Ischemia–Reperfusion Injury of the Intestine and Protective Strategies Against Injury REVIEW
Transcription
Ischemia–Reperfusion Injury of the Intestine and Protective Strategies Against Injury REVIEW
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. 0163-2116/04/0900-1359/0 ° 1359 MALLICK ET AL. 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). 1360 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). 1361 MALLICK ET AL. 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 1362 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 1363 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 1365 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). 1366 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. 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