aggravating pulmonary
injury (80).
NO has many beneficial effects in the intestine such
as scavenging of oxygen free radicals, maintenance of
normal vascular permeability, inhibition of smooth muscle proliferation, reduction of leukocyte adherence to the
mesenteric endothelium, prevention of mast cell activation, and inhibition of platelet aggregation (81–85).
Under physiological conditions, NO will predominate
in the microcirculation (86). However, during the early
phase of reperfusion in IRI there is an accumulation of
O2 − . This limits the accumulation of NO and prevent
any of its beneficial effects. Hence there is a tendency for
PMNs to adhere to the endothelium and for platelets to aggregate (87). In the absence of NO, the O2 − produced will
undergo spontaneous dismutation to form H2 O2 . H2 O2
formed in this way can promote the activation of phospholipase A2 (PLA2) and lead to the accumulation of proinflammatory mediators such as platelet activating factor
(PAF) and leukotrienes (LTB4 ) (summarized in Figure 3).
These changes can lead to activation of transcription nuclear factor kappa B (NF–κB), which is a primary regulator of cytokine and adhesion molecule gene expression. Thus, the loss of endogenous NO production has
disastrous consequences resulting in dysfunction of the
endothelium and PMN-mediated tissue injury.
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
ISCHEMIA–REPERFUSION INJURY OF THE INTESTINE
Fig 3. Role of nitric oxide in ischemia reperfusion injury.
Heme Oxygenase (HO)
HO-1 expression in various models of IRI of the intestine has been shown to offer cytoprotection during the
cascade of events in IRI (88–91). HO-1 is the rate-limiting
enzyme in the conversion of heme into carbon monoxide
(CO), biliverdin (which is rapidly converted to bilirubin),
and free iron (Fe2+ ) (92). The HO-1 system is thought to
play a pivotal role in the maintenance of antioxidant and
oxidant homeostasis during cellular injury (93). Three isoforms of HO have been identified so far: inducible HO-1;
constitutively expressed HO-2; and HO-3, which is related
to HO-2 but is less well characterized. The HO-1 system
exerts four major beneficial effects: (a) antioxidant function, (b) maintenance of the microcirculation, (c) antiapoptosis, and (d) anti-inflammatory function (93). The
antioxidant function relies on heme degradation, production of bilirubin (94), and formation of ferritin via Fe2+
(95). The production of CO, with its vasodilatory and antiplatelet properties, maintains the microcirculation and
may be involved in the anti-apoptotic and cell arrest mechanisms (93). The HO-1 system exerts anti-inflammatory
effects via modulation of endothelial adhesion molecules
and chemoattractant factors (96). Vachharajani et al. provided evidence that HO-1 and biliverdin modulate leukoDigestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
cyte recruitment by altering the expression of P-and Eselectins in the intestine, lungs, liver, and kidneys (97).
It has also been shown that HO-1 inhibits the NO system by downregulating iNOS, which contains a heme–iron
moiety (98).
Nakao et al. showed that inhalation of CO improved
graft function and survival in a rat model of small bowel
transplantation (90). Exogenous administration of bilirubin has shown to reduce intestinal injury in rat models of
IRI (99, 100). Doxorubicin has been shown to induce HO1 and attenuate lung injury following IRI of the intestine
(88). Squiers et al. have shown that HO-1 overexpression
in small bowel donors may decrease IRI and improve survival of both the animal and the transplanted bowel (91).
Recently Attuwaybi et al. demonstrated that subcutaneous
administration of hemin (HO-1 inducer) significantly reduced IRI of the intestine (89).
Pro-inflammatory Proteins
The precise chemical steps connecting the generation
of free radicals and secretion of inflammatory mediators by endothelial cells are not well understood. It appears that NO is a key factor involved in the synthesis
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MALLICK ET AL.
Fig 4. The relationship between oxidants and activation of NF-κB. The transcription
factor NF-κB is normally found in the cytoplasm of the cell in an inactive form as p50/p65/
I-κB complex. Stimulation of the cells with cytokines, oxidants, or bacterial products
leads to an increase in reactive oxygen metabolites, which then activates I-κB kinase.
This kinase phosphorylates the inhibitory complex, which is then ubiquitinated. Next,
proteolysis occurs by the action of the 26S proteasome complex and nuclear translocation
of the active NF-κB.
of pro-inflammatory proteins (101). NO may be exerting its effects at the transcription level, probably by the
regulation of NF-κB, which regulates the expression of
several genes that are involved in the process of IRI (102)
(Figure 4). NF-κB belongs to a family of dimeric transcription factor complexes which is normally found in the
cytoplasm of unstimulated cells in their inactive forms,
i.e., as the p50/p65/I-κB ternary complex or the p65/p105
inactive binary complex. Stimulation of cells with certain cytokines, oxidants, or inflammatory mediators such
as PAF and LTB4 results in phosphorylation and ubiquitination of the I-κB or p105 subunit (103, 104). This
results in translocation of the subunit to the nucleus to activate transcription of its target genes. NF-κB induces the
expression of adhesion molecules (ICAM-1, VCAM-1,
P-selectin, E-selectin), tumor necrosis factor (TNF-α and
-β), interleukins, chemokines, and enzymes (inducible nitric oxide synthase and cyclooxygenase-2) (105, 106). It
appears that in IRI, reoxygenation is the key stimulus
in the regulation of NF-κB. By maintaining the interaction between IκBα and NF-κB, upregulation of adhesion
molecules is inhibited (107). NO appears to prevent the
formation of substances that activate NF-κB as well as
to enhance the activity of proteins that inhibit NF-κB.
Previous studies suggest that NO may induce the de
novo synthesis or stabilize I-κBα, thereby limiting NF-κB
activation (108).
1364
Complement
Several studies have suggested that the complement system is a major candidate in the pathogenesis of IRI of the
intestine (109–112). P-Selectin has been shown to mediate
IRI of the intestine via complement (C5b-9) deposition in
the intestinal mucosa (113). Activation of the complement
cascade leads to a series of potent inflammatory events
including expression of the ICAM-1 gene and upregulation of cytokines such as TNF-α and interleukin (IL-1α)
(112). In a recent study it was shown by Montalto et al.
that complement mediates upregulation of intestinal iNOS
and diminishes protein levels of mitochondrial SOD and
the activity of Cu/Zn SOD (114).
Iron
During ischemia, metabolites such as lactic acid accumulate and the intracellular pH falls. This decreases
the stability of lysosomal membranes, activates lysosomal
lytic enzymes, inhibits the binding of transitional metals
such as iron to their carrier proteins (e.g., transferrin and
ferritin), and results in increased free intracellular iron
(Fe2+ ), which accelerates in vivo free radical formation in
the following (Haber–Weiss) reaction: Fe2+ + H2 O2 →
Fe3+ + OH− + H• (115). Using chelating agents of iron
such as desferrioxamine has proved to be effective in reducing IRI because these agents prevent the Haber–Weiss
reaction and hydroxyl radical formation (116).
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
ISCHEMIA–REPERFUSION INJURY OF THE INTESTINE
TABLE 1. A LIST OF STUDIES IN WHICH ISCHEMIC PRECONDITIONING WAS PERFORMED AGAINST REPERFUSION INJURY IN THE INTESTINE
First author (Ref. No.)
Species
Aksoyek (26)
Rats
Cinel (142)
Ferencz (138)
Rats
Dogs
McCallion (133)
Rats
Sola (126)
Rats
Tamion (139)
Rats
Unal (132)
Rats
Vlasov (128)
Rats
Wu (140)
Rats
IPC protocol
Mechanism
10 min of ischemia &
10 min of reperfusion
10 min of ischemia
4 cycles of 5 min of
ischemia & 10 min of
reperfusion
3 cycles of 2 min of
ischemia & 5 min of
reperfusion
10 min of ischemia & 5
min of reperfusion
↓ iNOS expression
4 cycles of 1 min of
ischemia & 10 min of
reperfusion
2 cycles of 5 min of
ischemia & 5 min of
reperfusion
10 min of ischemia &
10 min of reperfusion
20 min of ischemia & 5
min of reperfusion
Expression of HO-1
Anti-apoptosis
Oxidative stress
Outcome
↓tissue damage & bacterial
translocation
↓number of apoptotic cells
↑GSH & SOD
↑adenosine
Protects against mucosal
barrier dysfunction
↑NO synthesis
↓tissue damage in this
model of intestinal
transplantation
↓fluid requirements,
↓pulmonary edema,
↓lactate & TNF-α
*↓MDA, ↓MPO, ↓tissue
damage
↓neutrophil infiltration,
↓oxidative stress and
anti-apoptosis
↑NO synthesis
Anti-apoptosis
↓tissue damage
↓reactive oxygen species,
↓lipid peroxidation,
↓cytochrome c, &
↓caspase-6
Note. GSH, glutathione; HO-1, heme oxygenase-1; iNOS, inducible nitric oxide synthase; MDA, malonyldialdehyde; MPO, myeloperoxidase; NO, nitric oxide; SOD, superoxide dismutase.
*By-product of lipid peroxidation.
PROTECTIVE STRATEGIES AGAINST
ISCHEMIA–REPERFUSION INJURY
OF THE INTESTINE
The mechanisms of IRI of the intestine and the ways
to limit these have been under extensive research for almost a decade. Several therapeutic modalities have been
used successfully to attenuate reperfusion injury in animal models of IRI of the intestine. Potential strategies
to overcome IRI include several modalities: (a) ischemic
preconditioning (IPC), (b) antioxidants, (c) NO supplementation, (d) anticomplement therapy, (e) antileukocyte
therapy, (f) perfluorocarbons, (g) enteral feeding, (h) glutamine supplementation, and (i) glycine supplementation.
Ischemic Preconditioning (IPC)
IPC refers to a phenomenon whereby exposure of a
tissue to brief periods of ischemia protects them from the
deleterious effects of prolonged IRI (117). This fascinating
phenomenon was first described in 1986 by Murry et al.
in the canine heart (118). Subsequently beneficial effects
have been demonstrated in the liver (119), skeletal muscle
(120), brain (121), spinal cord (122), kidney (123), lung
(124), retina (125), and intestine (26, 126–128) in various
animal models. There is compelling evidence that IPC is
beneficial in the human heart (129) and the liver (130).
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
IPC of the intestine was first described by Hotter et al.
in 1996 (131) and subsequent studies have confirmed this
phenomenon (Table 1). During this procedure, the small
bowel is rendered ischemic by placement of an occlusion vascular clamp around the superior mesenteric artery.
After an ischemic interval of 5–20 min, the clamp is removed and the small intestine is reperfused for 5–15 min
before the prolonged ischemic insult. However, the ideal
IPC protocol including the time of short ischemia and
number of cycle(s) is still not established. Some studies have reported that more than one cycle of ischemia
and reperfusion is required to achieve this beneficial
effect (132, 133).
The effects of IPC can be differentiated into two
phases characterized by different time frames and mechanisms: (a) an early phase (early or classic preconditioning)
that immediately follows the transient ischemia and lasts
2–3 hr and (2) a late phase (late preconditioning), which
begins 12–24 hr from the transient ischemia and lasts
for about 3–4 days (134–136). Whereas early IPC occurs within minutes and involves the direct modulation of
specific cell functions (134), the late phase requires the
simultaneous activation of multiple stress-response genes
with de novo synthesis of several proteins (135). Despite
these differences, both phases of preconditioning can be
initiated by the same stimuli and share the same intracellular signal pathways to a certain extent (135). Because of
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MALLICK ET AL.
its sustained duration, late preconditioning might be particularly relevant for improving the results of small bowel
transplantation. However, the present knowledge of the
mechanisms responsible is quite preliminary. Recently,
Ferencz et al. demonstrated that synthesis of proteins such
as SOD and GSH was instrumental in the protection afforded by delayed IPC in a canine model of small bowel
autotransplantation (137).
The exact mechanism by which IPC confers protection
in the intestine is unclear. Several mediators have been
advocated to play a crucial role in this protective phenomenon including adenosine (132, 133), NO (126), oxidative stress (138), HO-1 (139), and anti-apoptosis (140).
Aksoyek et al. showed that IPC of the intestine decreases the translocation of bacteria from the intestine in a
rat model of IRI (26). In a rat model of intestinal transplantation, Sola et al. identified a protective pathway initiated
by IPC that involved the activation of NO synthesis (126).
This increase in NO synthesis was short-lived and detected
at the end of preconditioning. The use of L-NAME eliminated this protection.
Davis et al. showed that IPC completely prevented the
expression of P-selectin in the ischemic intestine and abolished the IRI-induced leukocyte rolling (127). These powerful anti-inflammatory actions of IPC were thought to be
triggered by stimulation of adenosine A1 receptors during
the period of preconditioning.
The protective effect of IPC has also been associated
with a decrease in xanthine accumulation and a diminished
conversion of XDH to XO (141). There is evidence that
IPC reduces apoptosis in the intestinal epithelial cells and
this is attributed to significant expression of Bcl-2 (142).
Tamion et al., in a rat model of hemorrhagic shock followed by resuscitation, showed that IPC reduced fluid requirements, lung edema, lactate, and TNF-α production
and induced a more than fivefold increase in intestinal
HO-1 expression (139). These effects were abolished by
the HO-1 inhibitor tin protoporphyrin (Sn-PP).
Antioxidants
The human body is endowed with many natural antioxidants, which, unfortunately, are not capable of protection against the attack of oxidant formation during an
IRI. It has been shown in many animal studies that supplementation of these antioxidants is helpful in reducing IRI-induced tissue damage (Table 2). The agents that
have been used are allopurinol (143), SOD (144), iron
chelator (e.g., desferrioxamine) (145), N -acetyl cysteine
(NAC) (146), ethanol (147), ascorbic acid (148), tocopherol (149), pentoxifylline (150, 151), captopril (45), and
verapamil (152).
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Invtraneous SOD mimetic (M40401), administered
15 min prior to reperfusion in a model of IRI, preserved
the architecture of the ileum, reduced the expression of
cytokines, and abolished the expression of P-selectin and
ICAM-1 (144). In some cases two antioxidants are administered simultaneously (e.g., SOD and catalase) in an
attempt to block the oxidants at more than one stage of
formation (153). Kojima et al. showed that an intraduodenal infusion of the antioxidants glutathione, rebamipide,
and dimethylsulfoxide attenuated the increase in apoptosis
in the intestinal mucosa after IRI (154). A newly developed free radical scavenger, edaravone, has been shown
to be effective in reducing IRI of the intestine through its
anticytokine and antichemokine effects (155).
NO Supplementation
Supplementation of NO has been shown to attenuate IRI
in the intestine in cats and dogs (156, 157). Kalia et al.
showed that a spontaneous NO donor (FK-409) reduced
both intestinal and lung damage after IRI of the intestine in rats (158). It was also shown that inhaled NO at a
low concentration exerts profound anti-leukocyte adherence effects in cat and dog IRI (159). Whereas the use of
selective inhibitors of iNOS has been shown to be beneficial, the use of nonselective inhibitors has been shown
to be deleterious in intestinal IRI (160). Recently, Naito
et al. demonstrated that the administration of a selective
iNOS inhibitor, ONO-1714, attenuated IRI of the intestine (161). Intraluminal administration of nitroglycerine,
a potent exogenous NO donor, prevented the increase in
intestinal permeability associated with IRI of the intestine
(162).
Anticomplement Therapy
IRI is significantly reduced by complement inhibition
or complement depletion or in complement-deficient animals (2). Administration of a complement (C5a) receptor
antagonist has been shown to protect the intestine against
IRI in a murine model (110). Arumugam et al. showed that
administration of an orally active C5a receptor antagonist
was highly effective in reducing damage to the intestine in
a rat model (163). The anti-C5 antibody inhibited TNF-α
expression and tissue injury. Zhao et al. showed that the
use of an antimurine C5 monoclonal antibody decreased
neutrophilic infiltration of both the intestine and the lungs
(164). Williams et al. showed that the administration of a
complement inhibitor of soluble complement receptor 1
(sCR-1) attenuated intestinal mucosal injury, reduced intestinal vascular hyperpermeabilty, and increased survival
in a rat model (165). It has been demonstrated recently
that the administration of human C1 esterase inhibitor has
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
ISCHEMIA–REPERFUSION INJURY OF THE INTESTINE
TABLE 2. A LIST OF ANTIOXIDANTS USED AGAINST REPERFUSION INJURY IN THE INTESTINE
Agent
First author (Ref. No.) Species
Mechanism
Allopurinol
Ferrer (205)
Rats
Anti-thrombin III
Ozden (206)
Rats
Oxidative stress,
scavenging free
radicals
Lipid peroxidation
Bilirubin
Hammerman (100)
Rats
Lipid peroxidation
Edaravone
Ceran (99)
Tomatsuri (155)
Rats
Rats
Antioxidant
Anti-cytokine &
-chemokine
Captopril
Buyukgebiz (45)
Rats
Free radical scavenger
Cyclosporine
Desferrioxamine
Epidermal growth factor (EGF)
Puglisi (207)
Balogh (145)
Berlanga (208)
Rats
Rats
Rats
Free radical scavenger
Lipid peroxidation
Lipid peroxidation
Glutamine
Harward (199)
Rats
Lipid peroxidation
Melatonin
Ustundag (209)
Rats
Oxidative stress
Kazez (210)
Rats
Lipid peroxidation
N -Acetyl cysteine
Sun (169)
Rats
Neutrophil infiltration
Nitroglycerine
Dun (211)
Rats
Lipid peroxidation
Pyruvate
Cicalese (212)
Rats
Free radical scavenger
Rapamycin
SOD
Puglisi (207)
Riaz (173)
Rats
Rats
Free radical scavenger
Oxidative stress
Trimetazidine
Tetik (213)
Rats
Free radical scavenger
Verapamil
Vitamins C & E
Mocan (152)
Gunel (149)
Rats
Rabbits
Oxidative stress
Lipid peroxidation
Outcome
↓tissue damage,
↓amylase, ↓MDA,
↓GSH, & ↓MPO
*↓MDA, ↓ MPO, ↓tissue
damage
↓blood and intestinal
thiobarbituric acid &
tissue damage
↓tissue damage
↓tissue damage, ↓MPO,
↓TBA-reactive
substances, ↓CINC-1
protein, & ↓CINC-1
mRNA
*↓MDA, ↓ MPO, ↓tissue
damage
↓tissue damage
*↓MDA
*↓MDA, ↓ MPO, ↓tissue
damage
↑GSH, ↓conjugated diene
(a by-product of lipid
peroxidation)
↑SOD, ↑glutathione
peroxidase
*↓MDA & ↓tissue
damage
↓MPO & ↓endothelial
permeability
↓tissue damage, ↓MDA,
& ↓LDH
↓tissue damage, ↓free
radical & neutrophil
infiltration
↓tissue damage
↓neutrophil rolling &
adhesion
*↓MDA, ↓ MPO, ↓tissue
damage
↓tissue damage
*↓MDA
Note. CINC, cytokine-induced neutrophil chemoattractant; GSH, glutathione; HO-1, heme oxygenase-1; iNOS, inducible nitric oxide
synthase; LDH, lactate dehydrogenase; MDA, malonyldialdehyde; MPO, myloperoxidase; NO, nitric oxide; RNA, ribonucleic acid; SOD,
superoxide dismutase; TBA, thiobarbituric acid.
*An indicator of lipid peroxidation.
been shown to attenuate reperfusion injury in a mouse
model of intestinal IRI (166).
Antileukocyte Therapy
There are broadly three therapeutic strategies to attenuate leukocyte-mediated IRI: (a) inhibition of leukocyte
activation, (b) inhibition of leukocyte adhesion molecule
synthesis, and (c) inhibition of leukocyte–endothelial
adhesion (2).
The activation of leukocytes in IRI is aided by the release of inflammatory mediators such as leukotriene-B4 ,
(LT-B4) platelet activating factor (PAF), and tumor necrosis factor-α (TNF- α) (65). Studies have shown that the use
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
of LT-B4 antagonists (167), PAF antagonists (168, 169),
and TNF-α inhibitors (170) limits IRI-induced leukocyte
activation.
The second strategy to attenuate leukocyte-mediated
IRI has been to inhibit leukocyte adhesion molecule synthesis. Transcription factors regulating leukocyte adhesion
molecule synthesis, such as NF-κB, are the targets for
BAY11-7085 (I-κ B inhibitor) (171) and α melanocyte
stimulating hormone (172).
The third strategy is to limit leukocyte–endothelial adhesion. Riaz et al. showed that the use of allopurinol
and SOD reduced leukocyte rolling and adhesion in a
dose-dependent manner (173). The use of monoclonal
1367
MALLICK ET AL.
antibodies directed against adhesion molecules reduces
the severity of IRI in the intestine. One restraining factor
that has limited the clinical use of monoclonal antibodies
against leukocyte–endothelial interaction is the possibility of an immune reaction (174). Pretreatment with an
anti-P-selectin antibody has been shown to reduce leukocyte adhesion by about 85%, and IRI-induced leukocyte
adhesion was significantly reduced in leukocyte function
antigen-1 (LFA)-deficient mice (66). However, Carmody
et al. demonstrated that eliminating P-selectin by using Pselectin knockout mice attenuated reperfusion injury, and
this beneficial effect was found to be independent of neutrophil adhesion (175). The administration of anti-LFA-1
antibodies has been shown to be effective in improving
allograft survival in small bowel transplantation (176). A
nonexhaustive list of antileukocyte and anti-inflammatory
agents used in IRI of the intestine is shown in Table 3.
Perfluorocarbons (PFCs)
PFCs are hydrocarbon molecules in which hydrogen
atoms are replaced by fluorine. They can dissolve 20–25
times more oxygen than plasma at room temperature. The
release of oxygen is facilitated by a low oxygen-binding
constant, causing a linear relationship between oxygen
saturation and partial pressure. This results in release of
oxygen to the tissues. Several studies have shown that
PFCs attenuate IRI of the intestine (177–179).
Intraluminal administration of oxygenated PFCs into
the intestine has been shown to preserve mucosal function and integrity after IRI of the intestine (180). Ohara
et al. showed that peritoneal lavage with PFCs reduced
intestinal and pulmonary damage following IRI of the intestine (181), whereas Vejchapipat et al. demonstrated that
extraluminal administration of PFCs did not protect the intestine from IRI in a rat model (182). The small intestine,
when placed in a bag containing PFCs, attenuated the expression of cytokines and decreased the intestinal damage
in a rat model of IRI (183). Partial liquid ventilation with
PFCs has been shown to reduced remote organ injury by
reducing the lung damage (184).
Enteral Feeding
Enteral nutrition has been shown to reduce the death rate
and remote organ injury in a mouse model (185). Enteral
feeding maintains the mucosal immunity and the resistance to infections. Fukatsu et al. showed that 5 days of gut
“starvation” with parenteral nutrition increases ICAM-1
and P-selectin expression, thereby attracting PMNs to
the intestine, compared with enterally fed animals (186).
These ICAM-1 changes were reversible with reinstitution
of enteral feeding. Five days of refeeding the parenterally
1368
fed mice with chow returned ICAM-1 levels to normal.
Furthermore, lack of enteral feeding has shown to alter
the levels of IL-4 and IL-10 in the lamina propria (187).
IL-4 and IL-10 inhibit endothelial expression of ICAM-1.
Glutamine Supplementation
Glutamine, considered to be a nonessential amino acid,
appears to be a conditionally essential nutrient during serious injury (188). Glutamine is the most abundant amino
acid in the plasma and skeletal muscle under normal physiological conditions, but the levels fall substantially after
injury or surgery (189). Several studies demonstrate that Lglutamine- and glutamine dipeptide (glycyl-glutamine and
alanyl-glutamine)-supplemented parenteral nutrition and
L-glutamine-supplemented enteral feeds decrease bacterial translocation, diminish experimental colitis, and enhance mucosal adaptation with refeeding or following
bowel resection (190, 191). In a porcine model of segmental small bowel autotransplantation, Li et al. showed
that glycyl-glutamine-enriched parenteral nutrition significantly increased graft mucosal glutamine and protein
levels and decreased intestinal permeability and bacterial translocation (192). Of interest, in a rat small bowel
transplantation model, significantly improved jejunal graft
maltose absorption and posttransplantation mortality were
demonstrated when harvested grafts were cold-preserved
in 1% L-glutamine versus saline alone or in University of
Wisconsin preservation solutions (193).
Intravenous infusion of L-glutamine has been demonstrated to increase the cytoprotective HO-1 and the antioxidants GSH and SOD, with a concomitant decrease in
TNF-α in IRI of the intestine (194). Glutamine-enriched
tube feeding was shown by Zhang et al. to enhance transplanted small bowel growth, nutrient absorption, and mucosal barrier function (195). Ikeda et al., in a mouse model
of IRI of the intestine, showed that supplementation of
TPN with glutamine partially supports mucosal immunity
by preserving respiratory and intestinal IgA levels, maintaining the proper IgA-stimulating cytokine milieu within
the intestine, and reducing intestinal ICAM-1 expression
and neutrophil adhesion (196). Wischmeyer provided evidence that glutamine enhances heat shock protein (HSP)
expression and thereby confers protection against a variety
of stressful stimuli (197, 198). Another probable mechanism is that glutamine given intravenously increased mucosal glutathione (GSH) levels and attenuated IRI-induced
cell membrane lipid peroxidation (199).
Glycine Supplementation
L-Glycine, a nonessential amino acid, protects the
intestine from IRI (27, 200, 201). Glycine has an
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
ISCHEMIA–REPERFUSION INJURY OF THE INTESTINE
TABLE 3. A LIST OF ANTILEUKOCYTE AND ANTI-INFLAMMATORY AGENTS USED AGAINST REPERFUSION INJURY IN THE
INTESTINE
Agent
First author (Ref. No.)
Species
α-Melanocyte
Anti-IL-8 antibody
Hassoun (172)
Tsuruma (214)
Rats
Rats
Anti-TNF antibody
Koksoy (31)
Rats
BAY-11-7095
Zou (171)
Rats
Inhibition of NF-κB
Inhibition of IL-8
expression
Inhibition of TNF
expression
Inhibition of I-κB
BN 52021
CP-105,696
Droy-Lefaix (215)
Souza (216)
Rats
Rats
PAF antagonist
Inhibition of leukotrienes
CINC Ab
Yagihashi (217)
Rats
Cyclic peptide AcF
(OpdChaWR)
Arumugam (163)
Rats
Inhibition of TNF
expression
Complement antagonist
Ethanol
Yamaguchi (147)
Mice
Fetal bovine serum
FK-409
Chen (218)
Kalia (158)
Rats
Rats
FR-167653
Kawata (156)
Yamamoto (7)
Dogs
Rats
Takeyoshi (9)
Dogs
GPI 6150
Mazzon (219)
Rats
Glycine
Lee (201)
Rats
Iijima (27)
Mice
Heparin binding EGF
Xia (220)
Rats
Inhibition of neutrophil
infiltration
Hepatocyte growth
factor
Hyperbaric oxygen
IL-10
Kuenzler (221)
Rats
Inhibition of TNF
Yang (222)
Lane (223)
Rats
Mice
Inhibition of TNF
Cytokine attenuation
Inosine
Dowdall (224)
Rats
Cytokine attenuation
Stroh (225)
Rats
Inhibition of neutrophil
infiltration
Lipocortin-1
Cuzzocrea (226)
Rats
Inhibition of neutrophil
infiltration
L-Arginine
Warnecke (227)
Rats
Inhibition of TNF-α &
IL-6
L-Propionyl
Carnitine
Digestive Diseases and Sciences, Vol. 49, No. 9 (September 2004)
Mechanism
Inhibition of neutrophil
infiltration
Inhibition of IL-8
NO donor
NO donor
Inhibition of TNF-α &
IL-1
Inhibition of TNF-α &
IL-1
P-Selectin & ICAM-1
blocker
Inhibition of neutrophil
infiltration
Inhibition of IL-6
Outcome
↓tissue damage & ↓MPO
↓tissue damage & TNF-α
↓neutrophil sequestration
↓tissue damage >30 min
of reperfusion &
↑tissue damage >6hr
reperfusion, ↓MPO,
↓IL-6, & ↓ICAM-1
↓tissue damage
↓tissue damage,
↓vascular permeability,
& ↓TNF-α in lungs &
intestine
↓tissue damage &
↓TNF-α
↓tissue damage, ↓TNF-α
& inhibition of
IRI-induced
neutropenia
↓leukocyte rolling &
adhesion
↓IL-8
Maintains WCC,
↓villi–leukocyte
adhesion, ↓ lung
damage, & ↑survival
↓tissue damage
↓tissue damage, ↓TNF,
↓IL-1, & ↓AST
↓tissue damage
Improves mean BP,
↓tissue damage,
↓MPO, & ↑ survival
↑mucosal protein &
DNA, ↓MPO
↓tissue damage,
↓bacterial
translocation, & ↑
survival
↓expression of P/ Eselectins, VCAM-1, &
ICAM-1
↓caspases
↓TNF-α & lung MPO
↓tissue damage, ↓TNF-α,
↓lung MPO, & ↓IL-6
↓tissue damage, ↓ gut
permeability, & ↓lung
MPO
↑survival, maintains
mean arterial pressure,
↓tissue MPO
Maintains blood pressure,
↓tissue MPO, &
↓tissue damage
↓tissue damage, ↓TNF-α,
↓hyaluronic acid, &
↓IL-6
1369
MALLICK ET AL.
TABLE 3.
Agent
First author (Ref. No.) Species
CONTINUE.
Mechanism
Outcome
Lexipafant
Sun (169)
Rats
PAF antagonist
M40401
Cuzzocrea (144)
Rats
Magnolol
Methyl prednisolone
Loong (228)
Warnecke (227)
Rats
Rats
P-Selectin blocker &
inhibition of ICAM-1
Inhibition of IL-6
Inhibition of TNF & IL-6
P-Selectin
Glycoprotein ligand
Farmer (229)
Rats
P-Selectin blocker
Pentoxifylline
Sener (150)
Rats
Pirfenidone
Arumugam (230)
Rats
Inhibition of neutrophil
infiltration
Inhibition of TNF-α
Rolipram
Souza (170)
Rats
Inhibition of TNF-α
UK 74505
Souza (168)
Rats
PAF antagonist
↓endothelial permeability
& ↓MPO
Improves blood pressure,
↓MDA, & ↓MPO
↓tissue damage &↓ IL-6
↓tissue damage, ↓TNF-α,
↓hyaluronic acid, & ↓
IL-6
↓tissue damage, ↓ IL-11,
IL-6, interferons, &
↓MPO
↓MDA, ↓MPO, &
↑glutathione
↓tissue damage &
↓TNF-α
↓intestinal & lung
permeability,
↓recruitment of
neutrophils, ↓ IL-10,
↓TNF-α in both lungs
& intestine
↓TNF-α, ↓MPO, ↓tissue
damage & mucosal
permeability
Note. Ab, antibody; AST, aspartate aminotransferase; BP, blood pressure; CINC, cytokine-induced neutrophil chemoattractant; EGF, epidermal growth factor; GSH, glutathione; HO-1, heme oxygenase-1; ICAM, MDA-malonyldialdehyde;
intercellular malonyldialdehyde; MPO, myelooperoxidase; NF-κB, nuclear factor kappa −B; NO, nitric oxide; PAF, platelet
activating factor; SOD, superoxide dismutase; TNF, tumor necrosis factor; VCAM; vascular cellular adhesion molecule;
WCC, white cell count.
impressive catalog of functions such as anti-inflammatory,
immunomodulatory, and direct cytoprotective functions
(200–202). Iijima et al. showed that the administration of
20% glycine attenuated mucosal damage, preserved the
intestinal protein content, reduced bacterial translocation,
and improved the overall survival in a murine model (27).
Glycine acts on inflammatory cells such as macrophages to
suppress the activation of transcription factors and the formation of free radicals and inflammatory cytokines (203).
Recently, Jacob et al. demonstrated that supplementation
of glycine caused a downregulation of pro-apoptotic bax
and caspase-3, whereas bcl-2 was upregulated (204).
CONCLUSION AND FUTURE WORK
IRI of the intestine is a complex, multifactorial pathophysiological process that involves the actions of oxygenderived free radicals, cytokines, nitric oxide, and PMNs.
Despite the complexity, attenuation of the reperfusion injury through ischemic and pharmacological preconditioning has been successfully applied to animal models of intestinal IRI. IPC has been found to be the most promising
strategy against IRI during the last few years, appearing to
increase the tolerance of the intestine to reperfusion injury.
However, although IPC has been shown to be beneficial
in the human heart and the liver, prospectively controlled
1370
studies in humans involving IPC of the intestine are lacking. Research focused on the application of novel drugs
that can mimic the effects of IPC to manipulate the cellular
events during IRI of the intestine is required.
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